:

..
.
..
..
.

1. ......................................................
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2. .......................................
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2-2
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2-7
2-8
2-9

3
9
22
24
36

55
57
65
73
79
82
86
89
92
94

3....................................

95

3-1
3-2
3-3

3-4
3-5
3-6
3-7
3-8
3-9
3-10
3-11

97
105
123
135
148
164
177
190
196
206
210

4. ..............................

213

4-1
4-2
4-3
4-4

5. /.....................................
5-1
5-2
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6. .........................................................
6-1
6-2
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6-4

2006

215
250
258
265

271
273
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289
291
295
310
320

.
.
. . 2549.

1-1
1-2
1-3
1-4
1-5

1-1

1-1

(vaginitis vulvovaginitis)

1-1A

vaginitis
1.





spermicides
2.
Trichomonas vaginitis
Bacterial vaginosis
Candida vulvovaginitis
3.
4. atrophic vaginitis




spotting

5.

1-1B

pH <4.5
epithelium estrogen (
menopause estrogen)
Doderleins bacilli (Normal Flora)
glycogen Lactic acid (pH <4.5)

1:

1-1C

Bacterial vaginosis
Trichomonas vaginitis
Candida valvovaginitis
GC.

:
:
:

1:

consistency
Floccular
pH
4.5

Gardnerella vaginalis
Trichomonas vaginalis
Candida albicans

candida

Floccular
4.5
Curd like

tricho

Homogeneous
>4.5
Frothy

bacterial
-

Homogeneous
>4.5
Thin

1-1

Differential Diagnosis of the Vaginitides

2: Differential Diagnosis of the Vaginitides
Clinical Elements
Bacterial Vaginosis
Trichomoniasis
Vaginal odor
+
+/Vaginal discharge
Thin, gray, homogenous
Green-yellow
Symptoms
Vulvar irritation
+/+
Dyspareunia
+
Vulvar erythema
+/Signs
Bubbles in vaginal fluid
+
+/Strawberry cervix
+/Saline wet mount
Clue cells
+
Motile protozoa
+
Microscopy
KOH test
Pseudohyphae
Whiff test
+
+/pH
>4.5
>4.5

Vaginal Candidiasis
White, curdlike
+
+/+
<4.5

1. Trichomonas Vaginitis

vaginitis
complicated UTI
pH 3-5
STD partner
Trichomonas vaginalis

cyst
1
flagella 4
undulating membrane Flagella

2: Trichomonas vaginalis

epithelium


UTI

Recommended Regimen : Metronidazole (Flagyl 200, 400) 2 g single dose pc irritate GI

Alternative Regimens : Metronidazole 500 mg bid pc 7
Metronidazole (Asiazole 250 mg) 250 mg tid pc 7
Tinidazole (Fasigyn 500 mg) 2 g single dose
Nimorazole 2 g single dose
Clotrimazole (Canesten) 100 mg vaginally 6 night in pregnancy

2. Bacterial Vaginosis
STD

sex
Intra uterine device douching
preterm labor
Gardnerella vaginalis
Gardnerella vaginalis
Facultative anaerobeic gram negative rod

Non inflammatory discharge WBC

Vagina pH >4.5
clue cell

3: bacterial vaginosis

1-1

Recommened Regimens : Metronidazole 500 mg bid 7 single dose

Clindamycin Cream 2% 7
Metronidazole gel 0.75% 5
Alternative Regimens : Metronidazole (Flagyl 200, 400) 2 g single dose pc
Clindamycin (Dalacin C 150, 300) 300 mg bid 7 days
metronidazole
Clindamycin ovules 100 g vaginally hs 3

3. Candida Valvovaginitis
Candida albicans Normal flora
STD

pH <4.5

curd like
Predisposing factor
Pregnancy
Oral contraceptive
Broad spectrum antibiotic
DM
Immunosuppressant

clotrimazole (Canesten 100 mg) 100 mg vaginally OD 6 days

clotrimazole 100 mg vaginally bid 3 days
clotrimazole 500 mg vaginally single dose
ketoconazole (Nizoral) 200 mg 2x1 pc 5 days
itraconazole (Sporal) 100 mg orally 2x2 pc 1 day
itraconazole 200 mg OD pc 3 days
Fluconazole (Diflucan 150 mg) orally 150 mg single dose pc

1-1D

1.
2.
3. 1-2
4. 2
5.
6.
7. 15

1.
2.
3. 1-2
4.
5.
6. 2
7.
8.

9.
10. 15
11.

1-2

1-2

1-2A
1-5

7
7-12
12-13

14
15-25

25-28

Estrogen Progesterone Corpus luteum

negative feedback 2
FSH LH Folicle
Dominant follicle
Dominant follicle estrogen
estrogen LH Surge
1.
2. follicle digestive enzyme prostaglandins
enzyme prostaglandins
LH Surge corpus luteum estrogen progesterone
1. endometrium secreatory phase
2. negative feedback FSH LH
Corpus luteum LH estrogen progesterone

1:

10

1-2B

1.
(minipills, microdose of progestin only, progestin only pill)
progestin 1 28
96-97%
Exluton = Lynestrenol
500 mcg/tab
Noriday = Norethisterone 250 mcg/tab
Ovrette = Levonorgestrel 75 mcg/tab

progestin 3-4
16-20
HPO-axis 10%

clotting mechanism estrogen clotting factor

estrogen thromboembolism, cardiovascular disease

estrogen
35 15
estrogen
(progestin carbohydrate metabolism)
antibiotic Rifampicin minipills
antibiotics

1 1
2-3
minipills


-Breakthrough bleeding
=
- Spotting
=

1-2

11

minipill
-
-
-

2.
(combined pills) 97-98%
estrogen progestin
Estrogen combined pills
Ethinyl estradiol (EE)
Mestranol metabolised EE

EE combined pill 20, 30, 35, 50 mcg EE

thromboembolism cardiovascular disease
EE 20 mcg breakthrough bleeding
Progestin 2
17-hydroxyprogesterone medroxyprogesterone, cyproterone acetate
19-nortestosterone norethisterone, lynestrenol, desogestrel, gestodene

3
1. Monophasic combined pill estrogen progestin
2. Biphasic combined pill Oilezz estrogen progestin 2
estrogen progestin
3. Triphasic combined pill TriquilarED 3 estrogen
progestin

1. HPO-axis FSH LH
2.
3. progestin estrogen
progestin
4.

21
1 1
7 ()

12

28
1 1
(
7 )

1. 1

2. 2 2 2
1x2 pc 7
3. 2 ()
7

4. 3
7

3.
(postcoital or Morning after pills) (75 %)

-
-
-
2
1. High dose progestin Postinor, Madonna Levonorgestrel 750 mcg/tab
1 2

- 72
12 1
- 4
2. Yuzpe regimen high dose EE 100-120 mcg +
Levonorgestrel 500-600 mcg

- high dose combined pill 72
12 high dose combined pill

- Microgynon (EE 30 mcg + Levonorgestrel 150 mcg ) 4
72 12 4

1-2

13

4.
Estrogen C18 steroid phenolic group C3 unsaturated A ring
- estrone estriol metabolite estradiol estradiol 17-alkyl
group ethinyl estradiol block metabolism estrone ethinyl estradiol

- mestranol 3-methyl ethinyl estradiol metabolised EE

estradiol

mestranol

estrone

estriol

ethinyl estradiol

Progestin 2
- 17-hydroxyprogesterone cyproterone acetate, medroxyprogesterone antiandrogenic

cyproterone acetate

medroxyprogesterone acetate

14

- 19-nortestosterone norgestrel, levonorgestrel, desogestrel,

gestodene
- gestodene active form desogestrel inactive form
3-ketodesogestrel active form

levonorgestrel
-

desogestrel

gestodene

drospirenone progestin 17-spirolactone

antimineralocorticoid

drospirenone

5.

1.
2.
3.
4. progestins antiestrogenic effect
5.
6. progestin proliferative effect estrogen

7. bacteria
8.
9. osteoporosis estrogen
BCP
1.
2. hirsutism sex hormone binding globulin (SHBG)
androgen
3. dysfunctional uterine bleeding (DUB),

1-2

15

6.

( EE
P )

- androgenic P Cyproterone acetate (Diane) Drospirenone
(Yasmin)
- EE P
- EE, P
- EE P
- EE P
- EE
- levonorgestrel free testosterone

ACHES
A = abdominal pain hepatic adenoma
C = chest pain pulmonary embolism, MI
H = headaches migraine
E = eye problem blurred vision, flashing light, blindness
S = severe leg pain thromboembolism estrogen
Estrogen thromboembolism coagulation factor cholesterol
Progesterone LDL HDL
1:
Estrogen excess
Estrogen deficiency
- dizziness, vertigo
-
-
-
-
-
-
- early and/or mild cycle
-
breakthrough bleeding
-

14

Progesterone excess
-
-
-
-
-

Progesterone deficiency
- late breakthrough bleeding

14

28

16

1-2C

1. metabolic
metabolic estrogen progestogen
hypothalamus

Carbohydrate metabolism progestogen glucose insulin
insulin insensitivity glucose tolerance
Lipid metabolism - estrogen
TG
LDL
HDL
- progestogen TG
LDL
HDL

metabolic progestogen
third generation gestodene, desogestrel
lipid metabolism atherosclerosis
3 gen of progestogen lipid metabolism 2 gen of progestogen

fibrogen factor 8 factor 10

antithrombin 3 fibrinolytic activity
estrogen progestogen
estrogen progestogen third generation

1. MI
2. low dose thromboembolism high dose
3. dose estrogen dose progestogen

2.
WHO
3-6
20-30
MI
3-5

stroke
35

1-2

17

hepatocellular adenoma

3.
Drug interaction
rifampicin, griseogfluvin, phenytoin, phenobarbital,
carbamazepine ampicillin, doxycycline

pulmonary hypertension atrail fibrillation
subacute bacteria endocarditis

20




35 20

? ?
? ?
?? ?

18

?
- 28
- 21

-

-
- 2-3

- 14

-
antibiotics

lab

FBS, HDL, LDL, TG

estrogen progestogen (EE 20-30 )

progestogen estrogen

dose
- estrogenic type 28
6 estrogen progestin

- progestogenic type
4 estrogen estrogen

progesterone 19-nortestosterone derivative androgenic

17 alpha-hydroxyprogesterone

1-2

19

4.

-
4 combine
4 minipill
-
combine
estrogen

low dose estrogen

co-carcinogen ,
5
progestogen

doxycycline, ampicillin enzyme inducer
phenobarbital

Oral contraceptive
Exluton
= Lynestrenol 500 mcg
Anamai 21 s
= Mestranol 50 mcg + Norethisterone 1 mg
Eugynon ED
= EE 50 mcg + Levonorgestrel 150 mcg
Anna 28s
= EE 30 mcg + Levonorgestrel 150 mcg
Microgest ED
= EE 30 mcg + Levonorgestrel 150 mcg
Nordette 21/28
= EE 30 mcg + Levonorgestrel 150 mcg
Marvelon 21/28
= EE 30 mcg + Desogestrel 150 mcg
Mercilon 21/28
= EE 20 mcg + Desogestrel 150 mcg
Minulet 21s
= EE 30 mcg + Gestodene 75 mcg
Meliane
= EE 20 mcg + Gestodene 75 mcg
Triquilar 28s
= Triphasic pill
Diane-35
= EE 35 mcg + Cyproterone acetate 2 mg
Yasmin
= EE 30 mcg + Drospirenone 3 mg

20

Depot contraceptive
Contracep
Depo- provera
Noristerat

= Medroxyprogesterone acetate 150 mg

= Medroxyprogesterone acetate 150 mg
= Norethisterone enanthate 200 mg

1
1



3


scale
thermometer



- (non-biodegradable) Norplant
- (biodegradable)
Norplant 1
6 silastic silicone rubber tubing levonorgestrel

Silastic capsule 6 5
2-3

30 mcg/
1. sperm
2.

1-2

21

2
-
-

- Speton vaginal tablet
-
-
-

- 5-10 1

- 4
(IUD)
blastocyst


fertilized
2-3
IUD IUD IUD
IUD 1 5


3 99.5%
progestogen Medroxyprogesterone acetate (Depo-provera )
- IM 150 gm 3
-
-

endometrium
mucous sperm

22

1-3

(Dysmenorrhea) 2 Primary dysmenorrhea Secondary

dysmenorrhea

1-3A

Primary Dysmenorrhea

Primary dysmenorrhea estrogen progesterone

prostaglandin E F

prostaglandins
(oral contraceptive)
3-4

25

Anti-inflammatory drugs prostaglandins

-
-
1-2
(oral contraceptive pills)
prostaglandins

1-3B

Secondary Dysmenorrhea

Secondary dysmenorrhea

Endometriosis ()

1-3

23

(IUDs)

24

1-4

1-4A

Introduction

Drug and Pregnancy

1960 Thalidomide tragedy
1949-1956 phocomelia ()
1959 1 case
1960 30 case
1960 134 case
1962 US FDA teratogenic test

- Organogenesis
2 - Growth and Functions
3 - Growth and Functions
Delivery
US-FDA 5 drug-risk categories
A : 1st, 2nd, 3rd trimester
B : adverse effect

1st trimester trimester
C : ADR ( teratogen)
category benefit risk

D : warfarin
X : category contraindication

Congenital malformation
potent weak, Nonteratogen teratogen
Unbound form placenta

toxic metabolism (
enzyme metabolize
enzyme metabolize )
dose

1-4

25

Synergist () Agonist ()


* Pregnancy and Lactation
-blockers
1st trimester: general malformation Organogenesis
2nd, 3rd trimester : growth retardation growth and develoption
Labor-delivery:
- Cardiac output (CO)
(CO = stroke volume x heart rate 1 =
1 x Heart rate)
- fetal hypoglycemia glucose
insulin)
-agonist
2nd, 3rd trimester : inhibit uterine contraction ()
Labor-delivery: - inhibit labor
- Fetal tachycardia ( 1 )
1: Categories
- Categories
Acataminophen B
Allopurinol C
Aluminium hydroxide C
Amlodipine C
Amoxicillin, Amoxy/Clav B
Atorvastatin X
Azithromycin B
Bromphen/pseudoephedrine C
Candesartan C/D (2nd and 3rd trimesters)

Captopril C/D (2nd and 3rd trimesters)

Clarithromycin C
Diclofenac B/D (3rd trimester) - premature closure of the
ductus arteriosus and may inhibit uterine contraction

- Categories
Gemfibrozil C
Loperamide B
Oral hypoglycemmics C (insuling category A drug of choice
)
Cimetidine, Famotidine, Ranitidine B
Omeprazole C
Metformin B (insuling category A drug of choice
)
Fluoroquinolones C ( broad spectrum
Methronidazole Fluoroquinolones
18 , )
Penicillin ()

26

1-4B

1. Antibiotics
Tetracycline
Tetracycline form complex calaium
Tetracycline hydroxyapatite

antibiotic
Streptomycin and Kanamycin
8
spectrum
Angiotensin converting enzyme inhibitor (ACEI) Captopril, Eenalapril, Lisinopril
Hypotension and renal failure
ultrasound scan
ACEI dialysis Hypotension
Chloramphenical
Grey baby syndrome

2: Teratogenic in humans
- Categories
- Categories
Thyroxine D
Radioisotope X
Thalidomide X
Live vaccine X ( vaccine
Cytotoxic drugs X
)
Vitamin D high dose X
Tetracycline D
Warfarin X
Androgen X
Isotretinoin X
Estrogen X
Anticonvulsants: Valproic acid D
Progesterone D
OCP X
Testosterone X
Diethylstilbestrol X
Statin X
Note : - Teratogen Diethylstilbestrol
- Class X
- Tetracycline (minocycline, doxycycline) fatty liver 8

2. Other Drugs
Antiiconvulsants Carbamazepine, Phenytoin, Phenobarbitall, Valproic acid
midface hypoplasia, short nose and long upper lip

monotherapy dose

1-4

27

Antineoplastics folic acid antagonists aminopterin, methotrexate

mental retardation, midfacial hypoplasia, facial asymmetry, neutral tube effect,
abortion
ultrasound neutral tube defect
Alkylating agent cyclophosphammide, busulfan, chlorambucil and nitrogen mustard

ultrasound
Antithyroid drugs Inorganic iodides, thioureas, propylthiouracil, methimazole, iodine
hypothyroidism and congenital goiter

propylthiouracil hyperthyroidism Iodide-131
Lithiium
congenital heart disease (CHD)


Lithium echocardiogram
Oral anticoagulants Warfarins and other coumarin derivatives
upper airway obstruction, optic atrophy, abortion, neonatal hemorrhagic (
hemorrhagic )
ultrasound hemorrhagic CNS
anticoagulant heparin SC heparin
Aspirin

Paracetamol
Meperidine-Demoral morphine, Pantapon, Methadone


Steroid
adrenal gland

Androgenic drugs androgenic progestins and testoaterone derivatives

28

Diethylstilbestrol
sperm
cervix uterine

Thalidomide
Limb reduction malformation ()
thalidomide ultrasound

Vitamin derivatives Vitamin A all-trans-retinoic acid, 13-cis-retinoic acid, tretinate

maldevelopment of facial, facial asymmetry, Abortion
teratogeniic effect
1
Ethanol
Fetal alcohol syndrome, thin upper lip
alcohol
Cocain
cerebral infarction, genitourinary anomalies
cocain
Hypoglycemic drug insulin drug of choice

1-4C

insulin resistance
hypoglycemia gestational diabetes malitus
plasma glucose insulin
neonatal hypoglycemia insulin
insulin
insulin

methyldopa (aldomet)125-250 mg 8 hydralazine
(Aprezoline) 10-50 mg 6


morning sickness
pregnancy sickness

1-4

29

Pyridoxine (Vitamin B6) 50-200 mg/day
Promethazine Cyclizine
Prochlorperazine

Metoclopramide extrapyramidal side effects
Dimenhydrinate

Al Mg
Mg

intercranial hemorrhage bleeding
NSAIDs

3


2-3
2
Dioctyl sodium sulfosuccinate Lactulose

Saline laxative Sodium Magnesium electrolyte
mineral oil
ano-rectal disorders
bisacodyl, senna

30

Candida albicans Trichomonas vaginalis

Candida imidazole Clotrimazole
fluconazole, Itraconazole

Trichomonas Metronidazole 200 mg 3 7

UTI
Penicillins, Cephalosporin Nitrofurantoin
Trimethoprim Co-trimoxazole
Tetracycline Quinolone

Chlorpheniramine
Non-sedating antihistamine
steroid

paracetamol
antihistamine, pseudoephedrine, phenylpropanolamine, ,

Calcium 1000 mg/day

Vitamin D Calcium 10 mcg
Vitamin C (bone and connective tissue)
70 mg

1-4

31

Folate DNA form neural

tube spinal cord 21-28
neural tube defect megaloblastic anemia 600 mcg/day
Vitamin B12 folate megaloblastic anemia
2 .6 mcg/day
Zinc DNA, RNA, Protein 15 mg
Iron hemoglobin

1-4D

home test hCG ovum

1-2 sperm
98-100%

3:
false positive


hCG ovarian cysts,

hCG
5

false negative


wax soap residual

Reagent

Example of commercially available products

Pregcolor Card
3
3

1. Pregcolor card
2.
3. 2
4. 3 C T
4.1. C = Control T = Test
4.2. C
4.3. 10

32

1:

1-4E

Ovulation Prediction Tests

Ovulation Prediction Tests 2

1. Basal Thermometry
day 1-14 37

scale 1 scale
thermometer
accurate
()

nadir

T
nadir

ovulation

T ovulation
T ovulation

T flat
curve
24 sperm
sperm
Note mucous method Comprehensive
Pharmacy Review OTC mucous method
T

1-4

33

2. Ovulation Prediction Tests/Devices

hormone LH
hCG
Ezy Plan

1.
2.
3. 3
4. 3-5 R 5

34

sperm ovum zygote 3

Embryonic period
9 (Fetal)
40
, , calcium, vitamin D, vitamin C connective
tissue protein, folate, vitamin B12, Zn Fe RBC
11-15 kg

, Protein, fluid, Vitamins and Minerals

fat, fluid , protein, fat
Fe, F ,vitamin D, vitamin K

1-4

References
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]

Womens health .

Vaginitis .
.
.
..
.
.. -
corticostearoids ..
.. ... .
http://www.thaihealth.net/h/article-print-523.htm
http://merck.micromedex.com/index.asp?page=bhgtables&article_id=BHG01ID05&table=BHG01ID05T01
http://www.plannedparenthood.org/pp2/portal/files/portal/medicalinfo/femalesexualhealth/pub-vaginitis.xml

35

36

1-5

(WHO)

1. (Perimenopause)

2-8 1
(Anovulation)
2. (Menopause)

3. (Postmenopause)

47-50
1.5

1-5A

(Oocyte) (Follicle)

1.
Oogonia (Atresia)
100-1000
Apoptosis (Programmed cell death)
2.
(Estrogen)
Stroma (Androgen)
(Gonadotropin)

Androstenedione
Androstenedione 1
Androstenedione

1-5

37

Testosterone


LH Stroma Hypertrophy
Hyperplasia
Androstenedione
Androstenedione
Estrogen

1
Androstenedione


Androstenedione Androstenedione

Gonadotropin (FSH LH)

FSH 10-20 LH
3 1-3

3.




1:

Androstenedione
60-300
Testosterone
20-80
Estradiol
40-400
Estrone
30-200

1-5B

30-150
15-70
10-20
30-70

Vasomotor
(Genitourinary system)
(Psychological and mood changes)
(Sexual transition and problem)

38

(Bone changes)
(Cardiovascular changes)
(Changes of central nervous system)
(Skin changes)

1. Vasomotor
Vasomotor symptoms (Hot flashes)
(Diaphoresis) (Night sweats)

2.

(Vulva) landmark Introitus

Pubic hair
(Vagina) (Rugae)
Mixed flora
Lactobacillus Pap smear Superficial epithelial cell Parabasal Basal
cell
(Uterus)
Erosion (Endocervix)
(Uterine prolapse)
(Cystocele) (Rectocele)

(Venous plexa)


(Frequency) (Urinary incontinence)
(Urethral meatus)

(Dysuria) (Urethritis) (Recurrent
urinary tract infections) (Distal urethra)

1-5

39

Urethral caruncle, diverticula

(Urethrocele)

3.

Luteal (Premenstrual syndrome)
(Neurotransmitter)

4.
(Skin flush)
(Reaction time of clitoris)
Bartholin (Vaginal lubrication)
(orgasmic platform)
(orgasm)

5.
(Natural menopause)
1-2 (Bilateral oophorectomy)
1.8-4.5 6
1

Osteoporosis Bone Mineral Density

(T score) 2
2: World Health Organization diagnosis criteria for osteoporosis and osteropenia
Bone Mineral Density (T score*)
Normal
<1 SD below normal
Osteopenia
1-2.5 SD below normal
Osteoporosis
2.5 SD below normal
Secere (established) Osteoporosis
2.5 SD below normal
*SD = Bone Mineral Density

6.
(Coronary artery disease)
(Stroke Cerebrovascular disease) (Peripheral artery
disease)

40

7.

Vasomotor

Alzheimer

8.

2

1-5C

Nonpharmacologic Treatment

1.
2-5
2. Bone mass

3.
4.


5. 1000
0.6
(Phytoestrogens1)

1-5

1-5D

41

Pharmacologic Treatment

1. Hormone Replacement Therapy[10]

Hormone replacement therapy (HRT) 2

(Osteoporosis)
estrogen
(Natural estrogen) 17-estradiol, Estradiol valerate, Estrone piperazine sulphate,
Conjugated equine estrogen, Estriol
(Synthetic estrogen) Ethinyl estradiol, Mestranol, Diethyl stilbestrol, Dienoestrol
HRT
renin coagulation factors
HRT
progestogen
2
Natural progesterone micronized progesterone 300-400 mg/day
lipid metabolism metabolism

Synthetic progesterone 2
- C 19 C 18 compounds Norgestrel, Norethisterone, Levonorgestrel
lipid metabolism HDL
progestogen
- C 21 compounds Medroxyprogesterone acetate (MPA), megestrol acetate
lipid metabolism antiestrogenic androgenic
anabolic
HRT C 21 compounds
lipid metabolism
androgenic
Utrogestran (200 mg) 100-200 mg/day

estrogen
2

estrogen

42

- 1 21

estrogen

estrogen

- (cyclic) 10
7
2 3

estrogen
progesterone

estrogen
progesterone

- (continuous)

estrogen
progesterone

estrogen
progesterone

- (continuous)

estrogen
progesterone

estrogen
progesterone

2 4

3: (cyclic treatment regimens)

Estrogen
Dose (mg)
Progesterone
Conjugated estrogen
0.625
MPA
Estradiol valerate
1, 2
Norethisterone
Micronized estradiol
1, 2
Norethisterone acetate

Dose (mg)
5, 10
2.5, 5
5, 10

4: (continuous treatment regimens)

Estrogen
Dose (mg)
Progesterone
Conjugated estrogen
0.625
MPA
Micronized estrogen
2
Norethisterone
Norethisterone acetate

Dose (mg)
2.5-5
0.35-2.1
1

1-5

43

- Conjugated equine estrogen 0.3, 0.625, 1.25 mg (Premarin)
- Estradiol valerate 1, 2 mg

- Conjugated equine estrogen

- Transdermal patch 0.025, 0.05 mg
- Gel (Oestrogel) estradiol 0.06% 1.5-3 mg/day

- Subcutaneous pellets (17-estradiol) 25, 50, 100 mg 25 mg 6
2
first
pass metabolism renin substance

[12]
1. Activelle tablet 28s (Estradiol + Norethisterone acetate) continuous therapy
2. Climara 50 patch (Estradiol)
3. Climen 28 (Estradiol valerate Cyproterone) cyclic therapy
4. Cyclo-Progynova 21 (Estradiol, Norgestrel) cyclic therapy
5. Estrofem tablet 28s Estradiol 1 2 mg
6. Oestrogel (17-estradiol)
7. Ovestin (Estriol) tablet 1 mg
8. Premarin (Conjugated estrogen) 0.3, 0.625, 1.25 mg
9. Premelle 2.5/Premelle 5 tablet 28s continuous therapy
10. Premelle Cycle 5 cyclic therapy

1.
2.
3.
4.
5.
6.
7.
8.
9.

44

2. Tibolone[10]
Tibolone estrogen, progesterone androgen
vasomotor symptom
breakthrough bleeding
tibolone 3-OH metabolite,
3-OH metabolite -4 isomer metabolite active metabolite 3-OH 3-OH metabolite
estrogenic effect -4 ketoisomer metabolite progestogenic androgenic effect 3-OH
metabolite parent drug 100
OH
C

CH

CH3

Tibolone

1: tibolone

tibolone metabolism
(impaired renal function)
tibolone metabolism CYP450 drug interaction enzyme inducer
enzyme inhibitor

1.25 mg
2.5 mg

3. Selective Estrogen Receptor Modulators (SERMs)[10]

SERMs (Modulator) recpetor estrogen
mixed agonist-antagonist
Estrogen receptor
Estrogen receptor (ER) 2 ,
estradiol
ER ER
SAR[14]
1. benzothiophene phenol ring estrogen receptor 3phenolic group estrogen
2. aryl ring 3 ring (propeller)
receptor biological activity

1-5

45

H3C

O
N
CH3

CH3

O
OH
HO

Tamoxifen

Raloxifene

2: SERMs

[4-6,10,14]

Tamoxifen (Nolvadex 10 mg/tab., Nolvadex-D 20 mg/tab. Usual dose: 20 40 mg/day, ED List:

, Preg. Cat. : D)
SERMs ER ER
Tamoxifen
Tamoxifen

Raloxifene (Celvista, Evista 60 mg/tab- Usual dose: 60 mg/day, NED, Preg. Cat. : X)
SERMs second generation Raloxifen

(hot flashes), , (Venous thromboembolism)

4. Bisphosphonate
bisphosphonate pyrophosphate
O C
SAR[14]
R1 Hydroxy group hydroxy apatitie resorption
R2 potency
- R2 amino group Neridronate, Alendronate, Pamidronate potent
amino group Etidronate, Clodeonate alkyl amine
potency
1) amine branch chain Olpadronate, Ibandronate
2) amine ring Risedronate, Incadronate, Tiludronate,
Zoledronate

46

- R2 carbon amino linear chain chain activity 4

Carbon(Alendronate) activity 3 Carbon (Pamidronate) 6 Carbon (Neridronate)
- R2 heterocyclic group potency heteroatom NH > CH2 > S > O
O

Bisphosphonate

O
R1

R2

R1

R2

Etidronate

OH

CH3

Clodronate

Cl

Cl

Tiludronate

Pamidronate

OH

CH2 CH2 NH2

Neridronate

OH

CH2 CH2 CH2 CH2 CH2 NH2

Olpadronate

OH

CH2 CH2 N

Cl

CH3
CH3

Alendronate

OH

CH2 CH2 CH2 NH2

Ibandronate

OH

CH2 CH2 N

CH3
(CH2)4 CH3

Risedronate

OH
N

Zoledronate

OH
N
N

3: bisphosphonate

Bisphosphonate Hydroxyapatite
(bone resorption) bisphosphonate , lysosomal enzyme,
prostaglandin, membrane permeability osteoclast
osteoclast osteoclast life span

Bisphosphonate

1-5

47

60 bisphosphonate
half-life 0.5-2

esophagitis
30


Osteomalacia3 Pagets disease etidronate
3 1-2
Ocular adverse reaction anterior uveitus, episcleritis, scleritis, conjunctivitis
Pamidronate IV injection
[4-6,14]

Etidronate (Didronel 200,400 mg/tab- Usual dose : 5-10 mg/kg/day, NED , Preg. Cat. : B(oral), C
(parenteral) )
potency osteoporosis Pagets disease cyclic dosing
Etidronate disodium 400 mg/ 2 calcium supplement 2.5
Alendronate (Fosamax 5,10,35,40,70 mg/tab- Usual dose : 5 mg/day or 35 mg/week , NED , Preg.
Cat. : C)
potency Etidronate 1000 approved FDA
osteoporosis Pagets disease
Pamidronate (Aredia 30, 90 mg/vial (powder for reconstitute) - Usual dose : 90 mg/day, ED List: ,
Preg. Cat. : D)
potency Etidronate 1000 Hypercalcemia malignancy tumor Pagets
disease
Risedronate (Actonel 5, 30, 35 mg/tab- Usual dose : 30 mg/day (Pagets disease), 5 mg/day or 35
mg/week(Osteoporosis) , NED , Preg. Cat. : C)
potency Etidronate 1000-5000 osteoporosis Pagets disease

5. Calcitonin
Calcitonin polypeptide hormone amino acid 32 3527
disulfide bridge amino acid 1 7 biological activity
proline amide
Calcitonin parafollicular cells Calcitonin

,
3

Osteomalacia

48

Calcitonin bone matrix Calcitonin Calcitonin receptor osteoclast

osteoclast osteoclast calcitonin receptor precursor
osteoclast differentiate osteoclast

Calcitonin (IV) (IM) (SC)

Calcitonin Calcitonin potency

25-50 salmon calcitonin

Calcitonin

[4-6,14]

Salmon Calcitonin (Miacalcin 200 units/0.09ml(nasal spray), 200 units/ml(inj.) Usual dose 200
units/day(intra nasal), 100 units/day (SC, IM) ED List: , Preg Cat : C)

6. Parathyroid Hormone (PTH)[10]

PTH hormone 115 Amino acid peptide
PTH active vitamin D bone resorption
, biosynthesis release vitamin D,

PTH PTH
osteoblast growth factor PTH 6-24

7. Vitamin D[13]
Vitamin D
Vitamin D
1.
1.1 Ergocalciferol (Vitamin D2)

1-5

1.2 Cholecalciferol (Vitamin D3)

2. Stratum granulosum vitamin D

: Organic Pharmaceutical Chemistry 2548

49

50

[4-6]

Ergocalciferol [Calciferol 500,000 units/ml (inj.), 8,000 units/ml (drops), Drisdol 50,000 units/cap.,
8,000 units/ml (drops)] - Usual dose 400-600 units/day, ED List : , Preg Cat : A, C (dose exceeding
recommend)

8. Calcium
1500 mg
, , , 1,25dihydroxyvitamin D, parathyroid hormone

1-5

51

References
[1] Barbara G. Wells, Joseph T. DiPiro, Terry L. Schwinghammer, Cindy W. Hamilton. Pharmacotherapy Handbook. 6th ed.
New York: McGraw-Hill; 2006. P 304.
[2] Carol S. Havens, Nancy D. Sullivan, and Patti Tilton. Manual of out patient Gynecology 3rd Edition: Little Brown and
Company. New York 1996, P. 105-111
[3] Leon speroff and Marc A. Fritz. Clinical gynecology Endocrinology and Infertility. 7th Edition: Lippincoff Williams and
Wilkins. New York 2005, P. 700-706
[4] Charles FL, Lora LA, Morton PG, and Leonard LL, eds. Drug Information Handbook. 13th ed. Ohio: Lexi-Comp; 2004.
[5] Prof. Thep Himathongkam, Prof. Sming Kaojarem, Assoc. Prof. Pinit Kullavanijaya, et al, eds.MIMS Thailand. 95th ed.
Bangkok: MediMedia (Thailand); 2004
[6] .. 2547
[7] , , , , . . :
. . 4. : , 2547: 359-378.
[8] . . 1. : , 2546: 302-303.
[9] . . 2. : , 2538 : 203.
[10] . . , ; 1 .. 2543. 93-149
[11] . . , ; 1 2546. 118121
[12] . . Dispensing Pharmacy Postmenopause Hormone 2548
[13] . . Organic Pharmaceutical Chemistry Vitamins 2548
[14] . . Organic Pharmaceutical Chemistry Calcium Homeostasis
2548

52

Phytoestrogens
Phytoestrogens
1. Isoflavonoids 2
1.1 Isoflavones (Soy)
1.2 Coumestans (Soybean sprouts) Clover
2. Lignans (Flaxseed)

Hops (Bourbon)
Phytoestrogens Isoflavones 2 Genistein Daiazein
Lignans 2 Enterolactone Enterodiol Coumestrol
Coumestans
Phytoestrogens Isoflavonoids Lignans Conjugated glycosides
Glycosidase (Active form)
1
Biochanin A

Genistein

Formononeti

Diadzein

Matairesinol

Enterolacton

Seoisolariciresinol

Enterodiol

P-Ethylphenol + Dihydrogenistein

Equol + O-Desmethylangolensin

Enterolacton

4: Phytoestrogens

Phytoestrogens Active form

Portal
vein (Enterohepatic circulation)

Phytoestrogens
Phytoestrogens


Phytoestrogens
(Estrogenic and antiestrogenic effects)
red clover
Equol

1-5

53

Phytoestrogens

(Endogenous estrogen)
Steroid
. Aromatase
Aromatase Androteindione
Estrone ( Aromatase
)
. 17-hydroxysteroid dehydrogenase
2 17-ketosteroids 17hydroxysteroids Estrone Estradiol
Phytoestrogens Estradiol
. Tyrosine specific protein kinase
Tyrosine kinase receptors growth factors Epidermal
growth factor, Platelet-derived growth factor, Insulin Insuline-like growth factor
Phytoestrogen
Tyrosine kinase
. DNA topoisomerase
Genistein
cell cycle G2 M
. Angiogenesis
Angiogenesis neovascularization
Angiogenic factors,
Phytoestrogens Angiogenesis

. Sex hormone binding globulin (SHBG)

Phytoestrogens Isoflavonoids Lignans SHBG SHBG

Phytoestrogens
(Hormone-dependent cancer)
. Antioxidant
Flavonoids Catechin Oxidation Low-density lipoprotein
oxidized LDL
Phytoestrogens

54

Phytoestrogens
(Climacteric symptoms)
Phytoestrogens

Phytoestrogens
(Coronary heart disease)
47 Cholesterol 9.3 LDL
cholesterol 12.4 Triglyceride 10.5 Cholesterol
Cholesterol HDL cholesterol
Isoflavones 40
HDL cholesterol 22
(Osteoporosis)
Ipriflavone Isoflavones 500
Osteoclast

Phytoestrogens

Genistein Tyrosine kinase
Angio-genseris Antioxidation Receptors

(Unopposed Estrogen)
Phytoestrogens
Unopposed estrogen
Phytoestrogens

2

2-1
2-2
2-3
2-4
2-5
2-6

2-7
2-8
2-9

2-1

57

2-1

(sclera)
conjunctiva (cornea)
(pupil)
(lens) (retina)
(aqueous humor) epilthlium ciliary body (posterior chamber)
pupil (anterior chamber) aqueous humor
(schlemm canal) iris muscle (trabecular muscle)

1:

(glaucoma)
(optic nerve head)

2-1A

1.

(halos)

(steroid)

58

2.

2-1B

1. (Open Angle Glaucoma)

(open angle glucoma)

2: (drainage canals)

2. (Closer Angle Glaucoma)

(closer angle glaucoma)
(iris)
48

3: (iris)

2-1

2-1C

59

, (ocular tumors),

2-1D

40
1.5 50 3

21
21 ( 10-20 )


: (
)

2-1E

(tonometry)
(ophthalmoscopy)

(perimetry)

60

iris cornea (gonioscopy)

4: (); ()

5: (); ();
()

2-1F

1.
2

Timoptic
Propine
Trusopt

Pilocarpine

Xalatan
Propine

6:

2-1

61

Cholinergic (Miotics)
parasympathetic ciliary muscle
aqueous humor
Pilocarpine HCl 1%, 2%, 4% (Isopto carpine) 2-4 onset 2 .
duration 8 .
:

: S/E cholinergic

Pilocarpine

Anticholinesterase
cholinesterase parasympathetic
parasympathetic
Physostigmine sulfate (Eserine), Echothiophate iodide (Phospholine iodide),
Demecarium bromide 1-2

Physostigmine

Adrenergic (Sympathomimetic)
sympathetic -adrenergic receptor

Dipivefrin HCl 0.1% (Propine), Epinephrine HCl 1%, 2% (Epifrin) 1-2

12 .
:
:

Dipivefrin

62

Beta blocker

Timolol maleate 0.25%, 0.5% (Timoptic, Glauco-Oph), Betaxolol HCl 0.25%, 0.5%
(Betoptic), Cartelol HCl 1%, 2% (Arteoptic), Levobutanol HCl 0.5% (Betagan) Metipranolol HCl 0.1%,
0.3% (Beta-Ophtiole) 2 onset 2 . duration 24 .
:
: S/E 1 2 -adrenergic bronchial spasm
, heartblock, COPD, asthma

Timolol

Betaxolol

Carbonic anhydrase inhibitor

40-60% CAI

o Acetazolamide (Diamox) 250 mg 2-4 onset 2 . duration 6-8 .

IV 500 mg ( 5-10 mg/kg) 4-6 .
o Methazolamide (Nepthazane) 50 mg 2 Acetazolamide
: renal calculi
digoxin ()
sulfonamide

Acetazolamide

Methazolamide

Brinzolamide 1% (Azopt), Dorzolamide 2% (Truopt) 2-3

Brinzolamide

2-1

63

Hyperosmotic agent

osmotic hypertonic

o Glycerol 50% solution
1-1.5 g/kg single dose
o Mannitol 20% solution IV 1-2 g/kg 30-60 onset 30-60 duration
5-6 .
:

Postaglandin analogues

Latanoprost 0.005% (Xalatan), Travoprost 0.004% (Travatan), Bimatoprost 0.03%
(Lumigan)
:

Latanoprost

Travoprost

Combination eyedrops >> Trusopt + Timoptic = (Cosopt) 2

Xalatan + Timoptic = ( Xalacom)

2.
(close angle glaucoma)

Laser surgery
laser laser
laser
laser
Microsurgery


1

64

2-1G

References
[1] . . 2. : . 2542. 176-89.
[2] http://www.agingeye.net/glaucoma/glaucomadrugtreatment.php [Accessed March 6, 2006]
[3] http://www.siamhealth.net/Disease/eye_ent/glaucoma/glaucoma.htm [Accessed March 6, 2006]

2-2

65

2-2

(cataract)
50

2-2A

senile cataract

10
:
lens cell intracellular space
lens fiber
lens protein molecular weight refractive index
Ca orthophosphate Ca oxalate connective tissue capsule

Osmotic intumescence
polyalcohols ketoses osmotic pressure lens lens fiber
glycolytic activity ATP glutathione
glycolysis glucose
glycolytic pathway deoxyglucose ATP
ionic pump pentose

Protein denaturation senile cataract protein denaturation

dimethylsulfoxide (DMSO) SH group lens cortical layers
protein protease
morgagnian cataract complete proteolysis cortex Ca orthophosphate senile
cataract
refractive index

2-2B

66

posterior subcapsular cataract

nuclear cataract reflactive index

2-2C

opthalmoscope
pupil red fundus reflex
white pupil leukocoria



hypocalcemia, myotonic dystrophy

2-2D

1. Congenital (embryopathic) Cataract

3
2
cortex fetal nucleus
zonular cataract 2

5
1. X-rays first trimester
2. first trimester corticosteroids, sulfonamides
3. metabolic disease embryo galactosemia
embryo embryo
4. first trimester , systemic herpetic infection

5.
Lamellar (zonular) cataract
lens fiber lens fiber
lens fiber deep concentric lamellar zonular
cataract 2 autosomal dominant

hypocalcemia lamellar

2-2

67

Maternal rubella

(nystagmus)
2 lens cortex
endophthalmitis
Oculocerebrorenal (Lowe) syndrome
X-linked recessive 2
mature hypotonia buphthalmos
corneal scarring (renal tubular dysfunction) rickets
hypophosphatemia
Downs syndrome
60% nystagmus

Galactosemia
galactose glucose
galactose lens fiber

(Lens extraction) Needling operation

Needling aspiration Ultrasonic fragmentation
ambryopia
(Aphakia)
cortical material
iridocyclitis
35% congenital cataract

2. Acquired cataract
acquired cataract
biomicroscope
Aged-related cataract
1. Juvenile cataract 3 congenital cataract

2. Presenile cataract senile cataract

cortex / nucleus
3. Senile cataract*** 60 96%
senile cataract phospholipids
nonfasting glucose lens
nucleus insoluble protein oxidation SH group
non disulfide covalent cross-link crystalline polypeptide pigment nucleus

68

Nuclear cataract
lens nucleus 50
refractive index

visual axis
Cortical cataract
soft cataract cortex lens fiber
(spoke-like pattern) equater axis

Posterior subcapsular cataract***

aging cataract lens fiber posterior capsule
gold and white granules visual axis

senile cataract
- Immature cataract
- Mature cataract
- hypermature cataract cortex

age-related cataract***
1.


cortical nuclear cataract

2.


corticosteroids, phenothiazines, miotic cholinergic cpd, cancer chemotherapeutic
agents, photosensitizing drugs, diuretic agents, major transquilizers, gout
3.
riboflavin, vitamin C, E carotenoids (antioxidants)
cortical nuclear cataract
UV
infrared
nuclear cataract
4.

2-2

69

3. Traumatic cataract


Perforating injuries lens 2
o satellite posterior supcapsular opacity
o lens capsule

Intraocular foreign bodies oxidized metal
Cu sunflower cataract chalsis lentis
Electric shock protein coagulation
Radiation X-rays first trimester posterior pole

4. Diabetic cataract***
IDDM 20-30 2 sugar cataract
anterior posterior subcapsular (snow flakes)
72
NIDDM age-related cataract
diabetic retinopathy
sugar cataract alcohol aldose
reductase lens capsule alcohol osmotic imbalance
Na/K-ATPase cation pump Aldose reductase inhibitor
retinal pericytes (mural cells)

5. Hypocalcemia cataract
Ca phosphate neuromuscular hyperexcitability
capsule

6. Toxic cataract

systemic corticosteroids posterior subcapsular cataract

Miotic drugs long acting anticholinesterase accommodative
estropia anterior subcapsular opacity
pilocarpine
Chlopromazine granular deposit anterior capsule

70

7. Complicated cataract
posterior subcapsular
chronic recurrent uveitis, , retinitis pigmentosa, retinal detachment
senile cataract
***
iodine salt, vit.B, C, E, adenosine triphosphate, ocular circulation,
hormone, organ extraction, reducing agents, aspirin, pirenoxine, Sodium dihydroazapentacene
polysulfonate
2.5% phenylephrine 2% homatropine eye drop
visual axis anterior chamber
angle-closure glaucoma
(lens extraction)
-
- uveitis
-
3
Intra Capsulars Cataract Extraction (ICCE) capsule
Extra Capsulars Cataract Extraction (ECCE) capsule
posterior capsule
Phacoemulsification with IOL (PE c IOL) (ultrasound)
IOL
2 , , , IOL

binocular vision
(Intraocular lens; IOL)
refractive power
(aphakia)
, RA, ,
2-3

intraocular lens polymethyl/methaacrylate (PMMP)

( ICCE)
2
- Posterior chamber lens iris
- Anterior chamber lens endothelial cell bullous
keratopathy

2-2

71

***

8. After cataract
posterior capsule ECCE membrane
lens epithelial cell anterior capsule posterior capsule
Elschnigs pearls Soemmerings ring
after cataract posterior capsule visual axis ECCE
(primary posterior capsulotomy) after cataract (secondary
posterior capsulotomy) 2
1. posterior capsule limbus pars plana
2. neodymium YAG laser

Pirenoxine (Catalin , Kary Uni)

- modified phenoxazine carboxylic acid
- lipid peroxidation mammal lens
- quinoid substance metabolism tryptophan
soluble protein insoluble (insoluble protein cataract )
Catalin Takeda
E
[Zuellig]
C: Pirenoxine
I: Senile cataract, diabetic cataract.
D: Dissolve 1 tab in 15 ml solvent.
Instill 1-2 drops 4-6 times daily.
P/P: Ophth soln 0.75 mg/tab x 15 ml
x 1s.

Sodium dihydroazapentacene polysulfonate (Quinax)

Quinax Alcon
E-D
[Summit]
C: Na dihydroazapentacene
polysulfonate
I: Senile, traumatic, congenital &
secondary cataract.
D: 2 drops 3-5 times daily.
P/P: Ophth soln 0.15 mg/ml x 15 ml

Kary Uni Santen

E
[Greater Mybacin]
C: Pirenoxine
I: Incipient senile cataracts.
D: Instill 1-2 drops 3-5 times daily.
AR: Hypersensitivity, blepharitis,
contact dermatitis.
P/P: Ophth susp 0.005% x 5 ml.

72

References
[1] . . 1 2549 214-215
[2] . 63 2548
[3] . . 3 2544 609-611
[4]

2-3

73

2-3

mucous membrane

(conjunctivitis)

2-3A

(photophobia)

1:

Toxic

2-3B

+
+
+

+
+

+
+

+
-

(Pink eye, Red eye Conjunctivitis)

1. (Bacterial Conjunctivitis)

: Staphylococcus aureus, Streptococcus pneumoniae Haemophilus influenzae

: , papillae,

:
10-14
5-7

74

2. (Allergic conjunctivitis)

:


:

: -
- vasoconstrictor/antihistamine 1 3-4 ,
(
steroids
refer ), Artificial tears
- Opthalmic NSAIDs () ketorolac
- antihistamine
-
Note : 2 2-3
() 5

: mast cell stabilizers 2% sodium cromoglycate, lodoxamide

maximum effective 1-2

3. (Viral conjunctivitis)

: adenovirus, picornavirus
(Epidermic keratoconjunctivitis)
Enterovirus type 70, Coxsaki virus A type 24

1-2
14
: (Watery to mucoid discharge)

: -
- 10-14
- : antihistamine artificial tears

2-3

: -

75

Antibiotics ED/EO
antibiotics
steroid
1

4. Neonatal Conjunctivitis
Neonatal Conjunctivitis 1
: silver nitrate 1%
Neisseria gonorrhoeae, Chlamydia trachomatis, Herpes simplex virus (HSV)

: - silver nitrate 1%
-
- Chlamydia
- Herpes virus
: - silver nitrate 48
- erythromycin/terramycin
- Topical antibiotic
- Systemic antibiotic
2:

Chloramphenicol

Chlortetracycline
Ciprofloxacin
Levofloxacin
Lomefloxacin
Gatifloxacin
Moxifloxacin
Fusidic acid
Gentamicin

Sulfacetamide
Tobramycin

Chloracil, Koro, Silmycetin

Chloroph
Cogetin
Aureomycin , Chlortralim
Ciloxan
Cravitopth
Okacin
Zymar
Vigamox (Preservative free)
Fusithalmic
Garamycinopth
Genta-0ph, Gental
Optal
Tobramycin Alcon
Tobrex

Eye drop 0.5%

Eye drop 5 mg/ml / Eye ointment 1%
Eye ointment 1% (Apply once daily)
Eye ointment 1% (Apply qid)
Eye drop 0.3%
Eye drop 0.5% (1 drop tid)
Eye drop 0.3% (1drop bid-tid)
Eye drop 0.3%
Eye drop 0.5% (1 drop tid *4day )
Eye drop 1 %
Eye drop 0.3% (1-2drop q 4 h) /eye
ointment 0.3% (Apply bid-qid)
Eye drop 0.3% (1-2drop q 4 h)
Eye drop 15% (1-2 drops q 2-3 h)
Eye drop 0.3%
Eye drop 0.3%/ eye oint.0.3%

76

3: Combination antibacterial

Neomycin + Gramicidin
+Polymyxin B
Neomycin + Polymyxin B
Polymyxin B + Trimethoprim
Polymyxin B 10000 u
+ Oxytetracycline 0.5%
4: Ocular decongestant

Antazoline HCl 0.05%

+ Tetryzoline HCl 0.04%
ZnSO4 0.02%
+ Naphazoline Nitrate 0.005%
Naphazoline HCl 0.025%
+ Pheniramine maleate 0.3%
Naphazoline HCl
Tetrahydrozoline HCl
5: Artificial tears

White petrolatum + Mineral oil

+ Anhydrous liq lanolin
Polyvinyl alcohol
HPMC
6: Eye Corticosteriods

Fluorometholone
Fluorometholone 0.1%
Tetryzoline 0.025%
Prednisolone acetate
7: NSAIDs agents

Ketorolac
Diclofenac Na

Neosporin, Polyopth, Xanalin

Spersapolymyxin
Primoptic
Terramycin

Opth. solution
Eye ointment (Apply 4-6 times/day)

Histaoph, Spersallerg

Eye drops (1-2 drops 4-6 time/day)

Oculosan

Eye drops (1-2 drops 4-6 time/day)

Naphacon-A

Eye drops (1-2 drops 4-6 time/day)

Naphacon forte
Visine

Eye drops 0.1% (1-2 drops 4-6 time/day)

Eye drops

Duratears

Eye ointment (preservative free)

Liquifilm tears
Isopto tears

Eye drops 1.4%

Eye drops 0.5%

Frarex, Flu oph, Flucon, FML,

Efemoline

Opth suspension 0.1%(1-2 drops bid-qid)

Eye drops (1-2 drops bid-tid)

Pred-forte / Pred-mild, Inf-oph

Eye drops 1% / mild-0.12%

Acular
Naclof, Voltaren ophtha, Volverac eye

Eye drop 0.5% (1 drop qid)

Eye drop 0.1%(1 drop qid)

2-3

77

8: Eye Corticosteriods with antibacterials

3Dexamethasone PO4 1 mg
*Archidex,Dexoph,*Dexylin,*Eyedex,
+Neomycin 3.5 mg
Neo-optal,*Vesoph
3Dexamethasone PO4 0.1%
Maxitrol
+ Neomycin 3.5 mg
+ Polymyxin B sulfate 6000 u/ml
Tobradex
Dexamethasone 1 mg
+ Tobramycin 3 mg
Dexamethasone
Sofradex
+ Framycetin
+ Gramicidin
Dexamethasone 0.1%
Spersadexoline
+ Chloramphenicol 0.5%
+ Tetrahydrozoline HCl 0.025%
Prednisolone
Pred-oph
+ Gentamicin
9:

(diffuse)

(diffuse)

(diffuse)

*Eye/ear drops
Eye drops
Ophth susp / Ophth oint

Ophth oint/Ophth susp

Eye drops (1-2 drops tid.-qid)
Eye ointment ( hs or bid-qid)
Eye drops (1 drop OD-qid)

Eye drops (1drop qid)

(ciliary)

:
-
-
-
-
- (Photophobia)
- (, )
- (Circumcorneal redness)
-

78

References
[1] Albert DM, Jakobiec FA, Azar DT, Gragoudas ES, Power SM, Robinson NL. Principles and practice of ophthalmology. 2nd
ed. Philadelphia: W.B. Saunders Company, 2000.
[2] Arffa RG. Diseases of the cornea. 3rd ed. Missouri: Mosby, 1991.
[3] Chawla HB. Ophthalmology : a symptom-based approach. 3rd ed. Oxford : Reed educational and professional publishing
Ltd, 1999.
[4] American Academy of Ophthalmology. Basic and clinical science course section 8: external disease and cornea. San
Francisco: The foundation of the American Academy of Ophthalmology; 2001. p.111-80.

2-4

79

2-4

(trachoma)

conjunctiva

2

1:

2-4A

chlamydia trachomatis serotype A, B, Ba

() 5-12

2-4B

, chemosis, diffuse injection, papillary hypertrophy, tarsal and

limbal follicles, superior keratitis, pannus,
Herberts pits pathognomonic sign limbalcorneal junction
epithelium pannus fibrovascular membrane limbus cornea
4


1
()
()
(pannus)

80

( )

2-4C

endemic trachoma 2 4
1. Follicles ( ) 5 upper eyelid
2. Typical conjunctival scar upper tarsal conjunctiva
3. Herberts pits Limbal follicles limbalcorneal junction
4. Pannus () upper limbus

TF : Five or more follicles on the upper tarsal conjunctiva

TI : Diffuse infiltration and papillary hypertrophy of the upper tarsal conjunctiva obscuring at least
50% of the normal deep vessels
TS : Trachomatous conjunctival scarring

TT : Trichiasis or entropion
CO : Corneal opacity

2-4D

tetracycline 250-500 . 4 doxycyclin 100 . 2

erythromycin 250-500 . 4 14
o tetracycline doxycyclin tetracycline
4 14 (
)

o tetracycline 4 6

2-4

81

o 5 2
- 1 6
10 6 10 6

(cornea)
20

2-4E

(trachoma) 2
1 2
3 4



(Entropion)

:

2-4F

82

2-5

(hordeolum, stye)

(sebaceous gland) 2
(external hordeolum)
(internal hordeolum)

1: - (external hordeolum); - (internal hordeolum)

anterior eyelid (hair follicle) External Hordeolum Stye (

) (gland of Moll)

posterior eyelid (meibomian gland) Internal Hordeolum

() (meibomian gland) (
)

(Chalazion)

2-5A

2-3

4-5
1-2

2-5

83

2-5B

Staphylococcus aureus

chalazion
4-10

2-5C

1.

4
20-30
Bacitracin ophthalmic ointment 4-6 7
2-3
Tobramycin ophthalmic solution 3-4
Erythromycin : 250-500 . 4
: 30-50 1 6 .
() 10-20
theophyllin, digoxin, carbamazepine,
cyclosporine, warfarin, lovastatin simvastatin

84

terfenadine(
), astemizole()
Dicloxacillin : 500 . 4 1
: 50-100 1 . 4

Tetracycline : 250-500 . 4
: 20-40 1 . 4
,
,

5-7

2.

3.
Chalazion
2-3

4.

fistula

2-5

85

20-30

2 3-4

contact lenses

()

86

2-6

(corneal ulcer)

(cornea) (eye ball)

5
1. Epithelium

2. Bowman layer
3. Stroma 90

4. Descemet membrane
5. Endothelium

1:

trigeminal nerve
subepithelium stroma epithelium
stroma

2-6A

( )


,
,
,

epithelium

2-6

87

epithelium
epithelium Neisseria gonorrhoeae, Corynebacterium diphtheriae, Listeria spp.,
Haemophilus spp.

2-6B

(ciliary injection),
papillae follicles

epithelium, infiltrate stroma

(hypopyon)

()

(combined broad-spectrum
antibiotic) fortified aminoglycosides(1.5%) fortified cephalosporin (cefazolin 50 ./.)
fluroquinolone streptococcus
1

atropine Cycloplegics
2 ciliary spasm posterior synechiae
()
(corneal transplantation)

2-6C

88

(
)

2-7

89

2-7

(otitis) 3
(Otitis Externa)
(Otitis Media)
(Otitis Interna)
(corneal ulcer)

2-7A

(Otitis Externa)

(otitis externa)
(Staphylococcus) ,
, ,

antibiotic, antibiotic corticosteroid 4

4 7-10

2-7B

(Otitis Media)

3
(Eustachaintube)
3
Acute Otitis media
: 3
Subacute Otitis media : 3 12
Chronic Otitis media : 12

( bacteria S.pneumoniae,
H.influenzae, M.catarrhalis)

90

10-14


Antibiotic
Amoxycillin (40mg/kg/day)
Amoxycillin-clave (40mg/kg/day)
Cefaclor (40 mg/kg/day)
Cefuroxime ( 250-500mg/day q 12 h)
Clarithromycin (15 mg/kg/day)
recurrent otitis media Amoxycillin-clave (20 mg/kg/day)
1:

2-7C

(Otitis Interna)

2 cochilea semicircular canal

2 (round
window)

labyrinth

2-7

91

Dimenhydrinate

Aspirin, Quinine, Streptomycin

2:
Trade Name
Otosamthong
Otosporin
Sofradex
Candid
Tarivid
Archifen Ear
Grammicin
Auralgan

Generic Name
furaltadone + polymyxin + neomycin + fludrocortisone
polymyxin + neomycin + hydrocortisone
dexamethasone + framycetin + gramicidin
1% clotrimazole
0.3% ofloxacin
1% chloramphenicol + 2% lidocaine
0.3% gentamicin
benzocaine + antipyrine

92

2-8

cilia olfactory sensitivity
(ostium)



"" sinusitis 2

(acute sinusitis)
(chronic sinusitis)

2-8A

o , , ,
o
o

2-8B

(Sinusitis)
38 -39 C

2

, ,
2-3
7-14

2-8

93

(Sinusitis)
3

2-8C

antibiotic



,
antibiotic
Streptococcus pneumoniae, Hemophilus influenzae
Branhamella catarrhalis Amoxicillin, Amoxicillin/clavulanic
acid, Cefprozil, Ceftibuten, Cefuroxime axetil, Cefaclor, Clarithromycin, Clindamycin, Erythromycin,
Trimethoprim/Sulfamethoxazole
Amoxicillin
Amoxicillin/clavulanic acid, Trimethoprim/Sulfamethoxazole, Cefprozil, Cefuroxime axetil Clarithromycin
anaerobe Clindamycin, Amoxicillin/clavulanic
acid, Metronidazole Cefoxitin

10
3-4

nasal decongestant nasal decongestant 2

1. Local Phenylephrine HCl 0.5%

Oxymetazoline HCl 0.05% 3-4 3-4

2. Systemic decongestant 3 Pseudoephedrine

decongestant
Note

94

2-9

(epistaxis/nose bleed)

2-9A

(sinus)




(hemangioma, angiofibroma)

(aplastic anemia) hemophillia, hereditary
hemorrhagic telangiectasia (Osler-Weber-Rendu)

2-9B

(aplastic anemia, )

2-9

95

References
[1] . .
2548
[2] . . 3. : ; 2544. 265-266, 579583.
[3] Dipiro T.J.,Talbert LR.,Yee C.G. et al.Pharmacotherapy.4th ed.Connecticut:Appleton&Lange;1999.p.1671-1675
[4] Charles FL,Lora LA,Morton PG and Leonard LL,eds.Drug Information Handbook.12th ed. Ohio:Lexi-comp;2004-2005
[5] http://www.niaid.nih.gov/factsheets/sinusitis.htm
[6] http://earnosethroat-clinic.tripod.com/nose1.htm
[7] http://www.si.mahidol.ac.th/sidoctor/e-pl/articledetail.asp?id=18
[8] http://www.entnet.org/healthinfo/sinus/antibiotics_sinusitis.cfm

3-1
3-2
3-3

3-4
3-5
3-6

3-7
3-8

3-9
3-10
3-11

3-1

99

3-1

3-1A

(pericardial cavity) pericardium fibrous connect

tissue 3
Epicardium
Myocardium (cardiac muscle)

Endocardium
subendocardium

3-1B

4 Left-Right atrium Left-Right ventricular atrium

ventricle atrioventricular valve (A-V valve)
atrium ventricle tricuspid valve 3
atrium ventricle Bicuspid valve mitral valve
2 L-ventricle
2 A-V valve chordae tendinae
papilar muscle ventricle ventricle

3-1C

Aorta

Vena cava
2 superior vena
cava inferior vena cava

Pulmonary artery
Pulmonary vein
Coronary
coronary artery 2 -
aorta
coronary vein

100

coronary sinus
vena cava

3-1D

(excitability) (contractility)
action potential
(conductivity)
3
Pacemaker cells P cell SA AV nodes

Purkinje cells
Purkinje system
Myocardial cells
SA node (Sino-Atrial node) right atrium superior
vena cava SA node
(pace maker) AV node right atrium coronary sinus AV node
ventricle bundle of his atrium ventricle
- 2 ventricle
Purkinje fiber

1: The cardiac conduction system. A. Cardiac conduction system anatomy. B. Action potentials of specific cardiac cells. C.
Relationship of surface electrocardiogram to the action potential.

3-1

101

SA node action potential

SA node Bachmanns bundle
SA node AV node Internodal pathways
myocardial conducting cells
AV node 0.1-0.2 sec AV node
bundle of his Purkinje system
atrium ventricular ventricle Ventricle
AV node
AV node

2:

Arrhythmias AV block
SA node Sinus tachycardia
Sinus bradycardia
SA node SA node
Ectopic focus (Ectopic area)
Electrocution gram (EKG, ECG)
Depolarization Repolarization
( SA node Ventricular muscle)
Depolarization Repolarization

3:

102

P wave
depolarization ()
SA node - AV node 0.08

QRS wave QRS complex Depolarization (-)

interventricular septum 0.08

T wave
repolarization 0.16
depolarization
P-R interval P wave QRS complex
SA node AV node bundle of his
AV node P-R interval 0.16
0.12-0.20
PS segment depolarization (P wave )
QRS complex base line 0.07

Q-T interval depolarization repolarization

0.36
0.42 0.43

ST segment repolarization repolariazation

0.04
Baseline

3-1E

SA node AVnode
nervous, chemical mechanical control

1. Nervous control
3
Inhibitory system cardio inhibitory center
(C.I. center) (vagus center medulla
motor nerve vagus nerve parasympathetic
nerve (SA node & AV node)
Acceleration system cardio acceleratory center
Medulla motor nerve
sympathetic (SA node & AV node) 1

3-1

103

2 afferent nerve impulse

aortic arch carotiod sinus vena cave
Sensory system

cerebral cortex hypothalamus impulse cardioacceleratory
vena cava sensory nerve (accelerate) cardioacceleratory center motor nerve SA AV node
ventricle aorta sensory nerve (inhibiting) cardio inhibitory center
motor nerve SA AV node vena cava

2. Chemical control
CO2
activity activity
activity

3. Mechanical control


250 . 135 /
300 .

0 Action potential repolarization
1 action potential All or none
fiber syncytium
Diastolic

Starling Law
Fiber tension
starlings law tension muscle fiber
resting length tension
muscle fiber muscle fiber tension
()

Systolic

104

Diastolic
End-diastolic volume (EDV)
Stroke volume (SV) SV = EDV - ESV
Ejection Fraction
SV/EDV
Cardiac output 1 Cardiac output (CO)
CO = heart rate x stroke volume ( / /)
Cardiac output
(heart rate) CO
CO filling time
EDV SV
(Stroke volume) EDV ESV (SV =
ECV - ESV)
EDV 1 (Venous return)
filling pressure
EDV
Frank-Starling law EDV SV
ESV ESV SV
ESV

ESV SV
EDV

preload

ESV

after load
Contractility

Stroke volume

Cardiac output

Heart Rate

Autonomic nervous system

4: Cardiac output

3-2

105

3-2

3-2A

Diuretic

volume depletion peripheral
resistance

1. Thiazides & thiazide-like agents

- HCTZ (hydrochlorothiazide)
- Indapamide
2. Loop diuretics
- Furosemide
- Bumetanide
- Ethacrynic acid
3. Potassium-sparing diuretics
- Spironolactone (aldosterone antagonist)
- Amiloride
- Triamterene
4. Miscellaneous
- Osmotic agents (mannitol,sorbitol and isosorbide)
- Acidifying salts (NH4Cl, NH4NO3)
Potency 2
1. Low ceiling dose
dose
thiazides

2. High ceiling dose

furosemide, ethacrynic acid, bumetamide

106

(edema)

Mild Hypertension
Cardiac failure
Renal disorders
Drug induced side effect Steroids

1. Thiazides & Thiazide-Like Agents

metabolism
Chlorothiazide large dose
(0.5-1g/day)
Chlorthalidone
organic acid secretory system proximal tuble
uric acid uric acid

thiazides NaCl reabsorption distal convoluted tuble block Na+/Cltransporter NaCl tubular fluid
Ca2+ reabsorption Loop diuretic

thiazides
insulin
blood urea nitrogen
creatinine

thiazides
thiazides lithium
carbonate lithium

sulfa

digoxin
digoxin

3-2

107

Nepheotic


25 mg/day (6.25-25 mg/day)

2. Loop Diuretics
Furosemide
Ethacrynic acid

medulla cortex

, Furosemide
Ethacrynic acid

Furosemide
Ethacrynic acid
Furosemide

(GFR<30 mL/min)

Furosemide (Lasix) 20-80 mg BID

3. Potassium-Sparing Diuretics

2

3.1. Aldosterone antagonists

aldosterone hormone antidiuretic hormone spironolactone
eplerenone competitive antagonist aldosterone

108

thiazides
androgen

thiazides
thiazides furosemide thiazides
Neprotic syndrome Post MI

spironolactone salicylate
salicylate canrenone
- Spironolactone (Aldactone) 50-100 mg/day ( ACEI severe
CHF mortality 30%)
- Eplerenone (Inspra) hypertension : 50 mg OD or BID ()
Post MI
: 25 mg OD

3.2. Triamterene, Amiloride

aldosterone hormone Triamterene Amiloride

Triamterene

megaloblastic

Aldosterone antagonists
Amiloride (Midamor) 5-10 mg OD or BID
Triamterene (Dyrenium) 50-100 mg OD or BID

1.

2. Furosemide Thiazides
3. Spironolactone triamterene
4. Spironolactone
Thiazides
Hydrochlorothiazide Amiloride Hydrochlorothiazide Triamterene

3-2

109

1: Dosage of Diuretics for the Treatment of Hypertention*

Antihypertensive agent (trade name)
Usual dose range in mg/d (Frequency per day)
Thiazide diuretics
Chlorthalidone (Hygroton)
12.5-50 (1)
Hydrochlorothiazide (Hydrodiuril, Microzide, Esidrix)
12.5-50 (1)
Indapamide (Lozol)
1.25-5 (1)
Metolazone (Mykrox)
0.5-1 (1)
Metolazone (Zaroxolyn)
2.5-10 (1)
Loop diuretics
Bumetanide (Bumex)
0.5-4 (2-3)
Ethacrynic acid (Edecrin)
0.25-100 (2-3)
Furosemide (Lasix)
40-240 (2-3)
Torsemide (Demadex)
5-100 (1-2)
Potassium-sparing agents
Triamterene (Dyrenium)
25-100 (1)
Amiloride hydrochloride (Midamor)
5-10 (1)
Aldosterone antagonists
Spironolactone (Aldactone)
25-100 (1)
Eplerenone (Inspra)
50-100 (1-2)
*These dosages nay vary from those listed in the Physicians Desk Reference (55th edition), with may be consulted for additional
information.

3-2B

Beta-Adrenergic Antagonist or Beta Blocker

1. block beta-1 beta-2-adrenergic receptors

2. Intrinsic sympathomimetic activity (ISA; partial agonist)
3. block alpha-adrenergic receptors Labetalol
4. membrane stabilizing
5.
6. Pharmacokinetics

block beta 1 receptor rate force

Renin ACEI
block beta 2 receptor vasoconstriction alpha receptor

cardiac
output reflex sympathetic
alpha receptor

110

block beta 2 receptor brochoconstriction
Asthma COPD
metabolism
o Beta blocker lipolysis
o Beta blocker glycogenolysis
hypoglycemia
hypoglycemia
o Beta blocker VLDL HDL

o membrane stabilizing block Na+ channel

1. beta receptor
2. Dose dependent Dose
3. plasma triglyceride HDL
4. block receptor diarrhea, constipation , nausea, vomiting
night mares, mental depression

insulin resistant sign of

hypoglycemia receptor
sensitivity blood pressure sudden death

asthma, COPD heart block

o
o first choice chronic angina incident
angina nitrate calcium channel blocker
o Arrhythmia supraventricular ventricular arrhythmia atrial fibrillation
o Myocardial infarction

o Heart Failure (HF) systolic dysfunction selective 3 metoprolol,

bisoprolol carvidiol diastolic dysfunction nonselective
propranolol
o Coronary Artery Disease (CAD)
o complication hypertension, acute myocardial infraction (AMI)
heart failure (HF)

3-2

111

o hyperthyroidism
o migraine propranolol, timolol metoprolol
o open-angle glaucoma timolol butatoxol
2: Dosage of Beta-Blockers for the Treatment of Hypertention*
Antihypertensive agent (trade name)
Usual dose range in mg/d (Frequency per day)
Nonselective beta-blockers
Carteolol hydrochloride (Cartrol)
2.5-10 (1)
Nadolol (Cargard)
40-320 (1)
Penbutolol sulfate (Levatol)
10-20 (1)
Pindolol (Visken)
10-60 (2)
Propranolol hydrochloride (Inderal)
40-480 (2)
Propranolol hydrochloride (Inderal LA)
40-480 (1)
Timolol maleate (Blocadren)
20-60 (2)
Selective beta-blockers
Acebutolol (Sectral)
200-800 (1)
Atenolol (Tenormin)
25-100 (1-2)
Betaxolol (Kerlone)
5-20 (1)
Bisoprolol fumarate (Zebeta)
2.5-10 (1)
Metoprolol tartate (Lopressor)
50-300 (2)
Metoprolol succinate (Toprol-XL)
50-300 (1)
Combined alpha and beta-blockers
Carvedilol (Coreg, Diratrend)
5-50 (2)
Labetolol (Normodyne)
200-1200 (2)
Labetolol (Trandate)
200-1200 (2)
*These dosages nay vary from those listed in the Physicians Desk Reference (55th edition), with may be consulted for additional
information.

Beta blockers
selective beta 1 blockers cardioselective beta 1 > beta 2
o atenolol (Tenormin) 25-100 mg OD depression
o metoprolol (Lopressor) 25-100 mg OD or BID
o esmolol (BREVIBLOC) 25-300 mcg/kg/min I.V infusion half life
control supraventricular tachycardial
beta blocker with intrinsic sympathomimetic activity (ISA) sympathetic
hypertension heart failure angina
o acebutolol (Sectral) 200-800 mg BID
o pindolol 20-60 mg /day
non selective beta blockers block beta 1 beta 2
o propranolol (Inderal) 40-80 mg BID first pass
metabolism 20% half life

o timolol (Blocadrem) 20-40 mg BID glaucoma

112

alpha, beta blockers block alpha 1, beta 1 beta 2 (beta 1 > beta 2)

o carvidilol (Dilatrend)
o labetalol (Trandate)

3-2C

Angiotensin Converting Enzyme Inhibitors (ACEIs)

angiotensin converting enzyme (ACE) angiotensin I angiotensin II

vasoconstrictor converting enzyme enzyme
angiotensin I ACEI angiotensin II
angiotensin II aldosterone angiotensin II aldosterone
endogenous
vasodilators bradykinin

CHF, CAD, MI, Hypertensive nephrosclerosis, Diabetic nephropathy

o captopril 12.5-25 mg/d 2

o enalapril 20 mg/d CHF 20 mg/d
o lisinopril 10-40 mg/d CHF 2.5-10 mg/d

Dry cough, Hyperkalemia, Hypotension, Renal insufficiency, Angioedema

ACEIs
renin
renin
angiotensin II
zinc ion fosiopril

ACEIs hypertension
Total Peripheral Resistant (TPR)
diabetic nephropathy renoprotective
glomerular efferent arteriolar resistant
ACEIs heart failure
first choice preload afterload cardiac remodeling
sodium water retention venous return

3-2

113

3: Dosage of Agents that Inhibit the Renin-Angiotensin System for the Treatment of Hypertention*
Antihypertensive agent (trade name)
Usual dose range in mg/d (Frequency per day)
ACE Inhibitors
Benazepril (Lotensin)
20-40 (1-2)
Captopril (Capoten)
25-150 (2-3)
Enalapril (Vasotec)
10-40 (1-2)
Fosinopril (Monopril)
20-40 (1-2)
Lisinopril (Prinvil, Zestril)
20-40 (1)
Meoxipril (Univasc)
7.5-30 (1-2)
Perindopril (Aceon)
4-8 (1-2)
Quinapril (Accupril)
20-80 (1-2)
Ramipril (Altace)
2.5-20 (1-2)
Trandolapril (Mavik)
2-4 (1)
Angiotensin II Receptor Antagonists
Candesartan (Atacand)
16-32 (1)
Eprosartan (Teveten)
400-800 (1-2)
Irbesartan (Avapro)
150-300 (1)
Olmesartan (Benicar)
20-40 (1)
Telmisartan (Micardis)
40-80 (1)
Valsartan (Diovan)
80-320 (1)
*These dosages nay vary from those listed in the Physicians Desk Reference (55th edition), with may be consulted for additional
information.

3-2D

Angiotensin Receptor Blockers (ARB)

competitive antagonist angiotensin II angiotensin type receptor type

type II aldosterone bradykinin
half life metabolize 24

ACEIs ACEIs HF
preload after load cardiac remodeling

o Losatan (Cozaar) 25-100 mg 1-2

o Valsartan (Diovan) 80-320 mg
o Irbesartan (Aprovel) 150-300 mg
o Cardesartan (Blopress) 8-16 mg
o Telmisartan (Micardis) 20-40 mg
o Olmesartan medoxomil (Olmetec) 20-40 mg

ACEIs angioedema

114

3-2E

Calcium Channel Blockers (CCBs)

Ca2+
sinus node pacemaker rate atrioventricular velocity

FDA approve Classic angina pectoris, hypertension supraventricular

arrhythmias vasospasm large coronary artery variant
angina
3
1. Dihydropyridine vasodilate
reflex
tachycardia angina pectoris induce angina pectoris
- First generation : nifedipine
- Second generation : nicardipine, amlodipine, felodipine, isradipine
- nicardipine amlodipine approve chronic stable angina
- slow cardiac conduction antiarrhythmia drugs
- peripheral vasodilator reflex sympathetic
(reflex tachycardia) afterload
- coronary
- Nicardipine ventricle (Systolic) nifedipine
conduction SA node
AV node
- Amlodipine effective chronic angina vasospastic angina effective
chronic angina diltiazem verapamil beta
blocker angina HF
- Felodipine isradipine approve hypertension
chronic stable angina
2. Diphenylalkylamines verapamil
3. Benzothiazepines diltiazem
- 2 Non- dihydropyridine
- slow cardiac conduction prolong refractory period AV node
ventricular rate supraventricular tachycardia
- contractility Left Ventricle dysfunction
- peripheral vasodilate coronary vasodilate
- diastolic heart failure negative inotrope non-selective beta blocker
calcium channel blocker diltiazem verapamil slow heart rate
diastolic filling nifedipine reflex tachycardia

3-2

115

o Verapamil (Isoptin) 40 mg 3-4

o Diltiazem (Herbessor) 30-60 mg 3-4
o Nifedipine (Adalat) 5-10 mg 3-4
verapamil > diltiazem > nifedipine

(cardiac arrest), (bradycardia)

hypotension
Ca2+ blocker
tone movement reflex
GI movement
Nifedipine precapillary dilation peripheral edema , reflex
tachycardia
Diltiazem headache nausea
Verapamil conspitation

verapamil diltiazem beta blocker AV

block heart failure
verapamil digoxin quinidine
AV block
Ca2+ blocker titrate dose
S/E
metabolized

116

4: Dosage of Calcium-Channel Blockers for the Treatment of Hypertention*

Antihypertensive agent (trade name)
Usual dose range in mg/d (Frequency per day)
Dihydropyridines
Amlodipine besylate (Norvasc)
2.5-10 (1)
Felodipine (Plendil)
2.5-10 (1)
Isradipine (DynaCirc)
5-20 (2)
Isradipine (DynaCirc CR)
5-20 (1)
Nicardipine (Cardene SR)
60-90 (2)
Nifedipine (Procardia XL)
30-120 (1)
Nifedipine (Adalat CC)
30-120 (1)
Nisoldipine (Sular)
20-60 (1)
Nondihydropyridines
Diltiazem hydrochloride (Cardizem SR, Cardizem XL)
120-360 (2)
Diltiazem hydrochloride (Cardizem CD, Dilacor XR)
120-360 (1)
Diltiazem hydrochloride (Tiazac)
120-420 (1)
Verapamil hydrochloride (Verelan, Verelan PM)
120-480 (1); 200-400 (1)
Verapamil hydrochloride (Covera HS)
120-480 (1)
*These dosages nay vary from those listed in the Physicians Desk Reference (55th edition), with may be consulted for additional
information.

3-2F

Alpha Blocker

Block post sympathetic alpha receptor vascular smooth muscle cells presynaptic
alpha 2 receptor catecholamine vascular smooth muscle cells vasoconstriction
(alpha 1 blocker)

arterial blood pressure Benign

prostatic hyperplasia (BPH)

o Prazosin (Minipress) 1-20 mg /day

o Doxazosin (Cardura) 2-4 mg/day

Hypotension, postural hypotension elderly

dizziness, palpitation, headache

postural hypotension dose

3-2G

Centrally acting alpha 2-adrenergic agonist

alpha 2 receptor norepinephrine

peripheral vascular resistant renal vascular resistant
methyldopa cardio vascular reflex postural hypotension

3-2

117

Methyldopa (US FDA Preg Cat .B) clonidine

heart rate cardiac output methyldopa

o Methyldopa 1-2 g/day

o Clonidine 0.2-1.2 mg/day

alternative

3-2H

Vasodilator (Nitrates, Nitrites)

nitrite ion (NO2) nitric

oxide (NO) enzyme guanylate cyclase (GC) cGMP GTP calcium
channel Ca2+ sarcoplasmic reticulum
Ca2+

arteriole
precapillary sphincter
Hemodynamic effect angina pectoris
venous pooling peripheral vein venous return left
ventricular end diastolic pressure (LVEDP) wall tension preload oxygen
consumption oxygen consumption reflex tachycardia
preload preload

left ventricular systolic pressure (LVSP)

systemic arterial blood pressure afterload oxygen
consumption
baroreceptor
reflex oxygen consumption menigeal
temporal artery

118

effective angina Nitroglycerin (NTG), Isosorbide dinitrate (ISDN),

Isosorbide mononitrate (ISMN) 2
1. short-acting sublingual NTG, NTG lingual spray acute angina attack (
)
2. long-acting ISDN, ISDM angina ()
S/E

hypotension vasodilation
nitrate-induce headache

nitrate 10-12

3-2I

Antiarrhythmic Drugs

Antiarrhythmic Drugs 4 class Vaughan Williams Classification

1. Class I sodium channel blockers ( 3 subclass IA, IB, IC)
2. Class II beta adrenergic receptor antagonist (beta blockers)
3. Class III potassium channel blockers prolong action potential duration
4. Class IV calcium channel blockers

Antiarrhytmic Drugs suppress prevent
Abnormal Impulse Formation ()
Abnormal Impulse Conduction ()

1. Class I (sodium channel blockers)

Class 3 subclass
Na+ channel open state inactivated state
(rate of dissociation rate of recovery)
Subclass
Class IA
Class IB
Class IC

sodium channel affinity

Open > inactivated
Inactivated > open
Open > inactivated

Rate of dissociation
Slow
Rapid
Very slow

Duration of channel blockade

Intermediate
Quick
Long

Class IA : Prolong repolarization ( increase QRS, QT interval and refractory period)

blocking open voltage-dependent Na+ channel atrial and
ventricular muscle cell, His-Purkinje system AV node
Phase 4 Threshold Phase 0
EKG QRS interval

3-2

119

Phase 0 Phase 0 Effective refractory

period
cardiac depressant supraventricular ventricular arrhythmia
Class IA block K+ channel Class II
TdP
o Quinidine
quinolone derivative
D-isomer Quinine
Suppression of supraventricular arrhythmia and ventricular arrhythmia oral
IV hypotension
AV node conduction velocity ventricular rate AV node conduction
digoxin quinidine
ADR
- diarrhea
- Higher dose cinchonaism (tinnitus, dizziness, blurred vision)
o Procainamide
Amide derivative local anesthetic procain
Metabolized active metabolite NAPA Class III
Indication
- IV : acute ventricular arrhythmia ( hypotension quinidine)
- Oral : supraventricular and ventricular arrhythmia
o Diospyramide
Indication
- Oral : prevention ventricular arrhythmia

antimuscarinic HF
blurred vision urinary retention
Class IB : Shorten repolarization (Decrease refractory period)
Blocking inactivated voltage-dependent Na+ channel
Automaticity Threshold Phase 0 Ventricle, His-Purkinje
system
Sodium permeability
Refractory period repolarization
conduction velocity conduction velocity
Ventricular arrhythmia ventricular tissue
o Lidocaine
Selective ischemic tissue
Indication
- IV (bolus cont.) : ventricular tachycardia other acute ventricular tachycardia

120

o Mexiletine & Tocainide
Indication :oral long-term :ventricular arrhythmia
ADR : Tocainide agranulocytosis and other blood cell
deficiency mexiletine
Class IC : Little effect on repolarization ( Increase PR, QRS & QT interval)
blocking open voltage-dependent Na+ channel Class IA
rate of dissociation Na+ channel Class IC Na+ channel
supraventricular and ventricular arrhythmia PVCs
PVCs Mortality &cardiac arrest
Flecainide Propafenone

2. Class II : Beta blocker (Increase PR interval and refractory period)

sympathetic cardiac automaticity impulse
Heart rate automaticity refractory period
SA node to AV node conduction velocity EKG PR interval
supraventricular arrhythmia AV node
Ventricle

Esmolol
- Indication : IV ; acute supraventricular tachycardia
- Short half life
Metoprolol & Propranolol
- Indication : oral or IV ; treat or suppress of supraventricular and ventricular arrhythmia
- MI IV oral

3. Class III :Potassium channel blocker & Prolong Repolarization (Increase QT interval and
refractory period)
Blocking K+ channel refractory period Phase 3
Prolong repolarization and action potential duration EKG QT interval
(Ventricle )
supraventricular ventricular arrhythmia Class III

o Amiodarone

onset 2
Half life 40

3-2

121

block Na+ channel,Ca2+ channel beta receptor

HF arrhythmia
S/E
- iodine
- Hypotension
- AV block
- Blue-gay skin discoloration ()
- arrhythmia Torsade de pointes
- Fetal pulmonary fibrosis
digoxin wafarin
o Bretylium : IV or IM acute ventricular fibrillation

4. Class IV : Ca2+ channel blocker (Increase PR interval and refractory period)

Ca2+ contractility force PR interval and refractory
period beta blocker supraventricular arrhythmia
Verapamil Diltiazem
- IV acute supraventricular tachycardian ventricular rate atrial fibrillation
- negative inotropic
5: Preferred Antihypertensive Agents for CVD

122

6: CKD and CVD Indications for Classes of Antihypertensive Agents

3-3

123

3-3

/
/ (Metabolism)

Pharmacophore

3-3A

Adrenergic Agent and Related Compound

Adrenergic Agent
Presynaptic Site

Presynaptic Site
NE, Epi NE

1. NE ( NE)
Carbidopa
2. NE Reserpine
*** 3. uptake NE (
NE NE

Anorexia )
Phenylpropylamines Amphetamine,
Pseudoephedrine, PPA (Phenylpropanolamine)
4. NE ()
Selegiline, Iproniazid

H H
N

HO
OH H
HO

Postsynaptic Site

Agonist Antagonist , receptor

***1. Agonist
Phenylethanolamines
SAR NE, Epinephrine,
Isoproterenol, Terbutaline, Albuterlol,
***2. Antagonist -blocker
Aryloxypropanolamines

NOTE!!!

SAR 3

+ Receptor
Amphoteric + N Phenolic

R
NE R=H
Epi R=Me

124

1. Presynaptic Site
Phenylpropylamines
OH
uptake
OH 2
intramolecular H-bonding

H H
N

4
3

OH C3 C4
OMe
OH
*** 2 .. H+ potent

R1 R2

R3
Uptake
max H

R3

R1 H
OH OH

OH

OH

N
CH3

OH

N
CH3

N
CH3

CH3

Ephedrine

CH3

Pseudoephedrine

PPA
H

H
N

N
H

CH3

CH3

CH3

Metamphetamine

Amphetamine

2. Postsynaptic Site
AGONIST - Phenylethanolamines
Agonist C1 R
configuration OH
.. .. amine

OH
1

*** ..R3 OH 2 (
C3 C4 OH )
Catecholamine
enz COMT
*** .. C3
OH (.. 4 OH )


ANTAGONIST

selective

R3

Agonist N primary
secondary amine
Aromatic ring 2 carbon atom

R2
*** ..R2 Me
enz
MAO
methyl
amine
Et selective
>

R1
*** ..R1 t-Bu (tertiary butyl)
2 (2
agonist)
( H 1
2
i-Pro
agonist t-Bu
selective 2 agonist )

3-3

125

OH
1

R3

Drugs
NE
Epinephrine (Adrenaline)
Ethyl NE
Isoproterenol
Terbutaline
Albuterol (Salbutamol)
Phenylephrine
(Benadryl)

R1
H
Me
H
i-Pro
t-Bu
t-Bu
Me

R2

R2
H
H
Et
H
H
H
H

R1

R3
3,4-(OH)2
3,4-(OH)2
3,4-(OH)2
3,4-(OH)2
3,5-(OH)2
3CH2OH,4OH
3-OH

Receptor Activity
+
>
>

2
2

ANTAGONIST - Aryloxypropanolamines
HO

*** R vary


.. Ortho Meta- -blocker
Para-
Selective 1-blocker
*** R
ester Half life
Esmolol
***/

R (
ionize )

H
S

CH3

CH3

Antagonist ..
S configuration

Me 1

HO
O

X=O,S

OH
HO
HO

H
N

CH3
CH3

HO

H
CH3

H
CH3

Nadolol

Pindolol

CH3

R'

R'=Alkyl,Aryl

non-selective -blocker + -blocker
Cavedilol

-blocker

HO

H
N

S N
Timolol

CH3
CH3
CH3

Aryl
Ortho- Meta-

126

Selective 1-blocker
HO

HO

HO

CH3

O
CH3

HO

Esmolol

O
HO

H
CH3

CH3

Acebutolol

CH3

H
CH3

O
O

CH3

Metoprolol

Atenolol

O
Me

Me

CH3

H2N

CH3

Aryl
Para-

CH3

Bisoprolol

Non-Selective -blocker + -blocker

HO

H
N

Carvedilol

N
H

1: Adrenoreceptor
Organ/Tissue
Arteriole

Type

Response
Vasoconstriction
Vasodilation
Contraction (Pupil dilation)
Lipolysis
Rate Force Velocity
motility
gluconeogenesis
Bronchodilation
Contraction
Relaxation

1
2
1

Radial muscle ()
Fat cell
Heart
Intestine
Liver
Lung
Uterus

,
1
,
, 2
2
1
2

Adrenergic Agent
Phenylpropylamines
R2 Me
propyl
H H

phenyl

R1 R2

Aryloxypropanolamines
propanol

ethanol
1

amine
R3

Uptake NE

OH

Phenylethanolamines

R3

R2

aryloxy

amine

HO
O

H
S

R1

CH3
CH3

phenyl
Agonist , receptor

amine
N

Antagonist ,
receptor

3-3

3-3B

127

Antihypertensive Drugs

Diuretics and Loop Diuretics

Angiotensin Converting Enzyme Inhibitors (ACEI)
Angiotensin II Receptor Blockers (ARB)
Calcium Channel Blockers (CCB)
Vasodilators

1. Diuretics and Loop Diuretics ()

Carnonic Anhydrase Inhobitors (CAI)
Heterocyclic Sulfonamide Sulfanilamide Acetazolamide
Metazolamide ( Sulfa drug )

Heterocyclic > Aromatic > Aliphatic

Me ..
Metazolamide
Me

N N

N N
H2NO2S

N
CH3
H
Acetazolamide

Sulfamoyl

inactive

NH2SO2

N
CH3
Metazolamide

Acetyl
Amine Potent

Thiazides / Hydrothiazides
Thiazide CAI Na+ Cl
CAI systemic acidosis () (
Sulfa drug )
H alkyl S
*** double bond

Cl Br CF3 NO2
Potent

4
5

H2NO2S

C=O
potency

R1

H
N

R1

O
O
Thiazide

Sulfamoyl free

Hydrothiazide
potent 10

R2

H2NO2S 7

H ** .. 2 4 5 8

R2

O
O
Hydrothiazide

SAR Hydrothiazide Thiazide

R1 R2 Hydrothiazide Thiazide

***R1 = benzyl > ethyl > H potency duration

***
R2 ()

128

4
4

Cl
7

H2NO2S

N
1

H
N

Cl

NH

H2NO2S 7

NH

O
O
Hydrochlorothiazide (HCTZ)

O
Chlorothiazide

Loop Diuretics
Loop of Henle ADR
Hypokalemia , uric , Hyperglycemia, Ototoxicity ( Sulfa drug )
Sulfamyl benzoic acid
R Cl CF3
Phenoxy Alkoxy Benzyl

.. 3 ..2

Furfuryl > Benzyl > Thienylmethyl

H2 NO2S

COOH

amino 3Aminobenzoic 2-Aminobenzoic

Cl

H
N

O
O

2
H2 NO2S

HN
3
2

H2 NO2S

COOH

COOH

Bumetanide
(3-aminobenzoic)

Furosemide
(2-aminobenzoic)

Loop diuretic ( SAR )

CH3
H
N
N

H
N

H
N

O
O O
Torsemide

3-3

129

Potassium Sparing Diuretics

Collecting Tubule Potassium 3

- Spironolactone Neutral form salt oral form

- Triamterene
- Amiloride
O

oral

O
Metabolism

17

17

H
S

H
CH3

O
Canrenone
(Active)

Spironolactone
(Active)

receptor site
N

H2N

e- withdrawing
inactive

NH2

N
N

NH2
Triamterene

Guanidine group
NH2+ Cl

O
Cl
H2N

N
H

N
NH2
Amiloride

NH2

130

2. Angiotensin Converting Enzyme Inhibitors (ACEI)

3 Zinc-Binding Group
- Sulhydryl
- Dicarboxylate
- Phosphonate
Zn2+

binding

[ ]

(CH2)n

group

N-Ring
X

(CH2)n

[ ]
Zn2+
binding
group

5 active site ACE

N-Ring
X

SAR
hydrophobic pocket
potency n=2

(CH2)n

C=O N-Ring
O

[ ]
Zn2+
binding
group

N-Ring
X

Zinc Binding Group 3

= Sulhydryl group
HS CH2
COOH
CH

NH

= Dicarboxylate

OH
P

X = Methyl

N-Ring Heterocyclic ring

COOH Ortho-
N
potency

= Phosphonate

*** Sulhydryl Zn2+ dicarboxylate > Phosphonate > sulhydryl

Sulhydryl C=O N-ring turm plane hydrolyse inactive
form disulfide bond duration
*** Dicaboxylate COOH ester PRODRUG

3-3

131

Sulhydryl

Phosphonate
H

O
O

COOH

(CH2)4

SH

CH2

COOEt

Me
Captopril

Na+OOC

Fosinopril Sodium

Dicarboxylate Prodrug
O
(CH2)2

CH

NH CH

(CH2)4
HOOC

COOH
Lisinopril

NH2

Dicarboxylate Prodrug

COOEt CH
3
O
N
H H
N
COOH

H
Ramipril

HOOC
O

HOOC
O
(CH2)2

CH

NH CH

COOEt

CH3

Enalapril Maleate

(CH2)2

N
HC

HC

COOH

CH

NH CH

COOH
Enalaprilat

COOH

CH3

132

3. Angiotensin II Receptor Blockers (ARB)

Angiotensin II Receptor
Angiotensin II 3 Acidic group Carboxylic acid, Phenylcarboxylate
pKa ~ 3-4
Phenyltetrazole pKa ~ 6
R carboxylic
methanol ether alkyl

Butyl group
Imidazole ring
Benzimidazole
lipophilic
Potent

Tetrazole Stability
Lipophylicity (
) tetrazole
Ortho-
Phenyl ring

N
N

Acidic Group

N
Cl
OH

O
H

N N

Losartan

N N

Irbesartan

H3C

O
O

N
N

COOH
H

O
H

N N
N
N

Valsartan

N N
N

Candesartan

3-3

133

4. Calcium Channel Blockers (CCB)

1,4-Dihydropyridine Non-Dihydropyridine

1,4-Dihydropyridine
reduction
piperidine oxidation pyridine pdt
inactive ( Rxn )

*** C4 Planar group

Phenyl Non-planar

*** X electron donating

withdrawing
Ortho- Meta-
Para- X

.. o- m-
perpendicular
Phenyl 1,4-DHP

H
R1 6 N 1

CH3
2

5
R2

*** C2 C6 Methyl Sym

Amlodipine C6 (R1) Methyl

3 R3

*** C3 C5 Symmetry
Ester Group ()
Nifedipine 2
Sym Identical

1,4-Dihydropyridine CCB
H
R1 6 N 1

CH3
2

5
R2

R1 6 N 1
Oxidation

3 R3

3 R3

H
R1 6 N 1

CH3
2

5
R2

5
R2

CH3
2

H
R1 6 N 1
Reduction

3 R3

5
R2

CH3
2
3 R3

H
R1 6 N 1
5
R2

CH3
2
3 R3

Compound
Amlodipine

R1

R2

R3

CH2O (CH2)2NH2

CO 2CH2CH3

CO 2CH3

2-Cl

Felodipine

CH3

CO 2CH2CH3

CO 2CH3

2,3-Cl2

Nicardipine

CH3

CO2CH2CH2-NH-CH2C6H5

CO 2CH3

3-NO 2

CO 2CH3

2-NO 2

CH3

Nifedipine

CH3

CO 2CH3

134

Non-Dihydropyridine
2

OMe
OMe
OMe
S
O

CH3
N

MeO
MeO

CN

Verapamil
(Phenylalkylamine)

O
Diltiazem
(Benzothiazepine)

5. Vasodilators
Direct acting Indirect acting
Severe Hypertension

2N

NH-NH2 HCl
N

N
N
Hydralazine

CN

H2N

N
O

NH2

NC
O
N

Fe

CN
CN

Na2 . 2 H2O

CN
Sodium Nitroprusside

Minoxidil

3-4

135

3-4

(sphygmomanometer) 2
Systolic Blood Pressure : SBP

Diastolic Blood Pressure : DBP

120/80 140/90

JNC-VI-VII WHO-ISH
2 2 120/80
140/90 mmHg systolic
diastolic
130/80



1: Classification and management of blood pressure for adults

BP
Classification
Normal
Prehypertension
Stage 1
Hypertension

SBP*
mmHg
<120
120-139
140-159

DBP*
mmHg
and <80
or 80-89
or 90-99

Lifestyle
Modification
Encourage
Yes
Yes

Stage 2
Hypertension

160

or 100

Yes

Initial Drug Therapy

Without Compelling
With Compelling
Indication
Indication
No antihypertensive drug indicated. Drug(s) for compelling
indications.
Thiazide-type diuretics for most.
Drug(s) for the compelMay consider ACEI, ARB, BB,
ling indications. Other
CCB or combination.
antihypertensive drugs
(diuretics, ACEI, ARB,
Two-drug combination for most
(usually thiazide-type diuretic and BB, CCB) as needed.
ACEI or ARB or BB or CCB).

DBP, diastolic blood pressure; SBP, systolic blood pressure

Drug abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; CCB,
calcium channel blocker
* Treatment determined by highest BP category.

136

3-4A

1. Primary hypertension
Primary hypertension Essential hypertension Idiopathic hypertension
90

2. Secondary hypertension
Secondary hypertension 10

(chronic renal disease)

aldosterone
catecholamines
pheochromocytoma
(coarctation of the aorta)

3-4B

(pathophysiology)

hydraulic equation arterial blood pressure (BP)

cardiac output (CO) precapillary arteriole (peripheral vascular
resistance, PVR)
BP = CO x PVR
moment-to-moment regulation cardiac output
peripheral vascular resistance 4 arteriole,
postcapillary venule (capacitance vessel)
intravascular fluid baroreflex humoral
mechanism renin-angiotensin-aldosterone system

vascular resistance nitric oxide
endothelin-1

3-4

137

1:

Primary hypertension

1. Neural components
Neural components
Postural baroreflex
carotid baroreceptor
baroreceptor central sympathetic

baroreceptor sympathetic
baroreceptor vascular resistance
( ) (
)

2. Humoral abnormalities
Humoral abnormalities renin-angiotensin-aldosterone system
(RAAS), natriuretic peptide, hyperinsulinemia
renin-angiotensin-aldosterone system (RAAS) angiotensin II

aldosterone sympathetic

natriuretic peptide

138

Hyperinsulinemia
sympathomimetic vascular smooth muscle hypertrophy

3. Vascular endothelial mechanism

Vascular endothelial mechanism (endothelium)

prostacyclin, bradykinin, nitric oxide
angiotensin II, endothelin I

4. (calcium) (potassium) (sodium)

(calcium)

(potassium)
(sodium)
cardiac output

2: Identifiable causes of hypertension

3-4C

Sleep apnea
Drug-induced or related causes
Chronic kidney disease
Primary aldosteronism
Renovascular disease
Chronic steroid therapy and Cushings syndrome
Pheochromocytoma
Coarctation of the aorta
Thyroid or parathyroid disease

Primary hypertension the

silent killer

Secondary hypertension

3-4

3-4D

139

Benefits of lowering BP

aorta, ,

heart
attack, stroke,

3-4E

3
1. Office BP measurement
2 White-Coat hypertension

2. Ambulatory BP monitoring 24
White-Coat
hypertension
3. Self-Measurement of BP
antihypertensive therapy
White-Coat hypertension

Sphygmomanometer

30



5

140

3-4F

(Patient evaluation)

(Patient evaluation)
1. other cardiovascular risk factors concomitant disorders

2.
3. target organ damage cardiovascular disease risk
3: Cardiovascular risk factors and Target Organ Damage
Cardiovascular risk factors
Major Risk Factors
Hypertension*
Cigarette smoking
Obesity* (body mass index 30 kg/m2)
Physical inactivity
Dyslipidemia*
Diabetes mellitus*
Microalbuminuria or estimated GFR <60 mL/min
Age (older than 55 for men, 65 for women)
Family history of premature cardiovascular disease
(men under age 55 or women under age 65)
GFR, glomerular filtration rate.
* Components of the metabolic syndrome

3-4G

Target Organ Damage

Heart
Left ventricular hypertrophy
Angina or prior myocardial infarction
Prior coronary revascularization
Heart failure
Brain
Stroke or transient ischemic attack
Chronic kidney disease
Peripheral arterial disease
Retinopathy
GFR, glomerular filtration rate

(Target organ damage)

(heart)
(left ventricular hypertrophy) (heart failure)
(prior coronary
revascularization) (prior myocardial infarction)
(fibrosis)
(brain)
(stroke or transient ischemic attack)

3-4

141

(kidneys)

albumin 2+
BUN creatinine
(eyes)

(retina)

( )

3-4H

(atherosclerosis)
Electrocardiogram
potassium
Urinalysis
1+
glomerulonephritis
Blood glucose atherosclerosis
Serum potassium potassium
aldosteronism potassium
potassium
Creatinine Glomerular filtration rate (GFR)
Lipid profile HDL, LDL, cholesterol triglycerides
atherosclerosis

3-4I

(Goals of Therapy)

cardiovascular disease renal

disease
140/90 mmHg
cardiovascular disease
130/80 mmHg 50
SBP
DBP
2

142

3-4J

(Lifestyle modification)

fiber

dynamic


(Relaxation therapy)

prehypertension

4: Lifestyle Modifications To Prevent and Manage Hypertension*

Approximate SBP Reduction

(Range)
520 mmHg/10 kg weight loss

Modification
Weight reduction

Recommendation
Maintain normal body weight (body mass index
18.524.9 kg/m2).

Adopt DASH eating plan

Consume a diet rich in fruits, vegetables, and

lowfat dairy products with a reduced content
of saturated and total fat.

814 mmHg

Dietary sodium reduction

Reduce dietary sodium intake to no more than

100 mmol per day (2.4 g sodium or 6 g
sodium chloride).
Engage in regular aerobic physical activity such
as brisk walking (at least 30 min per day,
most days of the week).

28 mmHg

Limit consumption to no more than 2 drinks (1

oz or 30 mL ethanol; e.g., 24 oz beer, 10 oz
wine, or 3 oz 80-proof whiskey) per day in
most men and to no more than 1 drink per
day in women and lighter weight persons.

24 mmHg

Physical activity

Moderation of alcohol consumption

49 mmHg

DASH indicates Dietary Approaches to Stop Hypertension.

* For overall cardiovascular risk reduction, stop smoking.
The effects of implementing these modifications are dose- and time-dependent and could be greater for some individuals.

3-4

3-4K

143

2: Algorithm for treatment of hypertension.

3-4L

stage 2 hypertension
serum potassium creatinine 1-2
3-6
heart failure

144

3-4M

Special Consideration

Ischemic Heart Disease
stable angina pectoris Beta-blockers long-acting
CCBs unstable angina myocardial infarction Beta-blockers
ACEIs postmyocardial infarction ACEIs, BBs, aldosterone
antagonists
Heart failure ventricular dysfunction ACEIs BBs
end-stage heart disease ACEIs, BBs, ARBs aldosterone
blockers loop diuretics
Diabetic Hypertension
130/80 mmHg 2
Thiazide diuretics, BBs, ACEIs, ARBs CCBs
CVD stroke ACEIs ARBs
diabetic nephropathy albuminuria
Chronic Kidney Disease BP
130/80 mmHg ACEIs ARBs
progression diabetic renal disease nondiabetic renal disease
serum Cr 35% hyperkalemia
Cerebrovascular Disease acute stroke BP 160/100 mmHg
recurrent stroke rate ACEI thiazidetype diuretic

o Thaiazide-type diuretic slowing demineralization in osteoporosis
gout hyponatremia
o Beta blockers atrial tachyarrhythmias/fibrillation, migraine,
thyrotoxicosis(short term), essential tremor perioperative hypertension
asthma, reactive airways disease 2nd or 3rd degree heart block
o CCBs Raynauds syndrome arrhythmias
o Alpha-blockers prostatism
o ACEIs ARBs ACEI
angioedema
o Aldosterone antagonists potassium-sparing diuretics serum
potassium

3-4

3-4N

145

1. Diuretics


1.1 Thiazide-type diuretics
1.2 Loop diuretics
1.3 Potassium-sparing diuretics aldosterone antagonists
2. Beta blockers competitive catecholamines -adrenoceptors
catecholamines Beta agonists receptor heart rate, venous return,
cardiac output
2.1 Selective beta1-adrenergic blocking agents
2.2 Non- selective beta-adrenergic blocking agents
2.3 Alpha,beta-adrenergic blocking agents
2.4 Beta-adrenergic blocking agents with ISA
3. Angiotensin converting enzyme (ACE) inhibitors Angiotensin converting
enzyme (ACE) Angiotensin II
ACE inhibitors
Angiotensin II aldosterone Angiotensin II aldosterone
sodium potassium
4. Angiotensin II Receptor Blockers (ARBS) Angiotensin II
aldosterone
bradykinin ACEIs

5. Calcium channel blockers (CCBs)

, , sinus node pacemaker rate
atrioventricular velocity
6. Alpha blockers Alpha nerve impulses 1receptor presynaptic 2-receptor peripheral vasodilation
7. Nervous system inhibitors
7.1 Centrally acting alpha2-adrenergic agonists methyldopa, clonidine
7.2 Adrenergic Neuron-Blocking Agents reserpine
8. Vasodilators

146

5: Oral Antihypertensive Drugs

Class

Drug (Trade Name)

Usual Dose
Range, mg/d

Usual Daily
Frequency*

Chlorothiazide (Diuril)
Chlorthalidone (generic)
Hydrochlorothiazide (Microzide, HydroDIURIL)
Polythiazide (Renese)
Indapamide (Lozol)
Metolazone (Mykrox)
Metolazone (Zaroxolyn)

125500
12.525
12.550
24
1.252.5
0.51.0
2.55

12
1
1
1
1
1
1

Bumetanide (Bumex)
Furosemide (Lasix)
Torsemide (Demadex)

0.52
2080
2.510

2
2
1

Amiloride (Midamor)
Triamterene (Dyrenium)

510
50100

12
12

Eplerenone (Inspra)
Spironolactone (Aldactone)

50100
2550

1
1

Atenolol (Tenormin)
Betaxolol (Kerlone)
Bisoprolol (Zebeta)
Metoprolol (Lopressor)
Metoprolol extended release (Toprol XL)
Nadolol (Corgard)
Propranolol (Inderal)
Propranolol long-acting (Inderal LA)
Timolol (Blocadren)

25100
520
2.510
50100
50100
40120
40160
60180
2040

1
1
1
12
1
1
2
1
2

Acebutolol (Sectral)
Penbutolol (Levatol)
Pindolol (generic)

200800
1040
1040

2
1
2

Carvedilol (Coreg)
Labetalol (Normodyne, Trandate)

12.550
200800

2
2

Benazepril (Lotensin)
Captopril (Capoten)
Enalapril (Vasotec)
Fosinopril (Monopril)
Lisinopril (Prinivil, Zestril)
Moexipril (Univasc)
Perindopril (Aceon)
Quinapril (Accupril)
Ramipril (Altace)
Trandolapril (Mavik)

1040
25100
540
1040
1040
7.530
48
1080
2.520
14

1
2
12
1
1
1
1
1
1
1

Candesartan (Atacand)
Eprosartan (Teveten)
Irbesartan (Avapro)
Losartan (Cozaar)
Olmesartan (Benicar)
Telmisartan (Micardis)
Valsartan (Diovan)

832
400800
150300
25100
2040
2080
80320

1
12
1
12
1
1
12

Diltiazem extended release (Cardizem CD,

Dilacor XR, Tiazac)
Diltiazem extended release (Cardizem LA)
Verapamil immediate release (Calan, Isoptin)
Verapamil long acting (Calan SR, Isoptin SR)
Verapamil (Coer, Covera HS, Verelan PM)

180420

120540
80320
120480
120360

1
2
12
1

Amlodipine (Norvasc)
Felodipine (Plendil)
Isradipine (Dynacirc CR)
Nicardipine sustained release (Cardene SR)
Nifedipine long-acting (Adalat CC, Procardia XL)
Nisoldipine (Sular)

2.510
2.520
2.510
60120
3060
1040

1
1
2
2
1
1

Thiazide diuretics

Loop diuretics

Potassium-sparing diuretics

Aldosterone receptor blockers

BBs

BBs with intrinsic sympathomimetic

activity

Combined -blockers and BBs

ACEIs

Angiotensin II antagonists

CCBsNondihydropyridines

CCBsDihydropyridines

Continued next page

3-4

147

Class
1 blockers

Drug (Trade Name)

Doxazosin (Cardura)
Prazosin (Minipress)
Terazosin (Hytrin)

Central 2 agonists and other centrally

acting drugs

Clonidine (Catapres)
Clonidine patch (Catapres-TTS)
Methyldopa (Aldomet)
Reserpine (generic)
Guanfacine (Tenex)

Usual Dose
Range, mg/d

Usual Daily
Frequency*

116
220
120

1
23
12

0.10.8
0.10.3
2501 000
0.10.25
0.52

2
1 weekly
2
1
1

Direct vasodilators
Hydralazine (Apresoline)
25100
2
Minoxidil (Loniten)
2.580
12
Source: Physicians Desk Reference. 57th ed. Montvale, NJ: Thomson PDR; 2003.
* In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval (trough
effect). BP should be measured just prior to dosing to determine if satisfactory BP control is obtained. Accordingly, an
increase in dosage or frequency may need to be considered. These dosages may vary from those listed in the Physicians
Desk Reference, 57th ed.
Available now or soon to become available in generic preparations.

3-4O

3-4P

148

3-5

Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac
disorder that impairs the ability of the ventricle to fill with or eject blood. As a consequence the heart fails to
pump sufficient blood to meet the bodys metabolic needs. The cardinal manifestations of HF are dyspnea
(breathlessness) and fatigue which may limit exercise tolerance, and fluid retention which may lead to
pulmonary congestion and peripheral edema.
heart failure (HF)

(cardiac output <
metabolic needs) HF (dyspnea)
fluid retention

3-5A

Classification and Etiology of Heart Failure

HF
1
1: Heart Failure

HF
Cardiac Output
High output failure
Low output failure
Site of Abnormality Right ventricular failure
Left ventricular failure
Biventricular failure
Ejection Fraction
Systolic dysfunction (EF <40%)
Diastolic dysfunction (EF : ~60-70%)
Pior Ischemic
Ischemic Failure
Non-ischemic Failure

Blood supply ()
Cardiac Output supply ()
HTN, AMI
Pulmonary arterial hypertention

Cardiac

X High output failure

( HF =
)
Blood supply Hyperthyroidism,
Anemia underlying disease

3-5

149

Y Low output failure

Isolated right ventricular dysfunction

Afterload

Left ventricular dysfunction HF

HF
HTN AMI

Biventricular failure Myocardial Infarction

HF Biventricular failure
Ejection Fraction
Ejection Fraction
EF = EDV ESV EF = Ejection fraction =
EDV
EDV = End diastolic volume = (max)
EF =
SV
ESV = End systolic volume = (min)
EDV
SV =Stroke volume= 1
*** EF 60-70% (EF=0.6-0.7)

Systolic Dysfunction
EF
40%

Low output

Diastolic Dysfunction EF




Low output

150

1: Cardiac output Normal heart, Systolic dysfunction Diastolic dysfunction

HF
(Chronic coronary ischemia)
(Myocardial infarction) Ischemic heart failure HF
( Persistent arrhythmia post Streptococcal rheumatic heart disease) Non- Ischemic heart
failure
HF Low output left ventricular systolic dysfunction
Coronary artery disease ( Ischemic heart failure)

**** Acute Myocardial Infarction

(muscle mass) systolic dysfunction
AMI
Remodeling HF
/
AMI systole diastole

3-5

3-5B

151

Clinical Manifestation of Heart Failure

Low output ( High output

)
Sign & Symptom 2
(Congestion)
(
)



2: Sign & Symptom Heart Failure
Symptoms (Subjective)
Signs (Objective)
Right ventricular dysfunction
Abdominal pain
Peripheral edema
Anorexia
Jugular venous distention (Neck vein distension)
Nausea
Hepatojugular reflux
Bloating
Hepatomegaly
Constipation
Ascites
Left ventricular dysfunction
Dyspnea on exertion (DOE)
Bibasilar rales
Paroxymal nocturnal dyspnea (PND)
Pulmonary edema
Orthopnea
S3 gallop rhythm
Pleural effusion
Tachypnea (SOB)
Reflux tachycardia
Cough
Hemoptysis
Nonspecific finding ( Left Right ventricular dysfunction)
Exercise intolerance
Tachycardia
Fatigue
Pallor
Weakness
Cyanosis of digits
Nocturia
Cardiomogaly
CNS symptoms

left ventricular dysfunction 3

152

3: Classification of Left Ventricular Dysfunction

Type of Failure
Characteristics
Low output, systolic dysfunction LV
(dilated cardiomyopathy) (60h (dilated LV)
70% of case)
h EDV SV (CO )
h EF 40%
h S3
Low output, diastolic dysfunction LV
(30-40% of case)
h
h
h (EDV )
h EF SV (CO )
h S4
High output, failure (uncommon) LV
h
h EDV
h SV & EF (CO )

Contributing factor
1.
2. Afterload

1.
2.
3. Preload

Metabolic Oxygen
demand

Key Findings Physical Examination Findings for Heart Failure

Sign
Elevated JVP
Hepatojugular
(abdominojugular) reflux
S3 gallop
Laterally displaced PMI
Pulmonary rales

Comments
Indicates right-sided HF; JVP greater than 10 cm (JVP visible with patient upright at 90
degrees) (Sens 10%, Spec 97%, PPV 2%)a
Positive if midabdominal pressure for 10 sec elevates JVP by greater than 4 cm for entire 10
sec; correlates with elevated left atrial pressure (LR = 8.0)
Most specific clinical finding, together with elevated JVP, in HF (Sens 31%, Spec 95%, PPV
61%)a; often missed because not listened for
Sens 66% for HF
Rales that do not clear with cough common in acute HF or decompensating chronic HF, but
uncommon in compensated chronic HF (Sens 13%, Spec 91%, PPV 27%)a
May be associated with stasis dermatitis (Sens 10%, Spec 93%, PPV 3%)a
PPP less than 25% correlates with low cardiac output

Peripheral edema
Narrow pulse pressure or
PPP
Tachycardia
Heart rate over 100 bpm (Sens 7%, Spec 99%, PPV 6%)a
a
LVEF less than 40% in 1306 patients with CAD undergoing cardiac catheterization

3-5

3-5C

153

Cardiac Workload

Heart Failure Workload

4

1. Preload
Venous return ( right atrium)
(EDV ) (stretch)
preload Frank-Starlings law (
muscle fiber
tension workload
)
venous vasodilatation venous return Preload
venous vasoconstriction ( HTN) Preload Aortic valve
ventricle ventricle
Preload
Systolic dysfunction
preload Diastolic dysfunction
EDV Preload EDV
Diastolic dysfunction
preload compensatory ?
CO preload Stroke volume
CO (CO preload CO
) HF preload CO
() preload
CO
Cardiac Remodeling

2. Afterload
Afterload
(Systemic vascular resistance)
(Arterial Blood Pressure)
Afterload (Contractility)
HF
Hypertension, Atherosclerosis Aortic valve
Afterload HTN Systolic dysfunction Diastolic
dysfunction 75% HF HTN

154

3. Contractility
Inotropic state
Preload Afterload (Myocardial
fiber) Coronary artery disease (CAD), MI, Vascular heart disease
Non-selective -blocker
(block 1 = force)

(Cardiac hypertrophy) CO
CO

4. Heart Rate
Heart Rate workload Energy demand HF CO
reflex HR CO SV
(CO = HR x SV) HF workload
HR m (
Coronary )
Myocardial Infarction HR Arrhythmia

*** 4 ....
- Contractility Afterload Systolic Dysfunction (
)
- Preload Diastolic Dysfunction ( preload venous return
)
- Preload Afterload Contractility -
Heart Rate Arrhythmia

3-5

3-5D

155

Compensatory Mechanism in Heart Failure

Cardiac Output
(workload)

1. Sympathetic Nervous System Contractility, Heart Rate (Tachycardia)

Cardiac Output Sympathetic
Catecholamines NE Heart Rate Contractility, Vasoconstriction
Renal Blood Flow NE Inotropic (Increase Contractility)
Chronotropic (Increase Heart Rate) CO
Contractility HR ( Workload)
Oxygen
Stroke
Volume Cardiac Output
NE Vasoconstriction
(Non-vital organ) Vital organ ( CNS,
myocardium ) Vital organ Blood supply
Vasoconstriction Preload Afterload
(Renal perfusion) Rennin-Angiotensin-Aldosterone System (RAAS)
(Cardiac Remodeling)

2. Rennin-Angiotensin-Aldosterone System (RAAS)

Cardiac Output NE
Renal perfusion
Renal vascular resistance
(Ineffective blood volume)
rennin Angiotensinogen Angiotensin I Angiotensin-Converting enzyme
Angiotensin I Angiotensin II 2

156

2: Renin Angiotensin Aldosterone System

Angiotensin II Renin Angiotensin Aldosterone System 3

AT1 receptor
Angiotensin II
Afterload
Angiotensin II Aldosterone
Preload

Angiotensin II Pro-onco genes

(Cardiac Remodeling)

3. Vasoconstriction
Vasoconstriction HF

Vasoconstriction Norepinephrine, Angiotensin II, Endothelin-I
Arginine Vasopressin
vasoconstriction vascular
resistance Cardiac Output Compensatory
Mechanism Afterload

3-5

157

4. Cardiac Remodeling Neurohormonal mediators

HF Cardiac Remodeling
Cardiac remodeling
(Ventricular Hypertrophy) (Loss of myocyte)
Interstitial fibrosis
4: Ventricular Hypertrophy
Type

Concentric hypertrophy Hypertension

Pressure overload

Eccentric hypertrophy

Post Myocardial Infarction

Systolic dysfunction

(Ventricular wall thickness)

Diastolic failure


Systolic failure

Ventricular Hypertrophy 4 1 2

3
ventricular hypertrophy
cardiac remodeling ,
Acute Myocardial Infarction, (Myocarditis),
Cardiomyopathy
Ventricular Hypertrophy
Ventricular Hypertrophy (Fibrotic) Cardiac
Remodeling

158

3-5E

Classification of Heart Failure

5: NYHA functional classification

Class
Description
I
Asymptomatic

II

Mild

III

Moderate

IV

Severe

Examples/comments
No limitation during ordinary physical activity; does not cause undue fatigue,
dyspnea, palpitation, or anginal pain
Slight limitation of physical activity; ordinary physical activity results in fatigue,
palpitation, dyspnea, or anginal pain
Marked limitation of physical activity; patients are usually asymptomatic at rest,
but less-than-ordinary activity causes symptoms
Inability to carry on any physical activity without discomfort; symptoms may be
present even at rest; with any physical activity, discomfort is increased

6: ACC/AHA stages of heart failure

Grade
Description
A
High risk for HF, but
asymptomatic and no SHD
B
SHD but asymptomatic

Examples/comments
Systemic hypertension, CAD, diabetes, prior rheumatic fever, history of alcohol
abuse or cardiotoxic drug abuse, family history of cardiomyopathy
Prior MI; LV hypertrophy, fibrosis, dilation, or hypocontractility; asymptomatic
valvular heart disease
SHD and prior or current
Dyspnea or fatigue caused by LV systolic dysfunction; may be asymptomatic, if
symptoms of HF
receiving treatment for prior symptoms of HF
Refractory HF with symptoms at Marked symptoms of HF at rest despite maximum medical therapy, frequently
rest; needs specialized
or currently hospitalized, requires continuous IV or mechanical support,
interventions
awaiting heart transplant, or in a hospice setting

C
D

ACC, American College of Cardiology; AHA, American Heart Association; CAD, coronary artery disease; HF, heart failure; IV, intravenous;
LV, left ventricular; MI, myocardial infarction; NYHA, New York Heart Association; SHD, structural heart disease.

3-5F

SOB, PND, Exercise intolerance, etc.

HF NYHA Stage I Stage II
(Slow progression)
(Decrease morbidity and mortality rate)

3-5G

(underlying cause)
(constrictive pericarditis)

3-5

159

(precipitating factors)

(fluid overload)
(decrease workload)
o (limit activity)

(maintain activity)
o preload
fowler
blood volume
preload
shift

o after load


o Heart rate Arrhythmias Ischemias Metoprolol,
Bisoprolol ( partialty selective 1-blockers) Carvediol ( mixed 1 and
nonselective -blocker) (Stable heart failure)
(Contractility) inotropic drugs
Digoxin, Milinone, Dopamine, Dobutamine, etc
(Sudden death)
Ventricular fibrillation
Amiodarone Arrhythmias
: 3

4

3-5H

Diastolic Heart Failure

Diastolic heart failure

Systolic heart failure ACEIs HF ARBs, Nitrates + Hydralazine
ACEIs 1-blockers

Ca++ channel blocker

Heart rate Ventricle Ventricle
Ca++ channel blocker Diastolic heart failure Long-acting dihydropyridine
Amlodipine

160

Diastolic heart failure Ventricular contractility

Positive inotropic drugs Digoxin Diastolic heart failure

3: Guideline Heart Failure NYHA

3-5

161

7: Commonly Used Disease-Modifying Oral Drugs for Heart Failure

Drug
Initial dose
Maximum dose
ACE inhibitors
Captopril
6.25-12.5 mg 3 times a day 100 mg 3 times a day
Enalapril
2.5 mg 2 times a day
20 mg 2 times a day
Fosinopril
5-10 mg 1 time a day
40 mg 1 time a day
Lisinopril
2.5-5 mg 1 time a day
20-40 mg 1 time a day
Quinapril
5 mg 2 times a day
40 mg 2 times a day
Ramipril
1.25-2.5 mg 1-2 times a day 5 mg 2 times a day
Beta-blockers
Bisoprolol
1.25 mg 1 time a day
10 mg 1 time a day
Carvedilol
3.125 mg 2 times a day
25 mg 2 times a day
(weight of 85 kg or
less)
50 mg 2 times a day
(weight of more than
85 kg)
Metoprolol tartrate
6.25 mg 2 times a day
75 mg 2 times a day
Metoprolol DR/XL
12.5-25 mg 1 time a day
200 mg 1 time a day
Aldosterone antagonist
Spironolactone
25 mg a day
25 mg 2 times a day

Comment
Monitor serum K and creatinine levels with all ACE
inhibitors.
Some heart failure experts prefer to use lisinopril 2
times a day because of its 11-hour half life.

Up-titrate at 2- to 4-week intervals in wellcompensated patients.

Closely monitor for fluid overload.
Give carvedilol with food to reduce orthostatic
hypotension.

Monitor K and creatinine levels.

Decrease dose to 12.5 mg every day if potassium is
more than 5.5.
Moderate evidence for disease modification.

ACE, angiotensin-converting enzyme; K, potassium; kg, kilogram(s); mg, milligram(s)

8: Commonly Used Symptom-Modifying Oral Drugs for Heart Failure

Drug
Initial dose
Maximum dose
Loop diuretics
Bumetanide
0.5-1 mg 1-2 times a day
10 mg a day
Furosemide
20-40 mg 1-2 times a day 200 mg 2 times a day
Torsemide
10-20 mg 1-2 times a day 200 mg a day

Thiazide diuretic
Hydrochlorothiazide 12.5-25 mg 1 time a day
Potassium-sparing diuretics
Amiloride
2.5 mg 1 time a day
Spironolactone

25 mg a day

Comment
Titrate to target weight.
Monitor serum K and creatinine levels.
If serum K less than 4 mEq/L, add K supplement or
K-sparing diuretic.
Occasionally patients will require doses greater than
the recommended maximum dose.

50 mg 1 time a day

Used to supplement loop diuretic.

20 mg 1 time a day

Combined use with a loop diuretic decreases the

risk of hypokalemia.
Use only with loop diuretic; monitor serum K and
creatinine levels. Higher doses used primarily in
patients with low K levels.

25-50 mg 2 times a day

Miscellaneous agents
Digoxin
0.125-0.25 mg 1 time a day 0.125-0.25 mg 1 time a day No titration except to avoid toxic effects.
Hydralazine
10-25 mg 4 times a day
100 mg 4 times a day
Take with food.
Isosorbide dinitrate
10 mg 3 times a day
60 mg 3 times a day
May exacerbate glaucoma.
K, potassium; L, liter(s); mEq, milliequivalent(s); mg, milligram(s).

162

9: Major Comorbidities that Impact HF Management

Disorder
Comments
Anemia
Chronic anemia (mean Hb 12 g/dL) is common in moderate to severe HF; erythropoietin and iron
therapy may improve symptoms
Arrhythmia, ventricular Amiodarone reduces mortality in patients with frequent VT but may be poorly tolerated; consider an
ICD in selected patients
Arthritis
Both standard NSAIDs and COX-2 inhibitors worsen renal function and cause fluid retention
Asthma/COPD
BBs are contraindicated in severe RAD; however, most COPD patients do not have RAD and are
candidates for BBs
AF
Convert AF to sinus rhythm or control ventricular response; reduce thromboembolic risk with warfarin
unless contraindicated
CAD/ischemic heart
Consider revascularization; use BBs, prophylactic nitrates, and low-dose aspirin; avoid CCBs such as
disease
verapamil and diltiazem
Cognitive dysfunction
Reduced cardiac output vs cerebrovascular disease (eg, associated silent cerebral infarcts)
Diabetes
Optimize both glucose and blood pressure control; avoid metformin and thiazolidinediones in HF
patients
Dyslipidemia
Standard statin therapy; review risk factors (including drug interactions) for myopathy
Electrolyte disturbance Loop diuretics may induce hypokalemia and hypomagnesemia and require monitoring of electrolytes,
especially after a large diuresis
Erectile dysfunction
Sildenafil (Viagra) generally tolerated; don't use concurrently with a nitrate
Gout
Diuretics may exacerbate gout; gout may present atypically in HF; avoid NSAIDs; consider colchicine
and allopurinol
Hepatic dysfunction
ACEI prodrugs (eg, enalapril, ramipril) require close monitoring.
Hypertension
ACEIs, ARBs, BBs, and diuretics effective for both HF and hypertension
Peripheral vascular
Claudication may worsen with BB therapy. Consider coexisting renal artery stenosis and potential for
disease
worsening renal function with ACEI or ARB
Renal dysfunction
ACEI and BB use in mild-moderate renal failure (CrCl 30-60 mL/min/1.73 m2) requires close
monitoring; spironolactone is contraindicated
Thyroid disease
Hyper- or hypothyroidism can exacerbate or cause HF; consider possible amiodarone-induced thyroid
dysfunction
Urinary frequency
Diuretics less likely to be well tolerated; alpha-blockers may cause hypotension or fluid retention
ACEI, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; BB, beta-blocker; CAD, coronary artery
disease; CCB, calcium channel blocker; COX-2, cyclo-oxygenase-2; CrCl, creatinine clearance; COPD, chronic obstructive pulmonary disease; Cr,
(serum) creatinine; dL, deciliter(s); g, gram(s); HF, heart failure; Hb, hemoglobin; ICD, implantable cardioverter defibrillator; m2, square meter(s);
min, minute(s); mL, milliliter(s); NSAID, nonsteroidal anti-inflammatory drug; RAD, restrictive airways disease; VT, ventricular tachycardia.

10: ACEIs
Target Dosing
Generic Name
Brand Name
Initial Dose
Survival Benefit
Captopril
Capoten
6.25 mg tid
50 mg tid
Enalapril
Vasotec
2.5-5 mg bid
10 mg bid
Lisinopril
Zestril, Prinivil
2.5-5 mg qd
20-40 mg bid
Quinapril
Accupril
10 mg bid
20-40 mg bid
Ramipril
Altace
1.25-2.5 mg bid
5 mg bid
Fosinopril
Monopril
5-10 mg qd
40 mg qd
Trandolapril
Mavik
0.5-1 mg qd
4 mg qd

Prodrug
No
Yes
No
Yes
Yes
Yes
Yes

Elimination
Renal
Renal
Renal
Renal
Renal
Renal/hepatic
Renal/hepatic

3-5

163

11: beta-blockers
Drug
b
Bisoprolol
Carvedilol b
Metoprolol succinate CR/XL b
a
b
c

Target Dose
Initial Dose a
1.25 mg qd
10 mg qd
3.125 mg bid
25 mg bid d
200 mg qd
12.5-25 mg qd c
Dose should be doubled approximately every 2 weeks or as tolerated by the patient until the highest tolerated or target dose is reached.
Regimens proven in large trials to reduce mortality.
In MERIT-HF, the majority of class II patients were given 25 mg/day, whereas the majority of class III patients were given 12.5 mg/day as their
starting dose.
Target dose for patients >85 mg bid.

12: loop diuretics

Usual daily dose (PO)
Ceiling dose*
Normal renal function
CLCR : 20-50 mL/min
CLCR : <20 mL/min
Bioavailability

Furosemide
20-160 mg/day

Bumetanide
0.5-4 mg/day

80-160 mg
160 mg
400 mg
10-100%
Average, 50%
Affected by food
Yes
Half-life
0.3-3.4 h
* Ceiling dose: single dose above which additional response is unlikely to be observed.

3-5I

Torsemide
10-80 mg/day

1-2 mg
2 mg
8-10 mg
80-90%

20-40 mg
40 mg
100 mg
80-100%

Yes
0.3-1.5 h

No
3-4 h

Systolic Heart Failure

4: Stages of Heart Failure and Treatment Options for Systolic Heart Failure.
Patients with stage A heart failure are at high risk for heart failure but do not have structural heart disease or symptoms of heart failure. This group
includes patients with hypertension, diabetes, coronary artery disease, previous exposure to cardiotoxic drugs, or a family history of cardiomyopathy.
Patients with stage B heart failure have structural heart disease but have no symptoms of heart failure. This group includes patients with left ventricular
hypertrophy, previous myocardial infarction, left ventricular systolic dysfunction, or valvular heart disease, all of whom would be considered to have New
York Heart Association (NYHA) class I symptoms. Patients with stage C heart failure have known structural heart disease and current or previous
symptoms of heart failure. Their symptoms may be classified as NYHA class I, II, III, or IV. Patients with stage D heart failure have refractory symptoms
of heart failure at rest despite maximal medical therapy, are hospitalized, and require specialized interventions or hospice care. All such patients would
be considered to have NYHA class IV symptoms. ACE denotes angiotensin-converting enzyme, ARB angiotensin-receptor blocker, and VAD ventricular
assist device.

164

3-6

3
Triglyceride (3 fatty acid + glycerol) TG
Adipose tissue
Cholesterol precursor bile acid, steroid hormone, cell membrane,
Moisture
Phospholipids cell membrane, emulsifier, cell signaling
3 form Lipoprotein (Lipid + Apolipoprotein)
Phospholipids, Free cholesterol, Apolipoprotein
Triglyceride Cholesteryl ester

1:

1: Classification and properties of plasma lipoproteins

Major lipid
Type of lipoprotein
Apolipoprotein
%TG %CH
Chylomicron (CM)
7% A-IV, B-48, C-I, C-II, C-III
84%
VLDL
19% B-100, C-I, C-III, E
51%
IDL (VLDL remnant)
30%
30% B-100, C-II, C-III, E
LDL
10%
50% B-100
HDL
3%
19% A-I A-II , C-I, C-II, C-III, E

Origin
Intestine
Liver
VLDL
VLDL
Liver + Intestine

Principle function
Transport of exogenous TG
Transport of endogenous TG
Precursor of LDL
CH transport
Reverse CH transport

3-6

3-6A

165

3
1. Exogenous pathway
Chylomicron
Diet () TG
CM
CM remnant
LIVER
TG, CH
Oxidation FFA (free fatty acid)
2. Endogenous pathway peripheral cell VLDL, LDL
LIVER
VLDL
IDL
LDL
Endocytosis Peripheral cell
HDL CH excess
3. Reverse cholesterol transport pathway cholesterol excess peripheral cell
HDL

2: Endocytosis cell

3-6B

Source of lipid

Source of lipid 2
Exogenous : Diet (TG, CH, PL) 1/3
Endogenous : (CH, TG) 2/3

(Endogenous)

166

Exogenous Pathway

Endogenous Pathway
LDL

Bile Acids

Dietary
Fat

Cholesterol

LIVER

Apo B-100
LDL Receptor

Endogenous

LDL
Receptor

Cholesterol

Intestine

Extrahepatic
Tissue

Dietary
Cholesterol
Remnant
Receptor

Chylomicrons

Apo E, CII, B-48

Remnants

Apo E, B-48

VLDL

Apo E, CII, B-100

Capillary

IDL

HDL

Apo E, B-100

Apo AI, AII

Capillary

Plasma
LCAT

LP Lipase

FFA

LP Lipase

FFA

3: Exogenous and Endogenous Pathway

3-6C

(Dyslipidemia)
Hypercholesterolemia CH LDL
Hypertriglyceridemia TG VLDL
Low HDL level HDL
3 Atherosclerosis 3
Lipid Triad / Atherogenic Dyslipidemia

3-6

3-6D

167

1. Fredrickson
2: Fredrickson (N=Normal)
Elevated plasma
Plasma Plasma
TYPE
NAME
component
CH
TG
uu
I
Hyperchylomicronemia
Chylomicron
N/u

Drug treatment
none

uu

N/u

Hyperbeta and
LDL + VLDL
Hyperprebetalipoproteinemia

uu

Hyper Remnant lipoproteinemia

Hyperprebetalipoproteinemia
Mixed lipidemia

uu

HMG CoA reductase

inhibitors
HMG CoA reductase
inhibitors, Fibrate,
nicotinic acid
Fibrate

N/u

uu

uu

Fibrate
none

IIa

Hyperdysbetalipoproteinemia

IIb

III
IV
V

Plasma

LDL

Floating LDL
VLDL
Chylomicron + VLDL

type IIa, IIb, IV

Sign of Hyperlipoproteinemias : Type II Tendinous xanthoma (), Eyelid juvenillis (
), Eyelid xanthelasma ()

2.
3: (Genotype)
Disorder
Manifestation
Single drug
Drug combination
Primary chylomicronemia
Chylomicron VLDL increased Dietary management
Niacin+Fibrate
(familial lipoproteinemia
Lipase or cofactor deficiency)
Familial Hypertriglyceridemia
-VLDL & Chylomicrons increased Niacin, Fibrate
Niacin, Fibrate
- severe
-VLDL increased; Chylomicrons Niacin, Fibrate
- moderate
may be increased
Familial combined
VLDL increased
Niacin, Fibrate
hyperlipoproteinemia
LDL increased
Niacin, reductase inhibitor, resin Niacin + resin, reductase inhibitor
Niacin + resin, reductase inhibitor
VLDL, LDL increased
Niacin, reductase inhibitor
Familial dysbetalipoproteinemia VLDL remnants, Chylomicron Fibrate, Niacin
Fibrate + Niacin
remnants increased
Niacin + reductase inhibitor
Familial hypercholesterolemia
-LDL increased
-Resin, reductase inhibitor, niacin - 2 or 3 of the individual drugs
- Heterozygous
-Niacin,
Atorvastatin
- Resin+Niacin+reductase inhibitor
-LDL
increased
- Homozygous
Lp(a) hyperlipoproteinemia
Lp(a) increased
Niacin

168

3-6E

Primary Dyslipidemia Polygenic

hypercholesterolemia, Familial combined hyperlipidemia, Familial hypercholesterolemia
Secondary Dyslipidemia
TG , , , Thiazide,
CH Hypothyroidism, Nephrotic syndrome
HDL , , , -Blocker
Dietary Dyslipidemia CH
(Coronary heart disease; CHD)

LDL CHD LDL

NCEP ATP III LDL 100 mg/dl
4: NCEP ATP III
Classification
TC (mg/dl)
Optimal / Normal
<200
Near of above optimal
Borderline high
200-239
High
240
Very high
Low
-

LDL-C (mg/dl)
<100
100-129
130-159
160-189
190
-

TG (mg/dl)
<150
150-199
200-499
500
-

HDL-C (mg/dl)
60
<40

LDL
Total cholesterol = LDL + HDL + VLDL
LDL
= Total cholesterol (HDL + VLDL)
= Total cholesterol (HDL + TG/5)
TG <400 mg/dl 9-12 . ( TG)

3-6F

NCEP ATP III 3 LDL (primary goal), TG, HDL

Metabolic syndrome (x) 5
Abdominal obesity >36 , >32
Blood pressure 130/85 mmHg
Fasting Glucose 110 mg/dl
TG 150 mg/dl
HDL male < 40 mg/dl female < 50 mg/dl

3-6

3-6G

169

CHD

CHD (Three risk categories for CHD) 3

1. (Established CHD & CHD risk equivalents) CHD
CHD Transient Ischemic Attack, Stroke, Peripheral
Vascular Disease, Abdominal Aortic Aneurism, , 10-year risk for CHD > 20%
LDL LDL 100 mg/dl
2. (No CHD + multiple 2 RFs) CHD
CHD (risk factor) 2 LDL 130
mg/dl
3. (No CHD + 0-1 RF) CHD
CHD (risk factor) 0-1 LDL 160 mg/dl

Risk factors
CHD ( risk factor for CHD Categories
Positive +1 Negative -1 factors Categories
)
5: CHD
Positive factor (+)
1. : 45 55
2. () CHD
55 65
3.
4. (140/90 mmHg )
5. Low HDL-C (<40 mg/dl)

3-6H

Negative factor (-)

1. High HDL-C ( 60 mg/dl)

CHD

CHD 10 (10 year risk for CHD)

Categories 10-year risk for CHD
Framingham calculation
Cat 3 0-1 risk factor 10-year risk risk factor 2
10-year risk

170

Lipid Management in Adults Algorithm Risk Calculator

4: Lipid Management in Adults Algorithm Risk Calculator

3-6

3-6I

171

Categories

1. LDL-C GOAL (Cholesterol)

Cat 1
Cat 2

Cat 3

LDL-C Goal Non-HDL

Risk levels
(mg/dl)
(mg/dl)
<130
CHD / CHD risk equivalents
<100
(<70)

LDL-C level
to
Start TLC
100

LDL-C level to
Drug therapy
100

Re-evaluate
(
LDL-C Goal)
1 year

1 year
1 year

No CHD + 2 RFs
10-year CHD risk 10-20%
10-year CHD risk < 10%

<130
<130

<160
<160

130
130

130
160

No CHD + 0-1 RF

<160

<190

160

190

130-159
<130

1 year
5 year

(Primary target) LDL-C (Cholesterol)

Categories Triglyceride 200-499 mg/dl atherosclerosis
Non-HDL (LDL+VLDL)

(Therapeutic Lifestyle Change, TLC)

NCEP ATP III
o 7 Cholesterol
200 .
o sterols 2
10-25 LDL
o
o
()

2. TG GOAL (Triglyceride)
TG Levels
Borderline High (TG = 150-199 mg/dl)
High (TG = 200-499 mg/dl)

Very High (TG 500 mg/dl)

Goal of therapy
Treatment
TG < 150 mg/dl
Life habit changes (TLC)
Achieve Non-HDL goal ( TLC + Drug Dose
Non-HDL )
LDL + Fibrates or Niacin
Non-HDL (LDL + VLDL)
TG TLC + Drug TG Fibrates
Acute pancreatitis
or Niacin + very low fat diet

172

3. HDL-C GOAL
HDL 40 mg/dl HDL TLC
HDL HDL Niacin side
effect CETP inhibitor Torcetrapib

3-6J

Cholesterol
- Bile-acid-binding Resins Bile acid ( CH )
CH CH CH
Bile acid
- Ezetimibe Cholesterol
Brush Border
Cholesterol VLDL
- HMG-Co A reductase inhibitors Efficacy
LDL & VLDL CH Statin LDL

- Nicotinic acid VLDL TG

Plasma lipoproteins
- Fibric acid derivatives TG
LDL ()
- Probucol Clearance LDL HDL

Nicotinic acid

GUT
- Bile acid
binding resins
- Ezetimibe

LIVER

VLDL

- HMG-CoA
reductase inhibitors
( Statin)

LDL

IDL

Probucol
Fibric acid derivatives

5: Site of action of lipid-lowering drugs

3-6

173

1.
Bile acid binding resins
resin Bile acid Bile acid
Bile acid CH CH
CH Ezetimibe
LDL Statin
TG VLDL Hypertriglyceridemia

Ezetimibe
CH Bile acid LDL
side effect
*** 2 LDL Statin Monotherapy LDL
Combination therapy Statin
dose Statin toxicity adverse effect Statin

HMG-CoA reductase inhibitors (Statin)

Enzyme CH HMG-CoA reductase CH
LDL CH LDL Catabolism
LDL VLDL LDL VLDL
CH
Nicotinic acid
VLDL lipoprotein lipase pathway TG
VLDL VLDL LDL
VLDL, LDL, TG, CH HDL Efficacy
Side effect
Fibric acid derivatives
Plasma lipoprotein VLDL, LDL HDL
VLDL LDL TG Hypertriglyceridemia
Drug combinations
Mixed hyperlipidemia side effect
Statin Fibric acid DI
Statins LDL Fibrates Nicotinic acid TG HDL

174

2. Adverse Effect and Drug interactions

Bile acid binding resins Drug interaction side
effect
Ezetimibe side effect side effect GI
HMG-CoA reductase inhibitors / Statin CYP 3A4 DI
Protein binding DI warfarin side effect
hepatitis check liver function test Monitor ALT 3
Stain Fibric acid derivative
Myopathy (Myalgia + Myositis + Rhabdomyolysis
)
Check Creatinine kinase 3 monitor
Nicotinic acid side effect Flushing ,
GI, hepatitis check
liver function test, Hyperglycemia
Gout hyperuricemia
Fibric acid derivatives side effect hepatitis
check liver function test DI Statin

3. Statin
LDL LDL % LDL
reduction % %
% LDL reduction =

LDL now LDL goal *100

LDL now

3-6

175

176

3-6K

(atherosclerosis)

cholesterol phospholipids
triglycerides
(celebrovascular disease)

(fatty streak) 6
LDL
macrophage LDL cholesterol cholesterol ester

LDL oxidized LDL macrophage (
) phagocytosis oxidized LDL macrophage foam
cell cholesterol cholesterol ester foam cell
growth factor macrophage

6: Stages of Atherosclerosis 3D E-Diagram

3-7

177

3-7

(Ischemic heart disease; IHD)

myocardial oxygen demand myocardial oxygen supply
(coronaryatherosclerosis)
(thromboembolism),
(inflammation of coronary artery) (coronary spasm)
atherosclerosis changes
(myocardial infarction)
nitrate, beta blockers calcium channel blockers

3-7A

(clinical manifestations)

(angina pectoris) (acute myocardial

infarction) (sudden death)
(congestive heart failure) (dysrhythmia) (valvular insufficiency) embolism
(dyspnea on exertion or fatigue)
4
1. Chronic stable angina (Exertional angina)
Chronic stable angina angina pectoris
1-3
100 3-5
2. Unstable angina pectoris
2-3 1-2 (angina
of recent onset) stable angina 10
nitroglycerine
(angina at rest)
stable angina pectoris unstable angina pectoris
unstable angina S3, S4 stable angina
pectoris
3. Acute myocardial infarction
Acute myocardial infarction

3-4

178

4. Prinzmetal's angina (Variant angina pectoris)

Prinzmetal's angina
Spasm of coronary artery EKG ST elevation
ventricular tachycardia ventricular fibrillation heart block

stable angina unstable angina
Stable angina, Unstable angina Coronary artery
Atherosclerosis Vasospastic angina Atherosclerosis

3-7B

S3, S4

(CBC)
cholesterol triglyceride HDL
cardiac enzyme
(electrocardiography) :
50
myocardial ischemia
ST segment depression / T wave inversion subendocardial
myocardial ischemia transmural ischemia ST segment elevation acute
myocardial injury

ambulatory dynamic ECG monitoring

24
ST segment silent ischemia

(exercise stress test)
(treadmill) (ergometer)

myocardial ischemia ST depression 1

55-60

3-7

179

echocardiography :
exercise test ischemia regional wall motion
abnormality wall motion exercise
exercise ischemia pharmacologic stress
dobutamine echocardiogram wall motion permanent
damage myocardial infarction echocardiogram
Radionuclide Scintigraphy :
exercise pharmacologic stress thallium 20130 Technitium isonitrile
sestamibi peak stress cold spot
(acute infarction area) ischemia
area myocardial perfusion scintigraphy radionuclide
ventriculography Technetium 99m Stannous Pyrophosphate hot spot
acute necrosis Radionuclide up take 2

unstable angina infarction

(cardio catheterization, coronary artheriography and left ventricular angiography)
X-ray

left ventricle stable angina
13 Q wave
(abnormal contraction of left ventricle)
angiogram invasive test
revascularization
non-exercise stress test :
oxygen demand
(dobutamine stress test) (pacemaker)
echocardiogram
exercise dipyridamole adenosine

ischemia

3-7C

Pathophysiology

ATP
Angina pectoris oxygen demand oxygen supply
artherosclerosis 50% 70%

180

chronic stable angina 80% vasospasm & thrombolytic occlusion 95%

CHD (coronary heart disease) collateral blood vessel

myocardial ischemia myocardial blood flow

Oxegen demand and supply

oxygen demand ( work load oxegen demand )
1. contractility (iontropic state)
myocardium fiber

2. heart rate
3. intramyocardial wall tension
ventricular chamber

oxygen supply
1. oxygen extraction 70-75%
80%
2. coronary blood flow coronary blood flow coronary
vascular resistance
adenosine, nitric oxide
3. oxygen availability, oxygen saturation, Hgb concentration

3-7D

CHD

coronary atherosclerosis, cerebrovascular disease, peripheral vascular disease

LDL TG

homocystaine
homocystaine stroke 4

2
HDL

3-7

181

40

3-7E

work load oxygen supple oxygen demand

3-7F

stable angina

1. Nitrates
nitrates
Short acting sublingual form buccal mucosa
2-3

o nitroglycerin sublingual : (angina pectoris)

0.3-0.6 mg 2-3 1-3
5
Nitroject 5 mg, 10 mg

o isosorbide dinitrate (sorbitrate sublingual) : Angitrit 5 mg, 10 mg, Hartsrb 5

mg , Isodil 5 mg 5
Spray Iso mack spray 1.25 mg/0.09 mL
Oral form
o Oral intermediate-acting nitrates isosorbide dinitrate : Isordil 10 mg, 30 mg,
Hartsorb 10 mg, 30 mg 30 duration
4-6 first pass metabolism
5-40 mg 4-6
24-48

o Oral long-acting nitroglycerine isosorbide dinitrate : Iso mack retard 20 mg, 40

mg 30 duration of action 8-21 2-3
/ sustained release isosorbide

o isosorbide mononitrate : Elantan 20 mg, Imdur 60 mg, Ismo-20

20 mg
Transdermal form reservoir
18-24 tolerance

182

12-16 / drug free interval tolerance

o Nitroderm TTS (nitroglycerine) 1 patch (25 mg 5 mg) 24 onset of
action 1
o Nitradise (nitroglycerine) 1 patch (16 mg 5 mg) 24
Nitro ointment 2 0.5-2.0 4
angina

reflex tachycardia heart
rate
nitrate tolerance

Dizziness, pre-syncope

0.16 mg 0.40, 0.64 mg



15-20

tolerance cross tolerance nitrate

10-12
beta blocker
angina attack
1 2
nitrate, , closed angle,
(hypotension), hypovolemia, ( intracranial
pressure) nitroglycerine myocardial infarction
adhesive amyl nitrite

2. Beta-adrenergic blocking agent

beta-blockers
Beta-adrenergic blocking agents (cardioselective activity)

o metoprolol (Bataloc ) 100 mg 50-150 mg oral bid

3-7

183

o atenolol (Tenormin ) long acting cardioselective blocker 5 0 mg, 100 mg

50-100 mg/day
non-cardioselective Beta-adrenergic blocking agents

o propranolol (Inderal ) 10 mg, 40 mg 10-20 mg oral tid-qid

480-640 mg/day

o nadolol (Corgard ) long acting nonselective beta blocker 40-240 mg/day

o timolol (Blocaden ) 5-20 mg oral bid

(Bradycardia)
(Hypotension)
(Fatigue)


(Sexual dysfunction)
(precaution and contraindication )
heart rate <50 /
heart block : AV block first degree
severe left ventricular failure
acute heart failure
vasospastic angina
, chronic obstructive pulmonary disease
beta-2-agonist salbutamol, terbutaline beta-1-blockers
cardioselective beta-2-agonist
receptor hypersensitivity
7-14 ischemic heart disease angina
attack, tachycardia, myocardial infarction 1-5
21 intrinsic sympathetic activity
extensive atheromatous vascular disease Raynaud's phenomenon
cardiac output beta-2-blocker beta blocker
intrinsic sympathetic action beta selective
beta blocker triglyceride LDL/HDL cholesterol
intrinsic sympathetic action pindolol, acebutalol, oxprenolol

184

3. calcium channel blockers

First generation
Nifedipine dihydropyridine
angina pectoris potent arteriolar
dilation 10-30 mg
3-4 20-45 aortic
stenosis, hypertrophic obstruction cardiomyopathy
heart block
o hypotension, , , , , dependent edema
o : Adalat cap 5 mg, 10 mg, Adalat retard tab 20 mg, Adalat CR
tab 30 mg, 60 mg
Verapamil diphenylalkylamine papaverine derivative AV node
heart rate supraventricular tachycardia
10 2-3 half-life 3-7
80-120 mg oral bid-qid left ventricular dysfunction negative inotropic
: Isoptin tab 40 mg, 80 mg, Isoptin amp 5 mg/2 mL, Isoptin SR tab
240 mg
Diltiazem benzothiazepine 30-60 mg oral qid 60-90 mg oral qid

o : Herbesser tab 30 mg, Herbesser 60 tab 60 mg, Herbesser

90 SR cap 90 mg, Herbesser R cap 100 mg
Second generation
2 (secondary generation calcium antagonists)
dihydropyridine (DHPS) coronary vasodilation, afterload blood flow
(myocardial contractility), myocardial oxygen demand, platelet aggregation half life
1 2 / elodipine, isradipine, nisaldipine, nicardipine,
nimodipine
Amlodipine
: AmLopine tab 5 mg, 10 mg, Norvasc tab 5 mg, 10 mg
Felodipine 2.5-5 mg 2-3 /
: Plendil exended release tab 2.5 mg, 5 mg, 10 mg, Felodipin Stada
Retard modifiled release tab 2.5 mg, 5 mg, 10 mg
Nicadipine inotropic action 20 mg 3 (coronary
spasm)
: Cardepine tab 10 mg, 20 mg, SR cap 40 mg, amp 2 mg/2 mL, 10
mg/10 mL

3-7

185

calcium channel blockers stable angina

beta blockers beta blockers beta
blockers monotherapy short acting dihydropyridine calcium
channel blockers reflex tachycardia

reflex
tachycardia

Peripheral edema
Gingival hyperplasia nifedipine

Bradycardia diltiazem/ verapamil
Constipation verapamil

diltiazem verapamil beta blockers AV
block heart failure verapamil beta blockers
SA node AV node
congestive heart failure
verapamil digitalis AV block SA
node AV node verapamil digitalis
digoxin
verapamil diltiazem
90 mmHg SA node AV node

verapamil diltiazem : ,heart failure

, sick sinus syndrome, AV block, atrial fibrillation, ventricular tachycardia, Wolff-ParkinsonWhite syndrome

verapamil sinus bradycardia, AV block, left ventricular

failure 60
quinidine idiopathic
hypertension subaortic stenosis
systolic left ventricular failure verapamil

186

1: Effects of Nitrates, Beta-blockers and Calcium Channel Blockers on Determinants of Cardiac Oxygen Supply and Demand
Determinant
Nitrates
Beta-blockers
Calcium Blockers
Heart rate

Contractility

Preload

Afterload

Collateral blood flow

4.

guideline first choice angina

Beta blocker chronic angina

Nitrate angina LV dysfunction
Calaium blocker angina blood pressure
Calaium blocker + Beta blocker tachycardia reflex sympathetic

5.
Antiplatelet agents
Aspirin 81-325 mg/day

o

o : Aspent enteric coated tab 300 mg, DS tab 600 mg, Bayer
Aspirin tab 500 mg , Anacin BD tab 81 mg, 325 mg
o : , , hypoprothrombinemia, vitamin K deficiency, bleeding
disorder, asthma
o : renal function
severe anemia anticoagulants

Clopidogrel (Plavix film coated tab 75mg) 75 mg/day

aspirin
o : , active bleeding peptic ulcer, intracranial hemorrhage
o : trauma, ,
ulcer, prolong bleeding time

Ticlopidine (Ticlid tab 250 mg) 250 mg/day

o : neutropenia, aplastic anemia
o : , neutropenia, thrombocytopenia,
, active bleeding disorders
3
o : neutrophil <1200/mm platelet count
< 80,000 /mm3
Lipid lowering therapy
CAD LDL cholesterol >130 mg/dL primary
target LDL < 100 mg/dL statins

3-7

187

ischemic event 30 simvastatin 5-80 mg , lovastatin 10-80 mg

, pravastatin 10-40 mg , fluvastatin 10-80 mg ,
atrovastatin 10-80 mg
Angiotensin converting enzyme inhibitor
CAD / LV systolic dysfunction
CAD other vascular disease (class IIa-level B)

6.

cholesterol






heart rate, blood pressure HDL, submaximal
workload, regression coronary atherosderasis
heart rate, blood pressure
myocardial dysfunction
(Percutaneous transluminal coronary angioplasty : PTCA)


ventricular function



bypass PTCA
unstable angina PTCA dissection
4-6
30
(stent) balloon
(direct atherectomy) (rotablator) laser
balloon
3 diffuse disease left maintrunk disease

188

Coronary artery bypass grafting (CABG)

CABG angina 80 mortality rate
1-2 CABG , PTCA ,
Significant obstruction left main coronary artery, Significant obstruction ( 70-75 cross
sectional area) all major arteries (triple vessel disease)
graft closure sphrenous vein grafts
10-15 1-2 / graft closure 50
10 internal mammary artery graft potency rate graft closure
10-15 10-15

3-7G

calcium blocker first choice nocturnal vasospastic angina antispasmodic

calcium blocker
long acting calcium blocker
max dose calcium blocker nitrate
beta blocker cardioselective non cardioselective

3-7H

Variant angina

Silent myocardial ischemia

cholesterol, hypertension
angina silent MI
beta blocker silent MI calcium blocker
aspirin, nitrate choice titrate dose

3-7I

Unstable angina (USA)

revascularization thrombus
ischemia
. second USA
Nitrate
o
o cardiac preload, coronary blood flow
Beta blocker
o nitrate
o calcium blocker + nitrate ischemia
Calcium channel blocker
o beta blocker AMI
beta blocker

3-7

189

Aspirin and Clopidogrel

o stable angina
Heparin
o UFH (unfracton heparin) thromboin inhibitor factor Xa inhibitor primary
antithrombin ACS (acute coronary syndrome) AMI
aspirin
o LMWHs (low molecular weight heparin) antithrombin , capillary permiabilitty
bleeding , thrombocytopenia , bioavailibility rebound
effect heparin
o aspirin heparin

190

3-8

(Acute Myocardial Infarction)

3-4

1:

3-8A

1. Atherosclerotic plaques
plaques

2. Plaques rupture
atherosclerotic plaques plaque
(Platelet aggregation)
3. Platelet aggregation
4. Vasospasm
thromboxane A2 (
)
Platelet vasospasm
spasm AMI
6
18-36

3-8

3-8B

191

unstable angina
30





S3, S4 gallop (crepitation)
20% AMI (silent)

3-8C

ergot trauma

3-8D

World Health Organization (WHO) 2 3

1. Symptom acute infarction
2. ECG criteria
Hyperacute stage
T wave
Acute stage
ST segment elevation
Inferior wall infarction
L 2, L 3, aVF
Anterior wall infarction
V 1-6
Anteroseptal wall infarction
V 1-4
Anterolateral wall infarction
L 1, aVL, V 1-6
Posterior wall infarction
mirror image anterior chest leads
Pathologic Q wave
24 leads

T-wave inversion
evolutionary change acute myocardial
infarction
3. Enzymatic criteria cardiac enzyme
creatinine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), white blood
cell (WBC) count, troponin

192

CK 3 isozyme BB, MM MB bans CK-MB

AMI 3-6
12-24 2-3
LDH 24-48 3-6
LDH
Troponin marker CK CK-MB
troponin LDH troponin peripheral circulation
troponin

3-8E

Complications

3 pump failure, arrhythmias, recurrent ischemia and

reinfarction
cardiac output perfusion pressure left ventricular dysfunction
compensatory mechanism (ventricular remodeling) oxygen demand oxygen supply

3-8F

acute myocardial infarction unstable angina

3
1. Prehospital phase hospital mortality ( sudden death serious arrhythmia)
50% myocardial infarction
emergency team cardiopulmonary resuscitation defibrillation
2. Hospital phase
o
o thrombolytic agent
myocardial oxygen demand oxygen supply
o acute myocardial infarction
3. Post hospital
o cardiac rehabilitation acute
myocardial infarction
o myocardial infarction (late mortality)
o myocardial infarction

3-8G

(Basic Treatment)

coronary care unit

ECG monitoring 24-48
Thrombolytic agents streptokinase, anistreplase, alteplase (t-PA), reteplase (r-PA)
tenecteplase (TNK) MI

3-8

193

30
plasminogen plasmin artherosclerotic plaque
coagulogram
75 ECG,
bleeding
: aortic dissection, acute pericarditis, internal bleeding, BP > 220/110 mmHg, recurrent
head trauma, CVA
: acute peptic ulcer, liver dysfunction, anticoagulant
antiplatelet and anticoagulant drugs aspirin, heparin low-molecular-weight heparin (LMWH)
thrombosis LMWH heparin
bioavailability monitor
glycoprotein (GP) IIb/IIIa receptor inhibitors platelet
aggregation fibrinogen receptor ( fibrinogen receptor
platelet aggregation thrombus ) aspirin heparin
ischemic chest pain ST segment elevation
-blockers

MI ( myocardial rupture ventricular
fibrillation)
metoprolol 5 mg IV 2 5 3 dose 50 mg
6 4 100 mg 12 propanolol, atenolol
asthma, COPD, CHF exaxerbation, bradycardia HR < 50 bpm, hypotension, heart
block
vasodilators oxygen demand myocardial wall stress preload /
afterload remodeling blood supply
ACE inhibitors mortality
anterior infarction, heart failure, tachycardia infarction
antianginal drugs nitroglycerin IV 5 g/min 5-10 g/min 3-5
systolic blood pressure > 90 mmHg , tachycardia,
blood pressure 24-48 nitroglycerine
coronary calcium
channel blocker nifedipine (), diltiazem ( heart rate
angina -blocker pulmonary
congestion negative inotropic), verapamil
myocardial oxygen demand

verapamil diltiazem -blockers heart failure
Narcotic analgesics morphine sulfate 2-4 mg IV infusion 5-10 5-15
4-6

194

( preload and oxygen

demand)
pethidine 50-100 mg IM IV, meperidine 25 mg
atropine IV
nasal oxygen ischemic pain 3-5 L/min
mask nasal canula 24-48 mild sedative
oxygen demand diazepam 2-5 mg 3-4 flurazepam 1530 mg
antiarrhythmics lidocaine, procainamide, amiodarone ventricular
arrhythmias peri-infarction period ventricular arrhythmias ventricular fibrillation
myocardial ischemia AMI

morphine meperidine
dioctylsodium sulfosuccinate 100 mg bisacodyl
24
4 g/d
bed rest early ambulation

3-8H

Intervention Treatments

Percutaneous transluminal coronary angioplasty (PTCA)

concentric plaque calcification
PTCA guidewire
guidewire

PTCA
5 recurrent stenosis 30 3
Coronary bypass grafting
internal mammary artery ascending aorta


5 graft

3-8

3-8I

195

secondary prevention

myocardial infarction
secondary prevention
Beta-blockers
sudden cardiac death reinfarction 25 2
infarction beta-blockers acute infarction
24 intravenous form metoprolol, atenolol 72
infarction oral form propanolol, metoprolol, timolol
beta-blockers, left ventricular ejection fraction 40, electrical
complication ventricular tachycardia, cardiac arrest, congestive heart failure

Calcium channel blockers

non Q wave myocardial infarction diltiazem recurrent infarction
1 reinfarction 43 diltiazem
non Q wave myocardial infarction 1
congestive heart failure

Angiotensin converting enzyme inhibitors (ACEIs)

myocardial infarction left ventricular ejection fraction 40
ACEIs recurrent infarction
captopril, enalapril
Aspirin
aspirin 160 mg/d 5 acute myocardial
infarction 25 streptokinase 42
aspirin 80-160 mg/d acute myocardial infarction

Lipid-lowering agent
niacin non-fetal myocardial infarction

196

3-9

Arrhythmia (Rate),
(Rhythm) (Origin) EKG

3-9A

(Abnormal Impulse Formation)

(Abnormal Impulse Conduction)
Arrhythmia

3-9B

Arrhythmia Provoking factors (Precipitating factors)

myocardial ischemia ()
sympathetic-parasympathetic imbalance
electrolytic imbalance
drugs Adrenergic agonist, Digitalis glycosides, Amitryptyline
myocardial diseases Acute rheumatic myocarditis

3-9C

(>100 /) tachycardia
(<50 /) bradycardia

Bundle of His supraventricular arrhythmia
Bundle of His ventricular arrhythmia
1: Arrhythmia
Originating in the Atria
(Supraventricular arrhythmia)

Sinus Bradycardia

Sinus Tachycardia

Sick sinus syndrome

Premature Atrial Contractions (PACs)

Paroxysmal Supraventricular tachycardia

Wolff-Parkinson-White syndrome (WPW)

Atrial flutter

Atrial fibrillation (AF)

Originating in the Ventricles

(Ventricular arrhythmia)
Premature Ventricular Contractions
Ventricular tachycardia (VT)
Ventricular flutter
Ventricular fibrillation (VF)
Torsade de pointes

3-9

197

Supraventricular arrhythmia Ventricular arrhythmia EKG

supraventricular arrhythmia QRS complex
Supraventricular arrhythmia PSVT, Atrial flutter, Atrial fibrillation
Ventricular arrhythmia Ventricular flutter, Ventricular fibrillation Torsade de
pointes
Conduction block AV block, Bundle branch block Supraventricular/
Ventricular arrhythmia Arrhythmias
Arrhythmias Arrhythmias
short-term atropine, pacemaker

3-9D

1: The cardiac conduction system. A. Cardiac conduction system anatomy. B. Action potentials of specific cardiac cells. C.
Relationship of surface electrocardiogram to the action potential

198

2:

Aorta
Sino-atrial (SA)
node
Pulmonary
artery
Left
atrium

Atrimentricular
Bundle (HIS)

Right
atrium

Left
ventricle

AtrioVentricular (AV)
node

Right
ventricle

Interventricular
septum

3:

3-9

199

(Automaticity)

1. (Conduction) SA node (Pacemaker)

2. (Both atrium) AV node

( AV
node)
3. Bundle of his left and right
ventricles
4. (Ventricular contraction)
SA node
AV node
()
Arrhythmias SA node
Sinus tachycardia Sinus bradycardia
(Re-entry) Paroxysmal
Supraventricular tachycardia

3-9E

(Non-pharmacologic treatment)

Automatic implantable Cardiac defibrillators (ICDs)

Arrhythmias
Antiachycardia pacemakers supraventricular tachycardia ventricular tachycardia
Catheter ablation electrode catheters

Direct current shock (DC Shock) ventricular fibrillation

Carotid massage carotid sinus vagus nerve

3-9F

(Anti-arrhythmic drugs)

Classification of Antiarrhythmic Drugs

Antiarrhythmic Drugs 4 class Vaughan Williams Classification
2: Class of Antiarrhythmic Drugs
Class I
= Sodium Channel blockers ( 3 subclass IA, IB, IC)
Class II
= beta-adrenergic receptor antagonist (Beta-blocker)
Class III = Potassium channel blockers + prolong action potential duration
Class IV = Calcium channel blockers

200

Antiarrhythmic Drugs suppress prevent
o Abnormal Impulse Formation ()
o Abnormal Impulse Conduction ()

1. Class I (Sodium Channel Blockers)

Class 3 subclass
Na+ channel Open state Inactivated state
(rate of dissociation rate of recovery)
3: Subclass of Class I (sodium channel blockers)
Subclass
Sodium channel affinity
Class IA
Open > inactivated
Class IB
Inactivated > Open
Class IC
Open > Inactivated

Rate of dissociation
slow
Rapid
Very slow

Duration of channel blockade

intermediate
Quick
Long

Class IA = Quinidine, Procainamide, Disopyramide

Quinidine
quinolone derivative
D isomer Quinine
Alkaloid cinchona bark
fever and malaria
oral
gut
metabolism
urine potent
compound + metabolite
o Moderately short half-life
o Sustain-release preparation
o ADR * most common = diarrhea
* less common = torsade de pointes
* thrombocytopenia
* high dose cinchonism (tinnitus, dizziness, blurred vision)
o Indication = suppression of supraventricular arrhythmia and ventricular arrhythmia oral
(long term) IV hypotension ( blocker)
o Quinidine AV node conduction velocity ventricular rate AV node
conduction digoxin quinidine
Procainamide
o amide derivative local anesthetic procaine (procaine side effect )
o gut
active metabolite N-acetyl procainamide (NAPA)
NAPA class III
o
o
o
o
o

3-9

201

o ADR * Long term = lupus erythematosus (arthralgia + butterfly rash)

o Indication
* IV : acute ventricular arrhytrhmia ( hypotension quinidine)

* Oral : supraventricular and ventricular arrhythmia ( quinidine )

Disopyramide
o Indication

* Oral : prevent ventricular arrhythmia

* response
o Antimuscarinic HF &
blurred vision + urinary retention

Class IB = Lidocaine, Mexiletine, Tocainide

unchanged in urine
Tocainide > Lidocaine Mexiletine
Mechanism & effect
o Lidocaine sodium channel ischemic tissue ( effect non-ischemic tissue)
o Mexiletine & Tocainide selective ischemic tissue lidocaine effect nonischemic tissue lidocaine
Lidocaine
o Indication
* IV (Bolus + cont. IV) : ventricular tachycardia
: other acute ventricular tachycardia
o
o ADR
* CNS side effect nervousness, tremor paresthesia
* conduction velocity tissue (ADR metabolite
lidocaine CYP 450 inhibitor cimetidine
Mexiletine & Tocainide
o Indication
* Oral (long-term) : ventricular arrhythmia
o ADR
* tocainide agranulocytosis and other blood
cell deficiency Mexiletine

Class IC = Flecainide, Propafenone

Class IA
Class IC

2. Class II (-Blockers) = Esmolol, Metoprolol, Propranolol

treat :

* supraventricular arrhythmia
* heart rate
* AV node conduction velocity
* AV node refractory period

202

Esmolol
o Indication
* IV : acute supraventricular tachycardia
o rapid metabolize plasma esterase enz.
o Short half-life

Metoprolol
o Indication

* oral or IV : treat or suppress of supraventricular arrhythmia and ventricular

arrhythmia
* MI IV oral

3. Class III (Potassium Channel Blockers) = Amiodarone, Bretylium, Ibutilide, Sotalol

Amiodarone
o
o onset 2

o Half-life 40
o potassium channel blockers block sodium channel, calcium channel
alpha-adrenergic receptor
o SA node automaticity AV node conduction velocity QT interval
o supraventricular arrhythmia and ventricular arrhythmia
o heart failure arrhythmia
o Side effect
* Amiodarone iodine
* Hypotension
* AV block
* Blue-gay skin discoloration ()
* arrhythmia torsade de pointes
* Fetal pulmonary fibrosis
o digoxin warfarin
Bretylium
o Indication
* IV IM : acute ventricular fibrillation

4. Class IV (Calcium Channel Blockers)

Class IV ( calcium channel blockers ) = Diltiazem, Verapamil
o Indication
* IV : acute supraventricular tachycardia
: ventricular rate atrial fibrillation
o negative inotropic
o Calcium channel blockers dihydropyridines arrhythmia

3-9

203

5. Miscellaneous Drugs
Adenosine
o acute supraventricular tachycardia
o Half-life 10 ()
o acetylcholine-sensitive potassium channel ( potassiumchannel opener )
hyperpolarization
Digoxin
o slow ventricular rate atrial fibrillation

6. antiarrhythmic drugs
4: Class Toxicities of Antiarrhythmic Drugs
Class I
Class II
Proarrhythmic effects
Sinus bradycardia
AV block
IA- Tosade de pointes
Depression of LV function
IC- CAST proarrhythmia
(adrenergic-dependent)
Negative inotropic effect
Infranodal conduction block

Class III
Sinus bradycardia
Tosade de pointes

Class IV
Sinus bradycardia
AV block
Negative inotropic effect

* Proarrhythmic effect drug induce arrhythmia antiarrhythmic drugs 2 torsade de pointes (druginduced long QT syndrome; DILQTS) CAST proarrhythmia (ventricular tachycardia CAST trial)
5: Antiarrhythmic Actions of Antiarrhythmic Drugs
Class I
Actions

Class II
Actions

Class III
Actions

Class IV
Actions

Quinidine (IA)
Procainamide (IA)
Disopyramide (IA)

++
+++
+++

+
+

++
+
+
stereospecific

Lidocaine (IB)
Mexiletine (IB)
Tocainide (IB)
Phenytoin (IB)
Encainide (IC)
Flecainide (IC)
Propafenone (IC)
Moricizine (I)
Propranolol (II)
Esmolol (II)
Sotalol (II/III)

+++
+++
+++
+
+++
+++
++
++
+
+

Amiodarone (III)
Ibutilide (III)
Bretykium (III)
Verapamil (IV)
Diltiazem (IV)
Adenosine (Misc.)

+++

+++
+++
++
stereospecific
+

++
+

Drug (Class)

+
+

Other Actions

Alpha-adrenergic blockade
Ganglionic blockade
anticholinergic

+
+

+++
++
+++
++

Alpha-adrenergic blockade, Muscarinic blockade

Sympathomimetic, Sympatholytic

++++
+++
++

Enhances potassium conductance, Inhibits

camp-induced Ca influx

204

6: Agents Used for Controlling Ventricular Rate in Supraventricular Tachycardias

Drug
Digoxin (Lanoxin)

Esmolo (Brevibloc)

Propranolol (Inderal)

Metoprolol (Lopresser)

Verapamil (Isoptin, Calan)

Diltiazem (Cardizem)

3-9G

Usual Maintenance
dose
Comments
PO: 0.125-0.5 mg/day;
Maximum response may take
adjust for renal failure
several hours; use with
caution in patients with renal
impairment
50-300 mg/kg/min
Hypotension common; effects
continuous infusion
additive with digoxin and
with bolus between
CCB
increases
0.5-1.0 mg IV repeated q 2 min IV: 0.04 mg/kg/min
Use with caution in patients with
(up to 0.1-0.15 mg/kg)
PO: 10-120 mg tid
HF or asthma; additive
effects seen with digoxin and
CCB
5 mg IV at 1 mg/min
PO: 25-100 mg bid
Use with caution in patients with
HF or asthma; additive
effects seen with digoxin and
CCB
5-10 mg (0.075-0.15 mg/kg) IV IV: 5-10 mg/hr
Hypotension with IV route; effects
over 2 min; if response
PO: 40-120 mg tid or 120additive with digoxin and BB;
inadequate after 15-30
480 mg in sustainedmay increase digoxin levels
min, repeat 10 mg (up
release form daily
to0.15 mg/kg)
0.25 mg/kg IV over 2 min; if
IV: 5-15 mg/hr
Response to IV therapy occurs in
response inadequate after PO: 60-90 mg tid or qid or
4-5 min; hypotension effects
15 min, repeat 0.35 mg/kg
180-360 mg in
additive with digoxin and BB
over 2 min
extened- release
form daily
Loading dose
10-15 mcg/kg LBW up to 1-1.5
mg IV or PO over 24 hr
(e.g. 0.5 mg initially, then
0.25 mg q 6 hr)
0.5 mg/kg IV over 1 min

Anti-arrhythmic Drugs

1. IA : Prolong repolarization (Increase QRS, QT interval and refractory period)

Blocking open voltage-dependent Na channel Atrial and
ventricular muscle cell, Purkinje system AV-node
(Automaticity) Phase 4 Threshold
Phase 0 ( EKG QRS interval)
(Slow conduction) Phase 0 ( Phase 0 )
Effective refractory period
Cardiac depressant Supraventricular Ventricular arrhythmia
Class IA Block K Channel Class III
TdP

2. IB : Shorten repolarization (Decrease refractory period)

Blocking inactivated voltage-dependent Na channel
Automaticity Threshold Phase 0 Ventricle, His-Purkinje
system
sodium permeability
Refractory period Repolarization
Conduction velocity Conduction velocity (
2 3 )
ventricular arhythima ventricular tissue

3-9

205

3. IC : Little effect on repolarization (Increase PR, QRS&QT interval)

Blocking open voltage-dependent Na channel Class IA
Rate of dissociation Na channel IC Na channel
Supraventricular ventricular arrhythmia IA PVCs
PVCs Mortality & Cardiac arrest

4. II : -blockers (Increase PR interval and refractory period)

Sympathetic cardiac automaticity impulse
heart rate Automaticity Refractory period
SA-node to AV-node conduction velocity EKG PR
interval
Supraventricular arrhythmia AV-node
Ventricle AF, Atrial flutter, WPW syndromes ventricle
Atrium ventricle

5. III : K channel blocker + Prolong Repolarization (Increase QT interval and refractory period)
Blocking K channel
refractory period Phase 3 prolong repolarization and action
potential
duration EKG QT interval (ventricle )
Supraventricular ventricular arrhythmia class III

6. IV : Ca channel blocker (Increase PR interval and refractory period)

Calcium ion Contractility force PR interval and
refractory period -blockers Supraventricular arrhythmia

Anti-arrhythmic drugs
Anti-arrhythmic drugs 4 Class Electrophysiologic & Pharmacologic effects
Class IA III Repolarization time ,QT interval TdP
Class II IV Heart rate,Ventricular contractility force Prolong Pr-interval
Bradycardia, Insufficient, cardiac output 2nd or 3rd degree AV-block)
Class IB Ventricular tissue Supraventricular arrhythmia
Class IC Post-AMI, HF Mortality

206

3-10

3-10A

Thrombogenesis

Platelet
collagen
Platelet Fibrin
Fibrin blood coagulation thrombin ADP (adenosine
diphosphate) platelet aggregation
Prostaglandin arachidonic acid ADP
Thormboxane A2 (TXA2) platelet thrombogenesis Vasoconstriction
Prostacyclin (PGI2) Thrombogenesis
Serotonin (5-HT) Platelet aggregation vasoconstriction

1: Simplified clotting cascade. Components in ovals are influenced by heparin; components in boxes are influenced by
warfarin.

3-10

207

endothelial damage factor extrinsic

pathway Thromboplastin (tissue factor) endothelial cell tissue factor factor VII
factor VIIa factor X intrinsic pathway clotting cascade factor XII
sub endothelial factor X factor XI
extrinsic intrinsic
1 extrinsic intrinsic factor X
Factor II (prothrombin) factor II (Thrombin) fibrin
Pathway

3-10B

Thrombosis is the process involved in the formation of a fibrin blood clot. Both platelets and series of
coagulant protein (clotting factor) contribute to clot formation. fibrin
blood clot platelet coagulant protein (clotting factor) clot formation
embolus clot
embolus Ischemia infraction
deep vein thrombosis (DVT)
pulmonary embolism (PE)

1. Anticoagulation
anticoagulation 2
Indirect thrombin inhibitor
o antithrombin unfractionated heparin (UFH), low-molecular-weight
heparin (LMWH), fondaparinux (Aristra) inhibit factor Xa
o Heparin Antithrombin III, thrombin antithrombin/thrombin
complex thrombin fibrinogen fibrin
o Heparin heparin
molecular wt s/e Enoxaparin (LMWH)
o Heparin drug interaction

Direct thrombin heparin

o active site thrombin vitamin K antagonist warfarin
(coumadin), Nicoumalone Vitamin K clotting factor
vitamin K H2 Vitamin K epoxides Descarboxyprothrombin Prothrombin
O2 Vitamin K prothrombin
o Drug interaction enzyme cytochrom P450
induce enzyme Carbamazepine, Babiturates inhibit enzyme
Cimetidine, Ethanol, Metrinidazole
o S/E bleeding

208

2. Antiplatelet drugs
Thrombus (
platelet bleeding platelet
thrombus ) thrombogenesis
platelet aggregation thromboxane platelet aggregation vasoconstriction prostacyclin
platelet aggregation ADP platelet aggregation
Aspirin
o ASA enzyme cyclooxygenase in platelet thromboxane platelet
aggregation dose low dose 1 grain (64.8 mg)
o thrombus
irritate
o angina, heart failure, hypertension ASA thrombus
acute angina, infraction stroke

3. Fibrinolytic drugs
fibrinolytic drugs fibrin thrombus fibrin plasmin
fibrin plasmin fibrin Enzyme
plasminogen plasmin Streptokinase, Antistreplase, Alteplase etc.
fibrin 3

3-10C

Antithrombolic Drug

1. Prothrombin time (PT) / International Normalized ratio (INR)

PT Extrinsic and common pathway of the clotting cascade
( intrinsic pathway)
Ca & Thromboplastin plasma sample
PT Clot formation Thromboplastin
PT WHO PT
INR
PT INR Thromboplastin
Thromboplastin ISI (International sensitivity index) INR

INR = (PT patient / PT mean normal)ISI

INR (Monitoring parameter) Warfarin Regularintensity therapy / Thromboembolic diseases INR 2.5
( 2.0-3.0) High -intensity therapy INR
3.0 ( 2.5-3.5)

3-10

209

2. Activated Partial Thromboplastin Time (aPTT)

aPTT Intrinsic pathway of the clotting cascade
Heparin UFH (Standard heparin)
aPTT Surface-activating agent ( Kaolin, micronized silica) Partial
thromboplastin reagent (phospholipids; platelet substitute) Ca Plasma sample
24-36

210

3-11

3-11A

Oxygen
oxygen 4
2

1. (Ischemic Stroke)
(ischemic stroke) 2
Thrombolic Stroke
atherosclerosis plaque
thrombotic stroke thrombosis
thrombosis
Lacunar infarction

Embolic Stroke

Embolic Stroke

5 Transient ischemic attack (TIA)

3-11

211

2. (Hemorrhagic Stroke)
(hemorrhagic stroke)
Aneurysm Ateriovenous malformation

3-11B
o
o
o
o
o
o

DM

Atrail Fibrillation, Vulvolar heart disease

3-11C

o
o
o
o
o

amphetamine

(>)

4 (Right cerebral hemisphere)

(Leftcerebral hemisphere) (Cerebellum) (Brain stem)

212

3-11D

global
aphasia motor aphasia dysarthria
(Sensory aphasia)

3-11E

3
1. Lysis occluding clot Clot
2. Anticoagulant
clot
3. Platelet antiaggregant
Lysis occluding clot
fibrinolytic drug Streptokinase Recombinant tissue plasminogen
activator (r-tPA) 3
bleeding
Antiplatelet aggregation
o Aspirin dose baby ASA 60 mg 300 mg

o Ticlopidine (Ticlid ) aspirin irritate 1% Leikopenia (

) 2 3

o Clopidogrel (Plavix ) Ticlopidine Leukopenia ASA GI

bleeding diarrhea Skin rash Aspirin
Anticoagulants Heparin, LMWH, Warfarin

3-11F

(Recurrence Ischemic Stroke)

4-1
4-2
4-3
4-4

4-1

215

4-1

9.6 35
(metabolic syndrome)

(acute) (chronic)

95 2 1

1:

4-1A

Glucose Homeostasis

50-100 mg%
Glucose toxicity
Glucose entry 2
1. exogenous glucose entry exogenous
glucose entry post prandial glucose
2. endogenous glucose entry
2 gluconeogenesis gluconeolysis endogenous glucose entry
fasting glucose
Glucose utilization 2
1.
insulin
2.
metabolism insulin insulin

216

4-1B

American Diabetes Association (ADA) 1997 WHO 1998 4

1 2
1:
Stage Normoglycemia

Types

Normal glucose
regulation

IGT or IFG

[1]

Hyperglycemia

Diabetes Mellitus
Not insulin requiring Insulin requiring for
control

Insulin requiring for

survival

Type 1
Type 2
Other specific types
Gestational Diabetes

1. Type 1 Diabetes Mellitus

1 cellular-mediated autoimmunity
ketoacidosis

1

1
1 autoimmune
2

1 human leukocyte antigen (HLA) complex
6


o

(molecular mimicry)
autoreactive T cell
autoimmune
o

regular T cell

4-1

217

o
1

2. Type 2 Diabetes Mellitus

2 Syndrome X Metabolic Syndrome



ketoacidosis


macrovascular microvascular



2 (insulin resistance)
(insulin deficiency)

3. Type 3 Diabetes Mellitus

steroid; prednisolone, thiazide, sympathomimetic amine

(pancreatitis), trauma, ,

4. Type 4 Diabetes Mellitus

(Gestational Diabetes Mellitus; GDM)

2 insulin

4-1C

3 2 3
(American Diabetes
Association; ADA) fasting plasma glucose (FPG) 126 mg/dl
oral glucose tolerance test (OGTT)

218

2: [2]
1. 200 mg/dl [
(polydipsia) (polyphagia) (polyuria)]

2. (FPG) 126 mg/dl (

8 .)

3. 2 75 OGTT 200 mg/dl

FPG 3 FPG 110 mg/dl FPG 110-125

mg/dl impaired fasting glucose (IFG) FPG 126 mg/dl

(WHO) .. 2541
(FPG 126 mg/dl) / 75 OGTT (2h PG
200 mg/dl) (WHO) 2h PG 75 OGTT
FPG 126 mg/dl 2h PG 200 mg/dl
microvascular
3: (WHO 1985 and 1998) (ADA 1997)
WHO (1985)
FPG 140 mg/dl /
2h PG 200 mg/dl
WHO (1998)
FPG 126 mg/dl /
2h PG 200 mg/dl
ADA (1997)
FPG 126 mg/dl

4-1D

[3]
(retinopathy)*
(nephropathy)*
Diabetic Peripheral Neuropathy*
Atherosclerosis**


Cutaneous Manifestations of Diabetes Mellitus
: * microvascular
** macrovascular

1. Diabetic Retinopathy
(diabetic retinopathy)
2
1. Non-proliferative diabetic retinopathy (NPDR) microaneurysm, hard exudate, retinal
hemorrhage, cotton-wool spot macular edema

4-1

219

2. Proliferative diabetic retinopathy (PDR) neovascular proliferation

vitreous hemorrhage

1
5 15
proliferative 25% 20 15- 20%

2. Diabetic Nephropathy
(diabetic nephropathy)
1 end
state renal disease 1 35% 2 3-16%
glomerular filtration rate (GFR) 120-140
GFR renal plasma flow (RPF) afferent
efferent arteriole glomerular transcapillary pressure gradient GFR




Microalbuminuria
microalbuminuia
(dipstick) (microalbuminuria
dipstick) 20200 30300 2
3 6
Macroalbuminuria/ overt proteinuria/ overt nephropathy
macroalbuminuia
(dipstick) trace 200
300 2 3 6

3. Diabetic Peripheral Neuropathy

(diabetic neuropathy)

distal symmetrical polyneuropathy
(painful neuropathy)
(autonomic neuropathy)
(neurogenic bladder)

220

4-1E

(cardiovascular system) (coronary heart
disease; CHD)[1]

4: [1]

Fasting plasma glucose (FPG)

80-120 mg/dl
Postprandial glucose (PPG)
80-160 mg/dl
A1C
<7%
Total cholesterol
<200 mg/dl
LDL-cholesterol
<100 mg/dl
HDL-cholesterol
>45 mg/dl
Triglycerides
<150 mg/dl
Body mass index (BMI)
male
20-25 kg/m2
female
19-24 kg/m2
Blood pressure (BP)
130/85 mmHg

>140 mg/dl
>180 mg/dl
>8%
>250 mg/dl
>130 mg/dl
<35 mg/dl
>400 mg/dl
>27 kg/m2
>26 kg/m2
>160/95 mmHg

(The Endocrine Society of

Thailand)

( 4)
4 4
FPG 4 A1C 1-2 (lipid profiles)

1-2
2-3
[1]
(glycemic control)
(blood pressure) (cholesterol) ABCs of Diabetes

4-1

5: ABCs of Diabetes[4]
Letter
A
A1C
B
Blood pressure/microalbumin
C
Cholesterol/aspirin
D
Diabetes education
E
Eye examinations
F
Foot examinations
G
Glucose monitoring
H
Health maintenance
I
Indications for specialty care

221

Standard of Care

1. A: A1C
A hemoglobin A1c (A1C)
(glycemic control) (hyperglycemia)
(microvascular complications)
(retinopathy) (nephropathy)
(neuropathy) A1C

6: ADA[4,6]
Glycemic control
A1C
Preprandial plasma glucose
Peak postprandial plasma glucose

<7.0%*
90-130 mg/dl (5.07.2 mmol/l)
<180 mg/dl (<10.0 mmol/l)

Blood pressure

<130/80 mmHg

Lipids
LDL cholesterol
Triglycerides
HDL cholesterol

<100 mg/dl (<2.6 mmol/l)

<150 mg/dl (<1.7 mmol/l)
>40 mg/dl (>1.1 mmol/l)

Key concepts in setting glycemic goals:

A1C is the primary target for glycemic control
Goals should be individualized.
Certain populations (children, pregnant women, and the elderly) require special considerations.
Less intensive glycemic goals may be indicated in patients with severe or frequent hypoglycemia.
More intensive glycemic goals (i.e., a normal A1C, <6%) may further reduce microvascular complications at the cost of increasing
hypoglycemia.
Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals.
* Referenced to a nondiabetic range of 4.0-6.0% using a Diabetes Control and Complications Trial-based assay.
Postprandial glucose measurements should be made 12 h after the beginning of the meal, generally peak levels in patients with
diabetes.
Current National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) guidelines suggest that in patients with
triglycerides 200 mg/dl, the non-HDL cholesterol (total cholesterol minus HDL) be utilized. The goal is 130 mg/dl.
For women, it has been suggested that the HDL goal be increased by 10 mg/dl.

222

Hemoglobin A1C
A1C (mean
plasma glucose; MPG) (pre- and post-meal glucose)
A1C[5] A1C 1%
(microvascular complications) 35-40%[4]
A1C <7% ( 6%)
PPG <180 mg/dl A1C
[4]
Fasting Plasma Glucose
(preprandial plasma glucose)
8 16 (fasting plasma glucose; FPG)
PPG

[5] ADA 90-130 mg/dl[4,6]
80-120 mg/dl[1]
Postprandial Plasma Glucose
(postprandial plasma glucose; PPG) ADA <180 mg/dl[4-6]
A1C 7% American College of Endocrinology
140 mg/dl 140 mg/dl
(cardiovascular disease; CVD)[5]
80-160 mg/dl[1]

2. B: Blood Pressure/Microalbumin
B (blood pressure; BP)
(microvascular and macrovascular complications)
urine microalbumin
(nephropathy) (CVD)[4,7]
Blood Pressure
(hypertension; HTN) CVD
>120/80 mmHg CVD (mortality)
(microvascular complication)
(retinopathy) (nephropathy)
<130/80 mmHg
[4]
angiotensin-converting enzyme (ACE) inhibitors
1 2 1 2
microalbuminuria macroalbuminuria albumin

4-1

223

Urine Microalbumin
(albuminuria)
(microalbuminuria: UAE 30-299 mg/day) (macroalbuminuria overt
proteinuria: UAE >300 mg/day)
(diabetic nephropathy) 1 2 microalbuminuria
(CVD)[4,7]
microalbuminuria
1 ACE inhibitors
(nephropathy) 2 microalbuminuria
macroalbuminuria ACE inhibitors ARBs
2 macroalbuminuria
ARBs 55
( CVD, dyslipidemia, microalbuminuria, smoking)
ACE inhibitors [4]

3. C: Cholesterol/Aspirin
C (lipid management)
(aspirin) (CVD) (stroke)
Cholesterol (lipid management)
CVD
LDL-cholesterol HDL-cholesterol
triglycerides (macrovascular disease)
LDL-cholesterol <100 mg/dl triglyceride <150
mg/dl HDL-cholesterol >40 mg/dl HDL-cholesterol
>50 mg/dl total cholesterol 170 mg/dl 180
mg/dl 2 [4,6]
Aspirin
(platelet aggregation)
tromboxane tromboxane
ADA
(macrovascular disease) 75-325 mg/day[4,6]
30
1 21
Reyes syndrome[4,6]
clopidogrel

224

4-1F

1. [7]

()

15
* 1 2
10-15
* SC
* IV

1 30
1-2%
()

()

4-1

225

2. [8]

1 4

4-1G

5
(sulfonylureas; SUs) (non-sulfonylureas)
(biguanides) (thiazolidinediones; TZDs) (alphaglucosidase inhibitors; AGIs) A1C
alpha-glucosidase inhibitors nateglinide[10,11]
7: [12]
Drug Class
Mechanism of Action
Insulin secretagogues
Sulfonylureas
uinsulin release
Non-sulfonylurea secretagogues
uinsulin release
Insulin sensitizers
Biguanides
vhepatic glucose production
uinsulin sensitivity in hepatic and peripheral tissues
Thiazolidinediones
uinsulin sensitivity in peripheral tissues
vhepatic glucose production
Decrease glucose absorption
Alpha-glucosidase inhibitors
vcarbohydrate absorption

Primary Site of Action

Pancreas
Pancreas
Liver; peripheral tissues
Peripheral tissues; liver

Small intestines

226

2: Pharmacological Approaches to the Major Metabolic Defects of Type 2 Diabetes Mellitus. Reprinted from: Inzucchi SE.
Oral antihyperglycemic therapy for type 2 diabetes. JAMA 2002;287:360-72.

1. Sufonylureas
sulfonylureas (SUs)
[10] first generation acetohexamide,
chlorpropamide, tolazamide, tolbutamide second generation glimepiride, glipizide, glibenclamide
(glyburide) second generation (potency)
(pharmacokinetics) (safety) first generation[12] .. 2547
3 glibenclamide tablet ( 2.5, 5 mg), gliclazide tablet ( 80 mg)
glipizide tablet[13]

sulfonylureas 2 acidic functional group (sulfonylurea)

aromatic ring alkyl group
duration of action
metabolism
alkyl = short duration
acetyl = intermediate duration
halogen = long duration

activity toxicity

C3-C7
double bond

O
R1

SO2 NH C

NH R 2

3: sulfonylureas

nitrogen sulfonyl carbonyl acidic proton

sulfonyl carbonyl nitrogen nitrogen
hydrogen hydrogen nitrogen

4-1

227
Sulfonylurea
O

Tolbutamide (Orinase)

CH3

SO2 NH

NH

CH2

NH

CH2

CH2

CH2

CH3

CH3

Tolazamide (Tolinase)

CH3

SO2 NH

Acetohexamide (Dymelor)

CH3

O
SO2 NH

NH

Chlorpropamide (Diabinese)

Cl

SO2 NH

NH

CH2

NH

Gliclazide (Diamicron)

CH3

SO2 NH

CH2

CH2

SO2 NH

NH

CH2

CH2

SO2 NH

NH

CH2

CH2

SO2 NH

NH

CH2

CH2

O
O

Gliquidone (Glurenor)

NH

H3C
CH3

Glipizide (Minidiab)

N
CH3

O
C

NH

N
Cl
O

Glibenclamide, Glyburide
(Daonil, Euglucon)

O
CH3

Glimepiride (Amaryl)

NH

CH3
O

N
CH3

O
SO2 NH

NH

CH3

CH2
O

4: sulfonylureas

R1 (duration of action)
R1
alkyl short duration acetyl halogen intermediate duration long
duration second generation carboxamide ethyl group
aromatic ring specific distance receptor
R2
alkyl group C3-C7 saturated ring

sulfonylureas sulfonylurea receptor beta

cell beta cell adenosine triphosphate-dependent
potassium channels (membrane depolarization)
(calcium influx) (secretory
granules)[12]

228

5: sulfonylureas beta cell KATP channels

membrane depolarization Ca2+ channel
secretory granules

sulfonylureas (weak acid) (hydrophobic)

chlorpropamide (hydrophilic) [15]
sulfonylureas lipophilic acidic
[15,16] (acidic or basic) - (hydrophilic or lipophilic) - (polar or nonpolar)
[15]
chlorpropamide glibenclamide (glyburide)
(hypoglycemia) [1] active metabolite
glibenclamide hydroxylated metabolites
chlorpropamide[15] sulfonylureas
half-life inactive metabolite
8: Pharmacokinetics of sulfonylureas[17]
Time to peak
Generic Name
(h)
Tolbutamide
3-4
Tolazamide
4-6
Acetohexamide
3
Chloropropamide
2-7
Glipizide
1-3
Glipizide XL
6-12
Glibenclamide (Glyburide)
2-6
Glimepiride
2-3

Half-life
(h)
3-28
4-8
4-6
36
7
7
10
5-9

Duration of Action
(h)
6-12
12-24
12-18
60
12-24
24
12-24
16-24

Metabolism
Hepatic
Hepatic
Hepatic
Hepatic
Hepatic
Hepatic
Hepatic
Hepatic

Renal Excretion of
Active Metabolite
Insignificant
No
Yes
Yes*
No
No
Yes
Yes(?)

*Parent drug undergoes prolonged excretion.

4-1

229

first generation tolbutamide tolazamide short-acting sulfonylureas

methyl group aromatic ring inactive carboxylic
acid metabolites 2-3 acetohexamide acetyl-carbonyl
group secondary alcohol chloropropamide chlorine 4 aromatic ring
1 second generation
second generation glimepiride, glipizide, glibenclamide (glyburide) lipophilic group
first generation entero-hepatic circulation recycling [16]

9: sulfonylureas[12,16]
Sulfonylurea
Tolbutamide
Tolazamide
Acetohexamide
Chloropropamide
Glipizide
Glibenclamide
Glimepiride

Trade Name(s)
Oramide, Orinase
Tolamide, Tolinase
Demylor
Diabinese
Minidiab
Daonil, Euglucon
Amaryl

Generation
first
first
first
first
second
second
second

Tablet
Strength (mg)
250; 500
250; 500
250; 500
100; 250
5; 10
1.25; 2.5; 5
1; 2; 4

Daily Dose (mg)

1000-3000
100-1000
250-1500
100-750
2.5-40
2.5-20
1-8

Frequency of
Administration
2-3 times/day
2-3 times/day
1-2 times/day
once daily
once daily
once daily
once daily

sulfonylureas FPG A1C 60-70 mg/dl 1.5-2.0%

UKPDS (The United Kingdom Prospective Diabetes Study)
metformin [16]

10: FPG, A1C [12]
Reduction on
Fasting Plasma
Reduction
Low-density
High-density
Drug Class
Glucose (mg/dl)
in A1C (%)
Lipoproteins
Lipoproteins
Sulfonylureas
60-70
1.5-2.0
No effect
No effect
Non-sulfonylurea secretagogues
60-70
1.5-2.0
No effect
No effect
Biguanides
60-70
1.5-2.0
v
Slightu
Thiazolidinediones
35-40
0.7-1.0
u
u
Alpha-glucosidase inhibitor
25-30
0.7-1.0
No effect
No effect

Triglycerides
Slightv
Slightv
v
v
No effect

(gestational diabetes melitus) sulfonylureas

(teratogenicity)
(neonatal hypoglycemia) glibenclamide
[19]
sulfonylureas
(antiplatelet aggregation) glimepiride, gliclazide, gliquidone
glibenclamide[20] gliclazide
double blind gliclazide

230

[21] glimepiride gliclazide[20]

(electronic property)
(lipophilic property)[20]
gliclazide glibenclamide
(diabetic retinopathy)[22]
sulfonylureas (weight gain)
(hypoglycemia)
30
beta-adrenergic
antagonist sulfonylureas beta-adrenergic
antagonist 15 g
chloropropamide
(hyponatremia) ADH (antidiuretic hormone) / ADH
antabuse effect[1]
11: [12]
Drug Class
Side Effects
Sulfonylureas
Hypoglycemia; weight gain; rash
Non-sulfonylurea secretagogues
Hypoglycemia
Biguanides
GI; vvitamin B12 levels; lactic acidosis
Thiazolidinediones
Alpha-glucosidase inhibitor

Edema/weight gain; increase liver enzymes;

induce ovulation
GI

Contraindications/Warnings
DKA; severe sulfa allergy
DKA
Renal/hepatic disease; congestive heart
failure; metabolic acidosis
Class III or IV heart failure; DKA; liver
disease
Cirrhosis; DKA; inflammatory bowel
disease; renal impairment

Note: GI = gastrointestinal side effects; DKA = diabetic ketoacidosis.

sulfonylureas
calcium channel
blockers, estrogen, isoniazid, niacin, oral contraceptives phenytoin sulfonylureas
azole
antifungals histamine-2 receptor sulfonylureas
sulfonylureas
sulfonylureas sulfonylureas 12

4-1

231

12: sulfonylureas [17]

Sulfonylurea
Drug
Chlorpropamide
Warfarin, chloramphenicol
Probenicid, allopurinol
Rifampin
Tolbutamide
Digoxin
Warfarin, chloramphenicol, sulfonamides
Rifampin
Glipizide
Salicylates, clofibrate
Trimethoprim-sulfamethoxazole, miconazole
Cholestyramine
Rifampin
H2 blockers
Glibenclamide
H2 blockers
Trimethoprim-sulfamethoxazole, miconazole
Ciprofloxacin
Rifampin

Mechanism
vHepatic metabolism
vRenal tubular secretion
uHepatic metabolism
vHepatic metabolism
uHepatic metabolism
Displace from proteins
Inconsistent/unclear
vAbsorption
uHepatic metabolism
vHepatic metabolism
vHepatic metabolism
Inconsistent/unclear
vHepatic metabolism
uHepatic metabolism

Effect
uHypoglycemia
uHypoglycemia
vHypoglycemia
uDigoxin level
uHypoglycemia
vHypoglycemia
uHypoglycemia
uHypoglycemia
vHypoglycemia
vHypoglycemia
uHypoglycemia
uHypoglycemia
uHypoglycemia
uHypoglycemia
vHypoglycemia

2. Non-Sulfonylurea Secretagogues
non-sulfonylurea secretagogues insulin secretagogue
sulfonylurea
(postprandial glucose concentrations) [10]

2
.. 2547 repaglinide
tablet ( 0.5, 1, 2 mg) sulfonylureas
sulfonamides[13]

non-sulfonylurea secretagogues carboxylic acid repaglinide

metglitinide (benzoic phenylacetic) nateglinide -phenylalanine
sulfonylureas 5-10
O

Meglitinide
HOOC

Cl

CH2 CH2 NH

CH3O

CH3

H3C
CH

Repaglinide
(Pradin, NovoNorm)

O
HOOC

CH2

CH2
NH

CH3CH2O

Nateglinide
(Starlix)

H3C
C

COOH
NH

CH

CH2

H3C

6: non-sulfonylurea secretagogues

232

non-sulfonylurea secretagogues beta cell

sulfonylureas beta cell
sulfonylureas
sulfonylureas

non-sulfonylurea secretagogues half-life ( 15-30 )

(hypoglycemia)

13: Pharmacokinetics of non-sulfonylurea antidiabetic agents[17]

Generic
Time to peak
Half-life
Trade Name
Name
(h)
(h)
1
Repaglinide Prandin, NovoNorm
1
1-5
Metformin
Glucophage
2-3
3-4
Rosiglitazone Avandia
1-2
3-7
Pioglitazone Actos
1-2

2
Acarbose
Precose, Glucobay
1-2
2-3
2
Miglitol
Glyset, Diastabol
*

Duration
of Action
4-6 h
>3-4 wk
>3-4 wk
>3-4 wk
4h
4h

Metabolism
Hepatic
Insignificant hepatic
Hepatic
Hepatic
Intestinal
Intestinal

Renal Excretion of
Active Metabolite
No
Yes*
No
No
Yes
Yes

Parent drug excreted >90% unchanged in the urine.

Pharmacologic effect not dependent on systemic absorption.
Fraction (2%) of drug absorbed is excreted unchanged in the urine.

non-sulfonylurea secretagogues sulfonylureas

nateglinide > repaglinide > glipizide, glimepiride, gliclazide >
tolbutamide, glibenclamide (micronized formulation) > chlorpropamide, glibenclamide (nonmicronized
formulation) [15]
repaglinide 0.5 mg 3 ( 16 mg)
nateglinide 60 mg 3 ( 360 mg)
1-30 [12]
14: Non-Sulfonylurea Secretagogues[12,16]
Generic Name
Trade Name
Tablet Strength (mg)
Repaglinide
Prandin, NovoNorm
0.5; 1.0; 2.0
Nateglinide
Starlix
125

Daily Dose (mg)

0.5-4 with meals
60-120 with meals

Frequency of Administration
2-3 times/day
2-3 times/day

repaglinide FPG 60-70 mg/dl A1C 1.5-2.0%

nateglinide A1C 0.5-1.0%
(postprandial hyperglycemia)[10,12]
sulfonyl

4-1

233

non-sulfonylurea secretagogues (weight gain)

(hypoglycemia) sulfonylurea secretagogues [10]

repaglinide CYP450 3A4 nateglinide CYP450 2C9

3A4 [12]
15: Drug interactions [12]
Drug Class
Drug Interaction
Sulfonylureas
Many
Non-sulfonylurea secretagogues
ueffect by CYP450 3A4 inhibitors; veffect by CYP450 3A4 inducers
Biguanides
Alcohol (urisk of lactic acidosis)
Thiazolidinediones
ueffect by CYP450 2C8 and 2C9 inhibitor-Gemfibrozil
Alpha-glucosidase inhibitors
Note: CYP = cytochrome P450 enzyme.

3. Biguanides
biguanides insulin sensitizer metformin, buformin phenformin
metformin
2 (BMI >25) sulfonylureas [18]

.. 2547 metformin hydrochloride tablet [13]
phenformin lactic acidosis

biguanide guanidine 2
metformin (dimethylbiguanide), buformin (buthylbiguanide) phenformin
(phenethylbiguanide) 7
Guanidine

H2N

NH2

NH

Metformin
(Glucophage)

Buformin

H 3C
N
H 3C

C 4H 9

C
NH

C
NH

NH C

NH2

NH

NH C

NH2

NH

CH2 CH2
N

Phenformin
H

C
NH

NH C

NH2

NH

7: guanidine biguanides

biguanides
insulin-stimulated uptake
metformin
hypoglycemia [14]

234

metformin 500-1500 mg bioavailability 50-60%

6 elimination half-life 1.5-4.7
[23]
16: Biguanides Antidiabetic Agents[12,16]
Generic Name
Trade Name
Tablet Strength (mg)
Metformin
Glucophage
500; 850
Glucophage XR
500

Daily Dose (mg)

1000-2550
500-2000

Frequency of Administration
2-3 times/day
once daily

metformin phenformin lipophilic

phenformin phenformin (hydrophobic) (weakly basic)
(nonpolar) CYP450 2D6 half-life 7.5-15
protein binding metformin (hydrophilic), (strongly basic)
(polar) half-life
lactic acidosis [15,23] 500 mg
[18] metformin
500-3000 mg 2-3 [16]

metformin sulfonylurea 2 metformin

1.2 sulfonylurea
(weight gain) 2.8-5.3 [23] metformin A1C 1.5-2.0% FPG
60-70 mg/L (2.8-3.9 mmol/L) LDL-cholesterol triglyceride 10-15%[11]
( 10)
metformin (metallic taste)
B12 B12
[12] ( 11)
lactic acidosis (renal and liver
dysfunction) (heart failure) (dehydration) (alcohol abuse)[10]
metformin metformin [14,16]
[12] ( 15)

metformin metformin
cimetidine metformin cimetidine metformin
metformin
cimetidine[17] metformin cimetidine

4-1

235

4. Thiazolidinediones
thiazolidinediones (TZDs) glitazones
(insulin sensitizer)
A1C insulin secretagouge
[24]
metformin
.. 2547 rosiglitazone meleate tablet ( 4, 8 mg) pioglitazone
hydrochloride tablet ( 15, 30 mg) severe insulin resistance (
metformin) metformin[13]

thiazolidinediones (TZDs) insulin sensitizer

ciglitazone troglitazone, rosiglitazone, pioglitazone troglitazone
side chain
tocopherol[12]
thiazolidinediones thiazolidine-2,4-dione
side chain 8
Thiazolidine- 2 , 4 -dione
Troglitazone
(Rezulin)

O
S

O
CH2 O

CH2

NH
O

Rosiglitazone
(Avandia)

O
CH3
N

S
CH2 CH2 O

CH2

NH

N
O

Pioglitazone
(Actos)

O
S

CH3 CH2

CH2 CH2 O

CH2

NH

N
O

8: thiazolidinediones

thiazolidinediones nuclear transcriptor factor PPAR- (peroxisomeproliferators-activated receptor-)

adipose tissue skeletal muscle, liver, pancreatic beta cells, vascular
endothelium macrophages[12,25]
[12] insulin response elements (InsRE)
(GLUT-glucose transporter) GLUT1, GLUT4
TNF- GLUT4
(adipocytes and skeletal muscle) [10,24]

236

thiazolidinediones
metformin[10,25] pancreatic beta cells
(decrease free fatty acids)[12,25]
(rodent studies) pancreatic beta cells[12]
thiazolidinediones
insulin sensitizer
[14]

9: thiazolidinediones PPAR- transcription factor

transactivation PPAR- heterodimer retinoid X receptor (RXR) DNA
PPAR response elements (PPRE) promoter region target genes
conformation PPARs cofactor protein coactivators coactivators nuclear
receptors transcription transrepression gene transcription
PPARs signal-transduction nuclear factor-B (NF-B) signaling pathway
DNA-binding-independent manner[25]

rosiglitazone pioglitazone plasma protein 99%

1-2
rosiglitazone 4 mg ( 2 mg 2 ) 8 mg
pioglitazone 15-45 mg/day 3-4
3-4 ( 13) rosiglitazone
N-demethylation hydroxylation pioglitazone
hydroxylation oxidation rosiglitazone pioglitazone conjugation
sulfate glucuronic acid

4-1

17: Insulin Receptors Sensitizers[12,16]

Generic Name
Trade Name
Tablet Strength (mg)
Rosiglitazone
Avandia
2.0; 4.0; 8.0
Pioglitazone
Actos
15; 30; 45

237

Daily Dose (mg)

4-8
15-45

Frequency of Administration
once daily
once daily

rosiglitazone pioglitazone

10: thiazolidinediones adiponectin adipose tissue free

fatty acid subcutaneous adipose tissue thiazolidinediones
hepatic insulin sensitivity
insulin sensitivity [25]

thiazolidinediones
prostaglandin
(dilutional anemia or hemodilution) (weight gain) 2-3
glycosylated hemoglobin 1%[25] fat mass
1 g/dl 3.3%
III IV New York Heart Association[10,12,25]
rosiglitazone pioglitazone
aspartate aminotransferase alanine aminotransferase 3 upper limit
thiazolidinediones
2
alanine aminotransferase 3 upper limit[12] ( 11)

238

thiazolidinediones
LDL-cholesterol
HDL-cholesterol pioglitazone
rosiglitazone[10] fasting plasma glucose 35-40 mg/dl A1C 0.71.0% ( 10)

rosiglitazone pioglitazone
CYP450 2C8 2C9 gemfibrozil ( 15)

5. Alpha-Glucosidase Inhibitors
alpha-glucosidase inhibitors (AGIs)
metformin [18]
sulfonylureas metformin[10] acarbose
(Precose, Glucobay), miglitol (Glyset, Diastabol) voglibose (Basen) .. 2547
acarbose voglibose [13]

acarbose carbohydrate-like polymer miglitol voglibose

polyhydroxylated cyclohexane
OH

Miglitol
(Glyset, Diastabol)

Acarbose
(Precose, Glucobay)

N
HO
HO

carvosine

OH

HO

OH
OH

HO

OH

H3C
HO

HN
HO

HOH2C

OH

OH

Voglibose
(Basen)
OH

NH

HO

HO
HOH2C

OH

O
HO

HO
OH

OH
OH

OH

11: alpha-glucosidase inhibitors

alpha-glucosidase inhibitors -glucosidase (isomaltase,

maltase, glucomaltase) brush border -glucosidase
oligosaccharide monosaccharide
monosaccharides acarbose
-amylase polysaccharide oligosaccharide

2%
1

4-1

239

51% 96
[14]
acarbose miglitol 25 mg 1-2
2-4 100 mg 3
[12]
18: Alpha-Glucosidase Inhibitors[12,16]
Generic Name
Trade Name
Tablet Strength (mg)
Acarbose
Prelose, Glucobay
25; 50; 100
Miglitol
Glyset, Diastabol
100
Voglibose
Basen
0.2; 0.3

Daily Dose (mg)

25-100 with meals
25-100 with meals
-

Frequency of Administration
3 times/day
3 times/day
3 times/day

alpha-glucosidase inhibitors A1C

0.7-1.0% ( 10)

(bowel
obstruction) (malabsorption) (liver cirrhosis)

[12]

alpha-glucosidase inhibitors
digoxin alpha-glucosidase inhibitors digoxin
digoxin

4-1H

(insulin) beta cell

preproinsulin
proinsulin insulin
6000 chain A (21
amino acids) chain B (30 amino acids)
(disulfide bridges) 2

12: human insulin

240

1. Mechanism of Action
(adipose tissues) (muscles) (liver)
intrinsic tyrosine kinase insulin receptor membrane permeability

2. Therapeutic Indications of Insulin

1
2 (primary failure)
(secondary failure)

(rapid-acting preparations)
diabetic ketoacidosis hyperglycemic nonketonic
coma (liver or renal failure)

3. Types of Insulin[26]
Very fast acting insulins
very fast acting insulins lispro (Humalog) insulin aspart
(Novolog) 15
15 5-15
45-90 3-4 regular insulin 30-45
lispro
Fast acting insulins
fast acting insulin regular insulin 2-5
5-8

13: Approximate Pharmacokinetic Profiles of Human Insulin and Insulin Analogues.

4-1

241

19: onset duration[26]

Type
Very fast acting
Lispro insulin
Aspart insulin

Onset

Peak

Duration

Comments

Humalog*

15 min

30 90 min

3 - 5 hr

Novorapid*

10 -20 min

1-3 hr

3 - 5 hr

Change conformation in insulin structure

that favors the formation of monomer
Replace proline with aspartic acid make
faster dissolution rate coz negative
charge of aspartic at physiologic pH

Humulin R*
Actrapid HM*

30 min - 1 hr

2 5 hr

5 8 hr

Iletin II Regular

30 min - 2 hr

3 - 4 hr

4 - 6 hr

Humulin N*
Insulintard HM*

1 - 3 hr

6 - 12 hr

20 - 24 hr

Iletin II NPH
Humulin L
Novolin L

4 - 6 hr
1 - 3 hr

8 - 14 hr
6 - 12 hr

16 - 20 hr
20 - 24 hr

Iletin II Lente

4-6 hr

8 - 14 hr

16 - 20 hr

Long acting
Ultralente insulin

Humulin U

4 - 6 hr

18 - 28 hr

28 hr

Human recombinant DNA-based

Usually used in combination with a
faster-acting insulin to provide proper
control at mealtimes
The complexation of insulin and high zinc
concentration in acetate buffer

Ultra-long acting
Glargine insulin

Lantus*

1.1 hr

No peak

Constant
concentration
over 24 hours

Human recombinant DNA-based

Injected once daily at bedtime
Change amino acids on A and B chain of
insulin make stabilizing insulin
hexamer

Humulin 70/30*
Mixtard 30HM*

0.5 hr
0.5 hr

1-5 hr
2-8 hr

24 hr
24 hr

Humalog Mix 75/25*

15 min

Dual

22 hr

12-20 min

1-4 hr

24 hr

70 % NPH and 30% regular

Available in vials, pen-fill cartridges,
and prefilled syringes
75%NPL(a new NPH formulation)and25%
lispro; available in disposable pen.
30% aspart insulin and 70% NPL

Fast acting
Regular insulin

Intermediate acting
NPH (Neutral
Protamine
Hagedron)

Lente

Brand Name

Human recombinant DNA-based

Often injected before meals to
compensate for the sugar intake from
food
Pork-based
Human recombinant DNA-based
The complexation of insulin, protamine
and zinc reduces solubility, and slower
dissolution rate at site of injection
Pork-based
Human recombinant DNA-based
The mixture of amorphous and crystalline
insulin in acetate buffer
Pork-based

Mixtures

Novomix 30*

242

Intermediate acting insulins

NPH (N) Lente (L) insulin 1-3
6-12 20-24
Long acting insulins
Ultralente insulin (complex with high
zinc concentration) (acetate buffer)
4-6 28
Ultra-long acting insulins
ultra-long acting insulins glargine
24 (without any peaks)
Insulin mixtures
insulin mixtures regular insulin lispro insulin
insulin aspart 10% 50%

4. Insulin Regimens
Once daily injection

intermediate acting : NPH

mixed insulin
: NPH/RI hypoglycemia
Twice daily injection
intermediate acting : NPH 2/3 1/3 12 .
mixed insulin
: NPH/RI 2/3 1/3 12 .
Multiple daily injection
RI tid + NPH

5. Insulin

insulin
SC RI
: (Pre-filled insulin pens)
pump ( basal line

2 )
(Inhalation) alveoli phase III
-
- peptidases ( insulin )
- insulin first pass metabolism
- alveolar-capillary barrier

4-1

243

6. Onset and Duration

Renal failure : decrease insulin clearance
Rate of absorption:

7. Complication of Insulin Therapy

hypoglycemia
lipodystrophy at injection site
- lipoatrophy loss subcutaneous pork insulin
- lipohypertrophy
immunopathology
- Insulin allergy Anaphylaxis non
insulin contaminant
- Immune insulin resistance anti-insulin antibody insulin

8. Insulin Resistant
insulin receptor insulin affinity
receptor 2 1

9.


1

4-1I

5
(improve glucose-dependent insulin secretion) (suppressing
glucagon secretion) (delaying gastric emptying)
(decrease appetite)[10]
exenatide (Byetta) pramlintide acetate (Symlin)

1. Exenatide[27,28]
exenatide (Byetta) Gila
monster 39-amino acid peptide amide (C184H282N50O60S) human incretin
glucagons-like peptide-1 (GLP-1)

244

14: exenatide

exenatide GLP-1 receptor GLP-1 (slow metabolic breakdown)

FPG PPG
exenatide 2
metformin, sulfonylurea combination

15: exenatide

exenatide (sterile solution) 250 mcg/ml

(subcutaneous) 5 mcg 2 60
10 mcg 2 1

2. Pramlintide Acetate[27]
pramlintide (Symlin) human amylin beta cell
PPG

16: pramlintide

pramlintide 1 mealtime insulin therapy

2 amylin beta cell

17: pramlintide

pramlintide pramlintide acetate 0.6 mg/ml

(vial) 5 ml (subcutaneous)
1 15 mcg 15 mcg 30-60 mcg
2 60 mcg 120 mcg

4-1

4-1J

245

NICE Guidelines National Institute

for Clinical Excellence ADA Clinical Practice Recommendations American Diabetes Association
(ADA) Global Guideline International Diabetes Federation CDA Clinical Practice Guidelines
Canadian Diabetes Association (CDA)
( carbohydrate 55-60%,
protein 15-20% fat 20-30%)

18: 2 Canadian Diabetes Association[29]

* When used in combination with insulin, insulin sensitizers may increase the risk of edema or CHF. The combination of
an insulin sensitizer and insulin is currently not an approved indication in Canada.
** If using preprandial insulin, do not add an insulin secretagogue.

May be given as a combined formulation: rosiglitazone and metformin (Avandamet).

246

20: Food and Drug Administration (FDA) approved Indications for Oral Antidiabetic Agents[12]
Drug
FDA- approved Indications
Sulfonylureas
Monotherapy or with metformin, thiazolidinediones, alpha-glucosidase inhibitors, or insulin
Non-sulfonylurea secretagogues
Monotherapy or with metformin
Biguanides (Metformin)
Monotherapy or with sulfonylurea or insulin
Thiazolidinediones
Monotherapy or with sulfonylurea, metformin, or insulin (Rosiglitazone not approved for use
with insulin)
Alpha-glucosidase inhibitors
Monotherapy or with sulfonylurea, metformin, or insulin (Miglitol only approved for use with
sulfonylurea)
Glucovance
Monotherapy or in combination with a thiazolidinediones
Metaglip
Monotherapy
Avandamet
Monotherapy

1. Monotherapy
5
A1C
alpha-glucosidase inhibitors nateglinide[10,11]
(monotherapy)
A1C 0.5-2%
[30] UKPDS metformin sulfonylureas

21: [29]
Key adverse effects
Key precautions/contraindications
Hepatic disease
Gastrointestinal upset, loose bowels
glibenclamide, biguanide, insulin sensitizers
biguanide
Significant renal insufficiency
Hypoglycemia
biguanide, sulfonylureas
insulin, insulin secretagogues (less with gliclazide, glimepiride,
nateglinide and repaglinide than with glibenclamide)
Significant cardiac failure
Edema, fluid retention
biguanide, insulin sensitizers
insulin sensitizers, rarely with insulin
Sulfa allergy
Moderate weight gain
sulfonylureas
insulin, insulin secretagogues, insulin sensitizers

sulfonylureas beta cell

(normal weight)[12,31] sulfonylureas
(hypoglycemia) NICE Guideline 3 gliclazide, glibenclamide, glimepiride[18]
gliclazide (Diamicron) sulfonylureas NICE Guideline
half-life (hypoglycemia)

4-1

247

severe renal disease

40 mg/day 160 mg/day 2 [18]
glibenclamide (Daonil, Euglucon) NICE Guideline
(hypoglycemia)
2.5
mg/day 15 mg/day[18]
glimepiride (Amaryl) second choice NICE Guideline
(hypoglycemia)
1 mg/day 4 mg/day
[18]
non-sulfonylurea secretagogues sulfonylureas
sulfonylureas
metformin (Glucophage) (BMI 25 kg/m2)
(weight gain)
(hypoglycemia) (heart failure)
(serum creatinine >130 mmol/l) lactic acidosis[32]
22: Options for monotherapy[31]
Drug Class
Sulfonylureas

Non-sulfonylurea secretagogues

Biguanides

Target population
Recent type 2 DM
diagnosis
Type 2 DM < 5 years
duration
Recent type 2 DM
diagnosis
Elevated postprandial
glucose
Overweight/obese
Insulin resistant

Advantages
Rapid fasting plasma
glucose
Low cost

Disadvantages
Weight gain
_Risk of hypoglycemia

of hypoglycemia
Short-acting
Meal-adjusted dosing

High cost

No weight gain
of hypoglycemia

GI side effects
High cost
Rare lactic acidosis
High cost
Weight gain
Slow onset of action
Issue of liver toxicity
High cost
GI side effects

Risk

Risk

Thiazolidinediones

Insulin resistant
Overweight/obese

Amount

of insulin
Risk of hypoglycemia

Alpha-glucosidase nhibitors

Elevated postprandial
glucose

Risk

of hypoglycemia

thiazolidinediones thiazolidinediones
HDL-cholesterol triglyceride hypoglycemia insulin
sensitizer [12] 6-10
[32] (weight gain)
thiazolidinediones
(edema) (CHF)[32]

248

alpha glucosidase inhibitor

50 mg/day 50-100 mg 3
[18]

2. Combination
A1C
(<7.0%) sulfonylurea + metformin sulfonylurea
+ thiazolidinedione ( metformin ) metformin + thiazolidinedione (
) A1C 1-2%
[30] sulfonylurea + alpha-glucosidase inhibitor metformin +
repaglinide metformin + alpha-glucosidase inhibitor[31]
Glucovance (glibenclamide metformin) Avandamet (rosiglitazone metformin)
23: Options for monotherapy[16]
Trade Name
Composition
Glucovence
metformin + glibenclamide
Metaglip
metformin + glipizide
Avandamet

metformin + rosiglitazone

Tablet Strength
500 mg metformin + 1.25, 2.5, or 5 mg glibenclamide
250 mg metformin + 2.5 mg glipizide;
500 mg metformin + 2.5 mg glipizide
500 mg metformin + 1, 2, or 4 mg rosiglitazone

(combination) (submaximal
doses) (monotherapy)
(maximal doses)
(triple therapy)
A1C [30]

References
[1] . : . ..2545. [PDF
on the internet], Available from: URL: http://www.thaiendocrine.org/news_files/news_file_186.pdf [Accessed May 10, 2006]
[2] . 3. .
2541.
[3] . : Evidence - Base Clinical Practice Guideline
2548. . 2548.
[4] Abbate SL. Expanded ABCs of Diabetes. Clinical Diabetes. 2003;21(3):128-33.
[5] Schrot RJ. Targeting Plasma Glucose: Preprandial Versus Postprandial. Clinical Diabetes. 2004;22(4):169-72.
[6] American Diabetes Association. Standards of Medical Care in Diabetes-2006. Diabetes Care. 2006;29(suppl 1):S4-42.
[7] McWeeny M. (). .
[8] . . .
[9] , , , , , ,
. . . [PDF on the internet],
Available from: URL: http://www.nephrothai.org/download/Prevention_of_DN.pdf [Accessed May 24, 2006]

4-1

249

[10] Kimmel B, Inzucchi SE. Oral Agents for Type 2 Diabetes: An Update. Clinical Diabetes. 2005;23(2):64-76.
[11] IDF Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation,
2005.
[12] Koski RR. Oral Antidiabetic Agents: A Comparative Review. Journal of Pharmacy Practice. 2004;7(1):39-48.
[13] . . .. 2547.
[14] Harmel AP, Mathur R. Davidsons diabetes mellitus: diagnosis and treatment. 5th edition. Elsevier Science. USA. 2004;71108.
[15] Melander A. Kinetics-Effect Relations of Insulin-Releasing Drugs in Patients With Type 2 Diabetes. Diabetes.
2004;53(suppl 3):S151-5.
[16] Mehanna AS. TEACHERS TOPICS; Insulin and Oral Antidiabetic Agents. American Journal of Pharmaceutical Education.
2005;69(5):1-10.
[17] Harrigan RA, Nathan MS, Beattie P. Oral Agents for the Treatment of Type 2 Diabetes Mellitus: Pharmacology, Toxicity,
and Treatment. Ann Emerg Med. 2001;38(1):68-78.
[18] NICE Guideline. Guide to the management of diabetes for primary care practitioners in West Hertfordshire. National
institute for clinical excellence.
[19] Langer O, Conway DL, Berkus MD, Xenakis EM-J, Gonzales O. a comparison of glyburide and insulin in women with
gestational diabetes mellitus. N Engl J Med. 2000;343:1134-8.
[20] Siluk D, Kaliszan R, Haber P, Petrusewicz J, Brzozowski Z, Sut G. Antiaggregatory activity of hypoglycaemic
sulphonylureas. Diabetologia. 2002;45(7):1034-7.
[21] Larkins RG, Jerums G, Taft JL, Godfrey H, Smith IL, Martin TJ. Lack of effect of gliclazide on platelet aggregation in
insulin-treated and non-insulin-treated diabetes: a two-year controlled study. Diabetes Res Clin Pract. 1988;4(2):81-7.
[22] Minami N, Ikeda Y, Abe M. Preventive and therapeutic effects of gliclazide on diabetic retinopathy: comparison with
glibenclamide treatment. Tohoku J Exp Med. 1983;141(Suppl):707-11.
[23] Davidson MB, Peters AL. An Overview of Metformin in the Treatment of Type 2 Diabetes Mellitus. Am J Med.
1997;102:99-110.
[24] . . . 3. ..2545.
[25] Jarvinen HY. Thiazolidinediones. N Engl J Med. 2004;351:1106-18.
[26] Life Clinic International. Insulin. [Homepage on the internet], Available from: URL: http://www.lifeclinic.com/focus/diabetes/
supply_insulin.asp [Accessed June 4, 2006]
[27] DeRuiter J, Holston PL. New Drug Review. U.S. Pharmacist. Jobson Publishing. [Homepage on the internet], Available
from: URL: http://www.uspharmacist.com/index.asp?page=ce/105131/default.htm [Accessed May 28, 2006]
[28] . Exenatide: FDA . [PDF on the
internet], Available from: URL: http://www.pharmacy.cmu.ac.th/dic/dic/newsletter/newpdf/newsletter8_5/Exenatide.pdf
[Accessed May 10, 2006]
[29] Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003
Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2003;27(suppl 2)
[30] Warren RE. The stepwise approach to the management of type 2 diabetes. Diabetes Research and Clinical Practice.
2004;65S:S3-S8.
[31] Luna B, Feinglos MN. Oral Agents in the Management of Type 2 Diabetes Mellitus. Am Fam Physician. 2001;63(9):174756.
[32] McIntosh A, Hutchinson A, Home PD, Brown F, Bruce A, Damerell A, Davis R, Field R, Frost G, Marshall S, Roddick J,
Tesfaye S, Withers H, Suckling R, Smith S, Griffin S, Kaltenthaler E, Peters J, Feder G Clinical guidelines and evidence
review for Type 2 diabetes: management of blood glucose. Sheffield: ScHARR, University of Sheffield. 2001.

250

4-2

(thyroid gland) 3 tetraiodothyronine (thyroxine; T4),

triiodothyronine (T3) calcitonin
T3 T4 thyroid hormone
metabolism calcitonin
calcium metabolism

4-2A

Synthesis, Storage and Secretion of Thyroid Hormone

synthesis, storage and secretion 3

1. follicle cells (thyroid epithelial cells) thyroglobulin follicle lumen plasma
iodide active transport
2. iodide oxidize thyroperoxidase H2O2 (iodination)
thyrosine thyroglobulin
3. follicle cells thyroid hormone

1: Thyroid hormone synthesis. Iodide is transported from the plasma, through the cell, to the apical membrane where it is
organified and coupled to thyroglobulin (TG) synthesized within the thyroid cell. Hormone stored as colloid reenters the cell
through endocytosis and moves back toward the basal membrane, where T4 is secreted. Nonhormonal iodide is recycled.

4-2

251

NH2
HO

CH2 CH COOH
Tyrosine
I

NH2

NH2
CH2 CH COOH

HO

Monoiodotyrosin
(MIT)

CH2 CH COOH

HO

Diiodotyrosin
(DIT)

I
NH2

HO

CH2 CH COOH

I
Triiodothyronine (T3)
I

I
NH2

HO

CH2 CH COOH

I
Thyrosine (tetraiodotyronine, T4)

2: tyrosine thyroglobulin iodine 2 3 tyrosine monoiodotyrosine (MIT)

3 5 diiodotyrosine (DIT) thyroglobulin (TG) tyrosine iodine
MIT DIT T3 (triiodothyronine) DIT 2 T4 (tetraiodothyronine;
thyroxine) thyroid gland T3 T4

3: follicle cells endocytosis T3 T4 vesicle lysosome proteolytic

enzyme T3 T4 thyroglobulin follicle cells T3 T4 plasma

252

4-2B

Transport and Metabolism

T3 T4 3 thyroid-binding globulin (TBG), thyroid-binding

prealbumin (TBPA) albumin
1: thyroid hormone
Thyroid-binding protein
Thyroid-binding globulin (TBG)
Thyroid-binding prealbumin (TBPA)
Albumin

T4
70
10
20

T3
77
8
15

T3 99.5 T4 99.96 3
unbound (free) thyroid hormone
peripheral tissue 5-monoiodinase T4 T3 T4
T3 T3 T4
T3 T4 metabolite deionization, deamination, glucoronidation sulfation
free form conjugated form

4-2C

Mechanism of Action

T3 T4 T4 T3 thyroid hormone receptors

cytoplasm translocate nucleus target gene

4-2D

Regulation of Thyroid Function

thyroid hormone hypothalamic-pituitary-thyroid axis TRH (thyrotrophinreleasing hormone) hypothalamus thyrotrophin (thyroid-stimulating hormone; TSH)
anterior pituitary TSH follicle cell adenylated cyclase cascade cAMP
secondary messenger thyroid hormone
Cold

Trauma

Stress

Hypothalamus
Somatostatin

TRH

Protiretin

Anterior pituitary
IThioureylenes
Excess of exogenous iodide
131
I

Thyrotrophin
Thyroid
T4
T3
4: thyroid hormone

4-2

253

T3 T4 hypothalamic-pituitary-thyroid axis negative feedback

T3, T4 iodine T3 T4
T4 T3 thyroid gland
nonthyroidal hormone
2: Thyroid Hormone Synthesis and Secretion Inhibitors
Mechanism of Action
Block iodide transport into thyroid
Impairs organification and coupling of thyroid hormones
Inhibits thyroid hormone secretion

4-2E

Substance
Bromine, Fluorine, Lithium
Thionamides, Sulfonylureas, Sulfonamide(?)
Salicylamide(?), Antipyrine(?)
Iodide (large doses), Lithium

Actions of Thyroid Hormones

thyroid hormones physiological action 2

metabolism
insulin, glucagon,
glucocorticoids catecholamines carbohydrate, protein fat metabolism
basal metabolic rate O2 ( O2
consumption)

thyroid hormone
growth hormone parathyroid hormone

triiodothyronine (T3) thyroxine (T4) 3-5 T4

T3

4-2F

Thyroid Function Test

thyroid function test

thyroid disorders FT4 TSH
Thyroid function test
FT4 (free thyroxine) FT4 FT4 TT4 (total
thyroxine) FTI4 (free thyroxine index) TT4 RT3U (resin T3 reuptake)
TSH
RAIU (131I radioactive iodine uptake) thyroid gland function 131I
radioactive iodine 131I hyperthyroidism 131I therapy
thyroid antibody ATgA (antibody to thyroglobulin)
TPO (thyroperoxidase antibodies) autoimmune TrAb (thyroid
receptor IgG antibody) autoimmune Graves disease
thyroid scan (Scan) thyroid gland function

254

3: Thyroid Function Test

Test
TT4
FT4

FT4I

RT3U

T4 U

TT3

FT3I
131

Normal Values
Measures
Hyperthyroidism
64-142 mmol/L
Total T4, both free and bound
u
(5-11 mcg/dL)
9-24 pmol/L
Direct measure of free T4 by
u
(0.7-1.9 ng/dL)
equilibrium dialysis or
analog metthod
Indirect estimate of active free
16-50 mmol/L
u
(1.3-4.2) calcula- T4 levels
ted index using
product of RT3U
and TT4
107-118 mmol/L
(6.5-12.5) calculated index by dividing TT4 by T4
uptake
0.25-0.37
Indirect measure of degree of
u
(25-37%)
saturation of TBG sites by
T4
0.6-1.2
Available binding sites on
u
TBG, prealbumin, and
albumin
1.1-2.0 nmol/L
Total T3 (free and bound)
u
(70-132 ng/dL)
0.28-0.75 nmol/L
(18-49 ng/dL)

I radioactive 5-15% at 5 hr
iodine up- 10-35% at 24 hr
take

TSH

0.5-4.7 mIU/L

Thyroid antibodies
ATgA
0-8%

Product of RT3U and TT3;

calculated estimate of active
free T3 levels
Iodine-trapping ability of gland

Pituitary TSH

Autoimmune process

Hypothyroidism
Comments
Affected
by
changes in TBG
v
v

Levels reflect true thyroid status; not affected by changes in

TBG
Compensates for changes in
TBG concentration; reflects
true thyroid status except in
euthyroid sick syndrome

Affected by changes in TBG

Affected by changes in TBG,

prealbumin, and albumin

Affected by changes in TBG; not

useful in diagnosis of hypothyroidism
See comments for FT4I

v or u in subclinical hypothyroidism

Often positive
Often positive
(Graves disease) (Hashimotos
thyroiditis)
Autoimmune process
Often positive
Often positive
(Graves disease) (Hashimotos
thyroiditis)
Immunoglobulin G in Graves Often positive
Often negative
disease
(Graves disease)

TPO

<100 IU/L
(<100 IU/mL)

TrAb

Negative

Thyroid scan

Isotopes scan with Detects hypofunctioning (cold)

123
I or 99TcO4
and hyperfunctioning (hot)
nodules and estimates size
of gland

Normals vary depending on degree of dietary iodide intake

and geographic area; interfered by iodide intake (i.e.,
contrast dye)
Most sensitive indicator of adequate circulating hormone
levels
TPO more sensitive than ATgA,
elevated even with remission

Indicates Graves disease,

predictive for neonatal Graves
disease during pregnancy
Not usually done unless discrete
nodules are felt on physical
examination

TT4, total thyroxine; T4, thyroxine; TBG, thyroxine-binding globulin; FT4, free thyroxine; FT4I, free thyroxine index; RT3U, resin T3 uptake; T4U, T4 uptake; TT3, total T3; FT3I,
free T3 index; T3, triiodothyronine; TSH, thyrotropin-stimulating hormone; ATgA, thyroglobulin antibody; TPO, thyroperoxidase antibody.

4-2

255

4: Summary of Laboratory Alterations by Drug or Disease State

131
Drug or Disease
Mechanism
TT4
RT3U
FT4/FT4I
TT3
I Uptake
Estrogens, oral contraceptive, u serum TBG
No change
No change
u
v
u
pregnancy, heroin, methaconcentrations
done, clofibrate, acute and
chronic active hepatitis,
familial u TBG
Glucocorticoids (stress
v
u
v
v
Slight v
v serum TBG
dosages)
concentrations,
v TSH secretion, v T4 to T3
conversion
Androgens, anabolic steroids, v serum TBG
No change
No change
v
u
v
danazol, L-asparaginase,
concentrations
nephritic syndrome,
cirrhosis, familial v TBG
Phenytoin in vitro, high- dose Displacement of
No change
v
v
u or little to No change
heparin, furosemide, salicy- T4 and T3 from
no change
lates (level >15 mg/100
TBG
mL), phenylbutazone,
fenclofenac, halofenate,
mitotane, chloral hydrate,
5-fluorouracil
Serotonin reuptake inhibitors v serum TBG v or no change u or v or v or no change v or no
u or no
(e.g., sertraline)
no change
change
change
concentrations;
?u T4 clearance
No change No change
No change
Iodide-containing com-pounds, Dilution of total No change if
v
contrast media, providonebody iodide
test not iniodine, kelp, tincture of
pools
terfered by
iodine, saturated solution
iodide (i.e.,
potassium iodide, Lugol,s
radioimmusolution, amiodarone
noassay)
No change No change No change No change Might be u
Strong diuresis by furosemide, Decrease total
ethacrynic acid; iodine
body iodide
deficiency
pools
Phenytoin, carbamazepine,
Hepatic enzyme v or normal u or no
v or normal No change No change
rifampicin, phenobarbital
inducer of T4
change
metabolism

Propranolol, old age, fasting,

malnutrition, acute and
chronic systemic illness
(e.g., euthyroid sick
syndrome)

Impair peripheral
conversion of T4
to T3; urT3

Normal or v No change

Normal or v Usually low

No change

Dopamine, levodopa, highdose glucocorticoids,

bromocriptine
Amiodarone, iopodate,
iopanoate

Dopamine suppresses TSH

secretion
Impair pituitary
and peripheral
conversion of T4
to T3

No change

No change

No change

No change

No change

No change

TSH
Comments
No change FT4/FT4I corrects for
TBG alterations;
TSH indicates true
thyroid status
v

Evaluate thyroid status

after steroids are
stopped

No change FT4/FT4I corrects TBG

alterations; TSH indicates true thyroid
status
No change FT4/FT4I corrects TBG
alterations; TSH indicates true thyroid
status

u or no change Sertraline reported to

cause hypothyrodism
No change No change in thyroid
status

No change No change in thyroid

status
No change in No change in euthyroid
euthyroid
patients not on T4
patients not
replacement
on T4 replacement
No change but Thyroid replacement
not necessary
in euthyroid
sick syndrome,
slight u or v
in TSH might
occur
v TSH secre- Not enough to interfere
with diagnosis of
tion
hyperthyroidism
Transient u Thyroid abnormalities
transient; should be
normal within 3 mo;
can cause thyroid
dysfunction in predisposed patients

256

4-2G

Thyroid Disorders

thyroid disorders hyperthyroidism hypothyroidism

thyroid disorders
5: Drug-Induced Thyroid Disease
Drug
Nitroprusside
Lithium

Mechanism
Metabolized to thiocyanate, an anion
inhibitor
Inhibits hormone release

Iodides and iodine-containing

compounds (e.g., amiodarone,
ipodate, iodinated contrast media)

Inability to escape from Wolff-Chaikoff

block

Iodides and iodine-containing

compounds (e.g., amiodarone,
ipodate, iodinated contrast media)
Amiodarone

Provides substrate to iodide- deficient

autonomous thyroid tissue; loss of
Woff-Chaikoff block
Destruction thyroiditis, with dumping of
hormones into circulation
?? related to u T4 elimination

Sertraline

Sulfonylureas, sulfonamides, resorcinol, Inhibits organic binding and

phenylbutazone
organification
Autoimmune process
Immunotherapy (e.g., interferon-,
interleukin-2)
Natural goitrogens (e.g., cabbage)
Contains thiocyanate and other
goitrogens

Drug-Induced Thyroid Effect

Goiter, hypothyroidism
Goiter, hypothyroidism,
hyperthyroidism
Hypothyroidism, goiter

Hyperthyroidism

Hyperthyroidism
Hypothyroidism, thyroidstimulating hormone
Hypothyroidism, goiter
Hypothyroidism, hyperthyroidism
Hypothyroidism, goiter

Comments
Increased risk with renal failure and
duration of use
Usually in patients with untreated thyroid
disease (e.g., Hashimotos thyroiditis)
Usually in patients with untreated
Hashimotos thyroiditis or following
treatment of Graves disease with
radioactive iodine or surgery and not
receiving thyroid replacement
Usually in patients with multinodular
goiters and autonomous nodules
(Jod-Basedow disease)
Associated with elevation of interleukin-6
levels
Prevalence unknown; unknown whether
disease occurs with other serotonin
reuptake inhibitors
Rare cause of thyroid disease
Generally transient, resolves without
treatment
Rare; occurs only with consumption of
large amounts of raw vegetables

thyroid disorders

5: thyroid disorders

4-2

257

TSH FT4 euthyroid

thyroid hormone level
thyroid gland function
hypothalamic - pituitary - thyroid axis
autoimmunnity thyroid antibody
Thyroid disorders
thyroid hormone thyroid hormone
(thyroid symptoms) (tenderness)
thyroid disorder

target system thyroid hormone

thyroid antithyroid drug
thyroid function test
thyroid disorders

6: thyroid disorders
Drug
Sympathomimetics (e.g.,
asthma and cold
preparations)
Digoxin and digitalis
preparations

Insulin

Coumadin

-Blockers (propranolol,

Hyperthyroidism
u sensitivity to catecholamines;
exacerbation of thyrotoxic
symptoms, especially cardiac
u volume of distribution and renal
clearance of digoxin; might need
u dosages to achieve
therapeutic effect
u insulin metabolism and clearance;
exacerbation of diabetes
u metabolism of clotting factors; v
half-life of clotting factors; v
coumadin needed for anticoagulation
u metabolic clearance

Hypothyroidism
Blunted response to sympathomimetics (insignificant)

Comments
u hyperthyroid symptoms even if
thyroid function tests normal

u sensitivity to digoxin therapeutic

and toxic effect; v digoxin
needed to achieve therapeutic
effect
Prolonged insulin effect; u risk of
hypoglycemia and v insulin to
control type II diabetes
v metabolism of clotting factors; u
half-life of clotting factors; u
coumadin needed for
anticoagulation
Not significant

Need to adjust dosages as thyroid

function changes to maintain
efficacy and avoid toxicity

metoprolol, atenolol)
Respiratory depressant (e.g.,
barbiturates, phenothiazines, narcotics)
Theophylline

Not significant

Not significant

Increased sensitivity to respiratory

depressant effects of sedativehypnotic agents
v metabolic clearance

L-thyroxine

v serum half-life to 3-4 days

u half-life to 9-10 days

Cortisol

v serum half-life to 50 min

u half-life to 155 min

Need to adjust insulin dosages in

patients with type II diabetes as
thyroid status changes
Need to adjust dosages as thyroid
function changes to maintain
efficacy and avoid toxicity
Might require higher dosages for
desired clinical response in
hyperthyroidism
Increased CO2 retention; might
precipitate myxedema coma; use
cautiously in hypothyroidism
Might need less drug for clinical
response; monitor for toxicity
Changes in time to steady-state levels
and monitoring of thyroid function
tests
Might need u steroids in management of hyperthyroidism

258

4-3

(hyperthyroid, thyrotoxicosis)

4-3A

Signs and Symptoms

(symptoms)
(nervousness) (anxiety) (palpitations) (emotion liability)
(heat intolerance) (cardinal sign)

(sign)
(onycholysis) (exophthalmos) (eyelid retraction)
(lid lag) pretibial myxedema
tachycardia gynecomastia neuromuscular fine tremor
protruded tongue (, ) outstretched hands () deep tendon
reflex hyperactive thyroid gland (thyromegaly)

4-3B

Diagnosis

T3 T4 serum concentration TSH serum concentration

RAIU (differential diagnosis)

4-3C

Thyrotoxicosis

1. Thyrotoxocosis with elevated RAIU

TSH induced hyperthyroidism
TSH secreting pituitary adenomas
tumor pituitary gland TSH tumor
feedback control tumor prolactin growth hormone
(amenorrhea) (galactorrhea) acromegaly
(transphenoidal surgery) bromocriptine tumor prolactin
Pituitary resistance to thyroid hormone
pituitary gland feedback control thyroid hormone TSH

4-3

259

Thyroid stimulators TSH

Graves disease
Graves disease autoimmune disease IgG
thyroid-stimulating antibody (TsAb) thyrotropin receptor thyroid cell
secondary messenger TSH feedback control
(heredity)
(spontaneous remission) Graves disease thyrotoxicosis
(dermopathy)
Trophoblastic disease
trophoblastic tumors hCG (human chorionic gonadotropin) hCG
serum concentration hyperthyroidism hCG
TSH thyroid hormone
Thyroid autonomy
Toxic adenoma (Autonomous thyroid nodule)
thyroid gland pituitary gland
hormone nodule hyperthyroidism toxic
adenoma thyroid nodule
Multinodular goiters (Plummers disease)
toxic adenoma nodule thyroid gland

2. Thyrotoxocosis with suppress RAIU

Inflammatory thyroid disease (Subacute thyroiditis)
Painful subacute thyroiditis (Viral or Quervains thyroiditis)
thyroid parenchyma
thyroid gland thyroid hormone thyroid
hormone thyroid gland
viral thyroiditis (2-6 )
antithyroid drugs -blocker,
aspirin (650 mg po 6 ) prednisolone (20 mg po tid)

Painless thyroiditis (Lymphocytic or Postpartum thyroiditis)

3 painful subacute thyroiditis
painless thyroiditis (postpartum period)

260

Ectopic thyroid tissue

Struma ovarii
teratoid tumor thyroid hormone
Follicular cancer
fllicular carcinomas Thyroid gland metastatic thyroid
hormone

3. Exogenous sources of thyroid hormone

Thyrotoxicosis factitia
hyperthyroidism exogenous thyroid hormone
(menstrual irregularities) (infertility) (baldness)

amiodarone iodine

4-3D

Thyrotoxicosis

1. Treatment Goal

sign symptoms hyperthyroidism

thyroid hormone TSH
systemic embolism
(osteoporosis)

2. Hyperthyroidism
3
antithyroid drugs
Antithyroid drugs hyperthyroidism 1
4
thyroid gland
( 6-75) hypothyroidism
1
(I131 therapy)
( 24-90) hypothyroidism

4-3

261

3. Hyperthyroidism
Propylthiouracil (PTU) - Propacil
propylthiouracil 2-thiouracil
tautomerization
OH

O
H

HN

CH3

CH3

CH3

CH3
HS

Keto form
Thioketo form

HS

CH3

CH3

Enol form

Thioenol form

Methimazole (MTZ) - Tapazole

methimazole 2-thioimidazole
tautomerization
HN

HS

N
CH3

N
CH3

Thioketo form

Thioenol form

propylthiouracil methimazole antithyroid drugs hyperthyroidism

2
1: Adverse effect of thionamides
Skin

Adverse Effect
Pruritic, maculopapular rash

Haematological

Rash with systemic symtomps,

i.e. fever, arthralgia
Agranulocytosis

Leucopenia

Other

Hepatitis
Vasculitis
Hypoprothrombinaemia
Aplastic anaemia
Thrombocytopenia

Comments
Most common in first 6 weeks
May disappear spontaneously with continued treatment
Can be treated with an antihistamine
Change to alternative agent
Occurs in 5% of patients
Discontinue drug
Alternative treatment required
Most common in first 6 weeks
Incidence increases with age
Discontinue drug
Reversible
Consider alternative treatment
Occurs in 0.5% of patients
Transient
Continue treatment
Dose not predispose to agranulocytosis
Rare
Discontinue drug

262

Adrenergic antagonist
-blocker pheripheral action thyroid hormone
ditiazem
OH

OH

HN

Metoprolol

Propanolol
OH
HO

OH
OH

O
O

HN

HN
H2N

Atenolol

2: Management of Hyperthyroidism
Maintenance Dose
Modality
(mg/day)
Thiourea drugs
Propylthiouracil (PTH) 50200-600
mg tablets
Methimazole (Tapazole) 510-60
and 10-mg tablets
-Adrenergic antagonists*
Propranolol
80-160
Nadolol
80-160
Lodine-containing compounds
Lugols solution
750
Potassium iodide (SSKI)
10-300
Miscellaneous
Potassium perchlorate
NA
Lithium carbonate
NA

Maximal Dose
(mg/day)
1200
120

480
320

Surgery

Actions
Inhibit thyroid synthesis (PTU
also inhibits peripheral conversion of T4 to T3); may
exert immunosuppressive
actions
Ameliorate action of thyroid
hormone in tissues

NA
NA

NA

2-10 mCi

NA

NA

Indications
First-line therapy for Graves
hyperthyroidism; short-term
therapy before 131I or surgery

Adjunctive therapy; often therapy required for thyroiditis

Inhibit T4 and T3 release

Preparation for surgery; thyrotoxic crisis

Inhibits iodine transport

Inhibits thyroid hormone synthesis and release
Ameliorates actions of thyroid
hormones in tissues; exerts
immunosuppressive action
(Graves disease)
Ablation of thyroid gland

No routine indications
No routine indications

750
400

Glucocorticoids

Radioactive Iodine
(RAI, 131I)

Nadolol

Removal of thyroid gland

Severe subacute thyroiditis;

thyrotoxic crisis

First-line therapy for Graves

hyperthyroidism; treatment of
choice for recurrent thyrotoxicosis; young adults to elderly;
contraindicated in pregnancy,
children, and active ophthalmopathy
Patients should be euthyroid
prior to surgery; caution in
elderly; cold iodine given prior
to surgery

NA, not applicable; SSKI, saturated solution of potassium iodide; * Not approved in the United States by the FDA for the treatment of thyrotoxicosis.

4-3

263

Antithyroid Preparations
1. Methimazole Yung Shin tab 5 mg
2. Propyl Propylthiouracil tab 50 mg
3. Propylthiouracil Greater Pharma Propylthiouracil tab 50 mg
4. Tapazole Methimazole tab 5 mg

1: hyperthyroidism

4-3E

Special Conditions

1. Graves disease and pregnancy

hCG subclinical
overt hyperthyroidism persistent
tachycardia (morbidity)
thyroid storm (spontaneous
abortion) PTU
300 mg 50-150 mg 4-6

264

2. Neonatal and Pediatric hyperthyroidism

TSAbs (thyroid stimulating antibody) hyperthyroidism
7-10 PTU 5-10 mg/kg/day MMZ
0.5-1 mg/kg/d 8-12 iodine (KI solution 1 / Lugols solution 1-3 /
) 2-3 thyroid hormone

3. Thyroid Storm
thyroid storm thyrotoxicosis
( 39.4C) (tachycardia) (tachypnea)
(dehydration) (delirium) coma thyroid storm
(precipitating factor) (trauma) RAI (radioactive
iodine) treatment antithyroid drugs
thyroid storm thyroid hormone
antiadrenergic drugs corticosteroids
thyroid storm
3: Thyroid storm
Drug
Regimen
Propylthiouracil (PTU)
900-1200 mg/day po in four or six divided doses
Methimazole
90-120 mg/day po in four or six divided doses
Sodium iodide
Up to 2 g/day IV in single or divided doses
Lugols solution
5-10 drops tid in water or juice
Saturated solution of potassium iodide
1-2 drops tid in water or juice
Propranolol
40-80 mg every 6 h
Dexamethasone
5-20 mg/day po or IV in divided doses
Prednisone
25-100 mg/day po in divided doses
Methylprednisolone
20-80 mg/day IV in divided doses
Hydrocortisone
100-400 mg/day IV in divided doses

4. Counseling
thyroid storm
6 - 2
4-6 adrenergic antagonist

(rash) (Flu-like symptoms)

4-4

265

4-4

(hypothyroid)
( 57 ) 10

4-4A

(hypothyroidism)

(symptoms) ()
(Lethargy) (Muscle cramps)
(myalgia)
(signs) objective weakness proximal muscle distal
muscle deep tendon reflexes relaxation
(periorbital puffiness) bradycardia
Carpal tunnel syndrome,
polyneuropathy cerebella dysfunction

4-4B

Triiodothyronine (T3) Tetraiodothyronine (Thyroxine; T4) serum concentration

thyrotropin-stimulating hormone (TSH) serum concentration thyroglobulin antibody
(ATgA) thyroperoxidase antibody (TPO)

4-4C

1. Primary hypothyroidism
Chronic autoimmune thyroiditis (Hashimotos disease)
Hashimotos disease antibodies enzyme thyroid peroxidase, thyroglubolin
thyroid cell antigen thyroid gland immune (cell and antibody
mediated) antibodies thyroid gland thyroid gland
hypothyroidism thyroid gland atrophy thyroid hormone
antibodies TSH

266

Itraogenic hypothyroidism
(radioiodine ) hyperthyroidism
(Graves disease) hypothyroidism 3-12
Other causes of primary hypothyroidism
hypothyroidism iodine deficiency, thyroid gland
goitrogens ( cretenism) iodine
hypothyroidism

2. Secondary hypothyroidism
Pituitary disease
pituitary gland pituitary tumor, , postpartum
pituitary necrosis (Sheehans syndrome) TSH thyroid gland
(atrophy) hypothyroidism pituitary disease TSH serum concentration
T4 serum concentration
Hypothalamic Hypothyroidism
TRH hypothyroidism

4-4D

hypothyroidism
Levothyroxine (T4 - Eltroxin)
I

I
NH2

HO

CH2 CH COONa

Levothyroxine Sodium

Lyothyronine (T3 - Cytomel, Tertroxin)

I

I
NH2

HO

CH2 CH COONa

Liothyronine Sodium

Thyroid Preparations
1. Eltroxin - Anhydrous thyroxine sodium tab 1,000 mcg
2. Euthyrox - Levothyroxine sodium tab 50 mcg, 100 mcg
3. Pondtroxin - Thyroxine sodium tab 100 mcg
4. Thiroyd - N/A tab 60 mg
5. Thyroid-s - N/A tab 60 mg
6. Thyrosit - Levothyroxine sodium tab 50 mcg, 100 mcg

4-4

267

1: Thyroid Preparations Used in the Treatment of Hypothyroidism

Drug/Dosage Form
Content
Relative Dose
Thyroid USP
Desiccated beef or
1 grain (equivalent to
Armour Thyroid (T4:T3 ratio)
pork thyroid gland
60 g of T4)
9.5 g:2.25 g, 19 g:4.5 g,
38 g:9 g, 57 g:13.5 g
76 g:18 g, 114 g:27 g
152 g:36 g, 190 g:45 g
Thyroglobulin
Partially purified pork 1 grain
Proloid 32-mg, 65-mg, 100-mg, 130thyroglobulin
mg, 200-mg tablets
Synthetic T4
50-60 g
Levothyroxine
Synthroid, Levothroid and other
generics 25-, 50-, 75-, 88-, 100-, 112-,
125-, 137-, 150-, 175-, 200-, 300-g
tablets; 200- and 500-g/vial injection
Liothyronine
Cytomel 5-, 25- and 50-g tablets
Liotrix
Euthyroid, Thyrolar 1/4-, 1/2-, 1-, 2-,
and 3-strength tablets

Synthetic T3

15-37.5 g

Synthetic T4: T3 in
4:1 ratio

50-60 g T4 and
12.5-15 g T3

Comment/Equivalency
Unpredictable hormonal stability, inexpensive
generic brands may not be bioequivalent

Standardized biologically to give T4:T3 ratio

of 2.5:1; more expensive than thyroid
extract; no clinical advantage
Stable; predictable potency; generics are
bioequivalent; when switching from
natural thyroid to L-thyroxine, lower
dose by 1/2 grain; variable absorption
between products; t1/2 = 7 d, so daily
dosing; considered to be drug of choice
Uniform absorption, rapid onset; t1/2 = 1.5 d,
monitor TSH assays
Stable; predictable; expensive; lacks
therapeutic rationale because T4 is
converted to T3 peripherally

L-thyroxine
thyroid hormone
2: L-thyroxine hypothyroidism

()
()
<45
75-100
50 1-2
hypothyroidism,
(1.6 /)
<45
50
50
hypothyroidism
1

1-2
45

45
25-50
12.5-25

1

1-2

()
100-200
100-200

100-200

268

4-4E

Special Condition

1. Myxedema Coma
myxedema coma hypothyroidism
(hypothermia), hypothyroidism
(delirium) coma myocardial infarction, sepsis
thyroxine 300-500 mcg I.V. bolus Hydrocortisone 100 mg 8
adrenal suppression mycedema coma rule out thyroxine 75-100
mcg IV maintenance dose thyroxine

2. Congenital Hypothyroidism
levothyroxine maintenance dose
45 10-15 mcg/kg/day
( 10 20 )

3. Hypothyroidism in Pregnancy
hypothyroidism
(stillbirths) psychological score
levothyroxine TSH serum concentration 1 unit/ml

4. counseling

brand
Hypothyroidism 2-3


levothyroxine 2
aluminum containing antacid

4-4

269

References
[1] Reasner CA, and Talbert RL. Thyroid Disorders. In DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, and Posey LM.
Pharmacotherapy: A Pathophysiologic Approach. fifth edition. McGRAW-HILL. pp 1359-76.
[2] . .
II: Drugs used in thyroid diseases.
[3] . .
: . 2548.
[4] . . Org Pharm
Chem II: Thyroid Hormone and Antithyroid Drugs.

5
/
5-1
5-2
5-3

5-1

273

5-1

(acute renal failure)

( 3 )

5-1A

Serum creatinine  50% baseline value, >0.5 mg/dl

Creatinine clearance  50% baseline value

5-1B

3
Pre-renal failure renal clearance


()
Intrinsic renal failure ()
ischemia, necrosis (intoxication)

Post-renal failure
anticholinergic, TCAs
cyclophosphamide
obstruction

1:
Types
Comments
Pre-renal failure
No damage, reversible, renal hypoperfusion
Intrinsic renal failure
Damage, ischemia, necrosis, prolong hypoperfusion
Post-renal failure
Obstruction

/ 5

274

5-1C

Fraction Excretion of Sodium (FeNa)

fraction excretion of sodium (FeNa) glomerulus

parameter tubular tubular sodium
100% FeNa 1% FeNa >1% tubular function

FeNa

5-1D

(Urine Na) / (Urine Cr)

(Serum Na) / (Serum Cr)

x 100

Urine Output

renal failure (urine output)

Anuria
: < 50 ml/day
Oliguria
: 400-500 ml/day
Non-oliguria : >500 ml/day

- anuria oliguria ClCr Cockroft-Gault ClCr <10 ml/min

- non-oliguria 2 anuria
oliguria
2

5-1E

Management of Acute Renal Failure

1. Hydration
acute renal failure (ARF) pre-renal failure 70%
intrinsic renal
failure post-renal failure

2. Diuretics

diuretic dehydrate hypoperfusion
furosemide, minnitol
diuretic radiocontrast-induced ARF
(radiocontrast-induced ARF radiocontrast media
)

5-1

275

3. Renal Dose Dopamine

dopamine renal dose dopamine
(~1-3 g/kg/min) rate dose
high dose dopamine vasoconstriction BP heart rate
shift adrenergic receptor vasoconstriction
hypoperfusion (renal shutdown)
renal dose dopamime
routine

4. Calcium Channel Blockers

calcium channel blockers 2
Hydropyridine
nifedipine
Non-hydropyridine verapamil, diltiazem
non-hydropyridine calcium
channel blockers (third generation) (, , )
calcium channel blockers ARF vasodilation proteinuria

5. Nutrition Support
ARF (hypercatabolic state) high caloric diet
low protein high essential amino acid
carbohydrate dyslipidemia
()

6. Acid-Base Balance: NaHCO3

NaHCO3 metabolic acidosis max conc., rate, drug interaction,
sodium load
oral IV drip
sodium CHF, edema, cirrhosis sodium retention
IV infusion rebound alkalosis NaHCO3
leak damage central vein

D5W NSS sodium retention
drug interaction

/ 5

276

7. Hyperkalemia
cardiac rhythm disturbances muscle weakness
K+ lab K+ RBC
K+ leak EKG
K+
neuromascular effect K+
EKG K+ K+

calcium gluconate 1 g
infusion 3-5
calcium chloride 1 g
2 high alert drug ..
Shifting K+ into intracellular fluid
K+ K+ K+

NaHCO3 IV infusion 1 ampule 50 mEq

Regular Insulin (RI) and dextrose
o IV bolus 5-10 units RI + 25 g dextrose
o Infusion 1 unit/kg/hr RI in D10W

RI dextrose shift glucose K+ K+

IV bolus, infusion RI
K+
sodium polystyrene sulfonate calcium polystyrene sulfonate K+ K+
resin 2 K+
K+
side effect 2 lactulose sorbitol
Na+ resin Na+ load Ca+ resin
Na+ resin lactulose sorbitol

Ca+ resin sorbitol Na+
resin

5-2

277

5-2

(chronic kidney failure)

GFR GFR damage
3 creatinin clearance
3

5-2A

Azotemia biochemical abnormalities BUN

Scr
Uremic syndrome azotemia , lack of energy,
pruitis intractable nausea and vomiting, leg cramps, asterixis, clouded sensorium, seizures

Chronic renal insufficiency

creatinin clearance 30-60 /
Chronic renal failure
cleatinin clearance 15-30 /
End stage renal failure
(renal replacement therapy) (peritoneal dialysis)
(hemodialysis) (renal transplantation)

5-2B

33%
30%
glomerular disease 10%

/ 5

278

5-2C

renal function
state
long term

5-2D

(gold blood sugar 80-120)

hypoglycemia
ACEIs angiotensin receptor blockers (ARBs) microalbuminuria/albuminuria

(dietary protein restriction)
o 0.6-0.8 g/kg/day
uremic syndrome
o
30-35 kcal/kg/day
o

( 2 )

5-2E

(dehydration) (fluid overload)

residual renal function
(hyperkalemia)


ACEI, ARB potassium-sparing diuretic
(hypermagnesemia)
creatinin clearance < 30 ml/min
tendon reflex
cardiac conduction

5-2

279

(hyperphosphatemia)

()

drug interaction phosphate-binding antacid

o magnesium-containing phosphate binder

o aluminum-containing phosphate binder

aluminum 3B
Blood microcytic anemia
Brain dementia
Bone adynamic bone disease
acute renal failure aluminum first choice

o calcium-containing phosphate binder side effect BBB aluminum

o phosphate-binding antacid dialysis

5-2F

secondary hyperparathyroidism

calcitriol (1,25-dihydroxycholecalciferol) active form

secondary hyperparathyroidism
calcium set point
secondary hyperparathyroidism

5-2G

o sodium overload
o rebound alkalosis

/ 5

280

o extravasation


(
) drug interaction

5-2H

5-2I

nausea vomiting gastritis peptic ulcer GI bleeding

domperidone, metoclopamide ( extrapyramidal side effect) cisapride
prokinetic agent cardiac arrhythmia

H2 receptor antagonist
proton pump inhibitor bismuth

5-2J

(pruritis)
NSAIDs NSAIDs cox II inhibitor
GI side effect side effect



o Hydroxazine 25-50 mg 6-12
o Diphenhydramine HCl 25-30 mg 8-12
o Cyproheptadine 2-4 mg 8-12
o Clemastine fumarate 1.34-2.68 mg 8-12
o Ketotifen 2 mg 2
emollients steroid

5-2

281

cholestyramine 5 mg 2
activated charcoal 6 / 4-6

erythropoietin

5-2K

Metabolic bone disease

o secondary hyperparathyroid parathyroid hormone
parathyroid
parathyroid osteoblast () osteoclast ()

dynamic bone disease
o aluminum intoxication aluminum
osteoblast osteoclast
adynamic bone disease
Glucose intolerance
o

5-2L

(restless legs) clonazepam

5-2M

3
Influenza vaccine 1
Hepatitis B vaccine double dose 5
Pneumococcal vaccine 5-6

/ 5

282

5-2N

(uremic bleeding)

erythropoietin
toxins RBC

erythropoietin (EPO) acute anemia onset ( 1 )

acute anemia
o EPO 2 IV 3 / subcutaneous 2 /
Sc pure red cell aplasia anemia antibody
RBC antibody
EPO alpha IV EPO beta darbypoietin
long half life
o dose 1 EPO
o side effect EPO hypertension

BP Sc RBC IV
RBC vasoconstriction
headche
hyperkalemia
Flu-like syndrome
o EPO
Hct = 33-36%
rate BP
EPO
-
- B12 folate
- Aluminum toxic
- Malignancy
- Infection inflammation bacteria
overgrowth
Fe 2
o FeSO4 enteric coat
elemental ion 200 mg/day
o IV 4

5-2

283

Iron dextran hypersentivity test dose

hypersentivity
Fractionated iron dextran hypersentivity
test dose hypersentivity
Ferrous hydroxide sucrose complex hypersentivity

Ferrous gluconate hypersentivity

o
o
o high dose
androgen side effect RBC muscle mass
EPO

5-2O

2 gout
allopurinol dose
dose renal function
dose maintenance dose renal function

/ 5

284

5-3

(end-stage renal disease) 2

dialysis (renal transplantation)
dialysis

Dialysis metabolic waste

semipermeable membrane dialysate
(concentration gradient) 2
1. Hemodialysis (HD, , )
2. Peritoneal Dialysis (PD)

5-3A

Hemodialysis (HD, , )

HD dialyzer
metabolic waste dialysate concentration gradient semipermeable
membrane dialyzer heparin anticoagulant
dialyzer HD 3 3-4
membrane

1: dialysis

metabolic waste 2
1. Diffusion membrane concentration gradient
2. Convection plasma water membrane
membrane dialysate pump plasma water

5-3

285

1. Dialyzer
Dialyzer
membrane membrane

- High efficiency membrane membrane
urea membrane (surface area)
- High flux membrane membrane membrane
vancomycin, vitamin B12

dialysate membrane
electrolyte metabolic acidosis
bicarbonate buffer

2.
Hypotension
diabete,
cardiac disease, autonomic dysfunction

convection
dialysate ( dialysate 37 0C)
vasodilation
acetate buffer bicarbonate dialysate acetate
direct vasodilator
hemodialysis
dialysis
hypotension
Midodrine 10-20 mg dialysis 30
Sertraline 50-100 mg
L-carnitine iv 20 mg/kg dialysis
Muscle cramps
plasma water
convection
, IV hypertonic saline glucose
vitamin E 400 IU

Hypersensitivity
membrane

/ 5

286

Dialysis disequilibrium

coma
HD urea urea
urea osmolarity
cerebral edema, HD
intracellular pH dialysis
IV hypertonic saline mannitol
dialysis
Amyloidosis
-2-microglobulin-containing amyloid
membrane
carpal tunnel syndrome

high flux membrane

(, )

5-3B

Peritoneal Dialysis

PD (peritoneal membrane) semipermeable

membrane dialysate 2-3 dialysate bag (peritoneal cavity)
dialyste dialysate

dialysate

concentration gradient
Dialysate bag

2: peritoneal dialysis

dialysate fresh dialysate

hemodialysis

5-3

287

plasma water membrane

dialysate pump dialysis PD convection PD
osmotic pressure dextrose dialysate convection
Peritoneal dialysis
1. Continuous ambulatory peritoneal dialysis (CAPD, )
PD 4-8
dialysate dialysate 3-4
2. Automated peritoneal dialysis (APD) dialysis
dialysate

- Continuous cycling peritoneal dialysis (CCPD)
- Nocturnal intermittent dialysis (NIPD)

1.
Peritonitis
Exit-Site Infection
Weight Gain dextrose osmotic agent dialysate
excessive weight gain

insulin
insulin (IP) PD dialysate bag
bioavailability

2. HD PD
Patients lifestyle
- HD dialysis center 3 / 3-4
- PD PD dialysis center
HD
Vascular access site for hemodialysis
HD

Patients self care ability for peritoneal dialysis

PD dialysate

6-1
6-2
6-3
6-4

6-1

291

6-1

(
)
6
/

6-1A

1: (Lesion)

292

6-1B

Atrophic

Wheals / Hives

Cyst

Lichenification

Excoriation
hollowed-out or linear area
covered by a crust

Scar

, (contact dermatitis)

6-1C

( )

:
(eczema), (urticaria)

6-1D

acute, chronic
,

6-1E

6-1

6-1F

293

/

6
6

6-1G

:

/ /

1.
1:

,
macule, papule
,
,

macule, papule, vesicle

(eczema)
acute:
sub-acute:
chronic:

(urticaria)

, ,

(wheal)

(pityriasis alba)
(vitiligo)

1-10 cm
(psoriasis) macule, papule,
plaque

endogenous eczema:

exogenous eczema:

(contact dermatitis)

24 .

294

2.
2:

macule, patch //

candidiasis

(Herpes
simplex)
(Varicella
zostor)
/

, ,
(Tinea corporis)

, (Tinea cruris)
(Tinea capitis)
(Tinea facici)
, , (Tinea
pedis)

3
Versicular:
Interdigital:
Moccasin:
/ (Tinea unguium)
,

patch
,

vesicle

: ,
: , , , ,

,

vesicle
, nodule ,
()

broad
spectrum antibiotic,
corticosteroid

,

, ,
(
)

References
[1] . . : .
1. : (),2549. 249-283
[2] . : . 3 (). :
, 2544
[3] . . 2. : .., 2549

6-2

295

6-2

6-2A

steroid salicylic acid



steroid

Fungus

Eczema

Drug eruption

Exogenous eczema

Others

Endogenous eczema

Virus

Atopic eczema

Bacteria

Parasite

erythrasma

Urticaria

Pityriasis alba
Irritant contact
dermatitis

Allergic contact
dermatitis

Phototoxic CD

Photoallergic CD

Nummular eczema
Dyshidrosis
Seborrheic eczema
Lichen simplex chronicus

1:

Other eczema

296

6-2B

1.


acyclovir steroid

wet dressing

2.
steroid

-

- 2

-


- base

steroid
steroid

3.
2-3 ()
12
1

6-2

6-2C

297

1. (Urticaria)
(urticaria)


histamine ()

2. (Eczema or Dermatitis)
(Eczema or Dermatitis) Exogenous Eczema Endogenous Eczema
2
Eczema

Endogenous Eczema

Exogenous Eczema
contact dermatitis
Irritant contact dermatitis
Allergic contact dermatitis

Atopic eczema
Pityriasis alba ()
Nummular eczema
Dyshidrosis
Lichen simplex chronicus
Seborrheic dermatitis

2: exzema

Exogenous Eczema
1. Irritant contact dermatitis

2. Allergic contact dermatitis ( 2 )

-
-
-
- Neomycin, Diphenhydramine

298

Endogenous Eczema
1. Atopic eczema

2. Pityriasis alba ()
3. Nummular eczema

4. Dyshidrosis

5. Lichen simplex chronicus

6. Seborrheic dermatitis
()
Pityrosporum ovale
atopic eczema irritant dermatitis
1.

2. 30-50%

3. 5
4.
5.

3. (Drug Eruption)

4. (Psoriasis)
(keratinocyte)
4 ( 28 )



20 40 1-2

6-2

6-2D

299

1. (Tinea versicolor or Pityriasis versicolor)

Malassezia furfur normal flora

(stratum corneum)

Topical
- Sodium Thiosulfate solution 25%
1 2 2-4
- Selenium Sulfide suspension 2.5% (Selsun) 15-30
1-2
- Imidazole cream, 2% ketoconazole shampoo (Nizoral)
-
- Whitfields ointment
- Zinc pyrithione (Head and Shoulder shampoo)
- Terbinafine cream
Systemic
- Ketoconazole 400
200 10-14
200 3
- Itraconazole 200 7

2. (Dermatophytosis or Ring worm)

Microsporum spp., Trichophyton spp., Epidermophyton spp. 3

stratum corneum keratin

Topical
- Whitfields ointment (benzoic acid 6% + salicylic acid 3%) (
)
- Tolnaftate (Tonaf) 2-3

300

- Ciclopirox olamine (Loprox), Terbinafine (Lamisil) 1-2

- imidazole: clotrimazole (Canesten), miconazole (Daktarin), isoconazole (Travogen),
ketoconazole (Nizoral), econazole (Pevaryl) 2 3-4
1-2 broad spectrum , ,
candida
Systemic

- Griseofulvin (Fulcin)
500-1000 /
4-6 4-6 6-9

- Ketoconazole (Nizoral) 200 2-3

CYP 3A4 inhibitor
hepatitis
- Itraconazole (Sporal) 100 15
CYP 3A4 inhibitor hepatitis

3. Candida (Candidiasis)

Candida albicans

Topical
- Nystatin 2-3
- Imidazole cream
Systemic
- Ketoconazole 200
- Itraconazole 100

4. (Herpes simplex)

Herpes simplex virus

6-2

301

12

- wet dressing
- Acyclovir 200 5 ( 4 ) 5-10

(primary attack)
- Acyclovir 5% cream (Zovirax, Zevin, Virogon) 5
( 4 )
- steroid

5. (Varisella zoster)

Varicella zoster

23
46
13
postherpetic neuralgia

- wet dressing
- Acyclovir 800 5 ( 4 ) 7

- Analgesic ibuprofen 400
- Antibiotic
- (postherpetic neuralgia)
Amitriptyline 25 / Carbamazepine

302

1: (postherpetic neuralgia) Gnann J. W. Jr., Whitley R. J.

Herpes Zoster. NEJM 2002; 347:340-346.

6. (Warts)

Human Pappilloma Virus

3
1.
2.
3.

1. ()
- 40% salicylic acid ointment cellomack , duofilm
- Retinoic acid
- () 25% Podophyllin protectant Vaseline
ZnO paste 25% Podophyllin
4

2.

7. Impetigo contagiosa

Streptococcus spp. Staphylococcus spp.

6-2

303

8. / (Furuncle/Carbuncle)

S. aureus

()

9. (Erysipelas)

group A beta hemolytic S. pyrogenes

(Impetigo), ,

- (wet dressing) NSS 0.9% Hydrogen

peroxide 0.3% solution Cloxacillin Dicloxacillin (
Penicillin Erythromycin Clindamycin)
- Gentamycin (Garamycin), Mupirocin (Bactroban), Fusidic acid
(Fucidin)
- 1% Framycetin (Sofra-Tulle)
-
Betadine

10. (Scabiasis)

-
-
- Lindane (gamma benzene hexachloride 1%) (Jacutin gel 0.3% , Hexin cream 1%)
()
8-12 6-8

- Precipitated sulfur 3-5% ointment
3-5

304

- Benzyl benzoate lotion 25% ( )

24 3

- Antihistamine Atarax

11. (Pediculosis)

Lindane 12
Benzyl benzoate lotion 25% ( )

Petrolatum ophthalmic ointment 8-10

12.
2
1. Creeping eruption 2 Ancylostoma spp., Strongyroides stercoralis

2. Gnathostomiasis (Gnathostoma spinigerum)

6-2E

(Acne)

Propionibacterium acne lipase

free fatty acid
(comedone) (close comedone) (open comedone)
(macule) (papule) pustule

1.
Testosterone () ()

cell (
) bacteria

2.
3.
4. , steroid, INH, Dilantin
5.
6.

6-2

305

(/) comedone

P. acne

Topical
- Benzyol peroxide (Panoxyl) 2.5, 5,10% cysteine
free oxygen radicals oxidize bacterial protein
30 5-10
2
- Tretinoin (topical vitamin A acid) cell
cell stratum corneum P.acnes
( Benzyol peroxide )
- Adapalene (Differin) gel 0.1% Retinoid like compound
- Sulfur/Resorcinol/Salicylic acid keratolytic mild antibiotic
1 2
- Clindamycin solution 1% (Dalacin T), Erythromycin solution 2% (Stiemycin) 2
P.acnes, free fatty acid 2
- Azeleic acid cream 20% (Skinoren) Bacteriostatic P.acnes, free fatty acid
2

Tretinoin (Retin A)

Isotretinoin (Roaccutane)

3:

Systemic
- Tetracyclin 1-2 / 2-4 3-4

- Erythromycin 1-2 / 2-4

306

- Isotretinoin (Roaccutane) antibiotic

P.acnes
S/E
- Cyproterone acetate (Diane-35) antiandrogen
antibiotic S/E

2: James W. D. Acne .NEJM 2005; 352:1463-1472
Drug
Dose
Side Effect
Topical agents
Retinoids
Tretinoin
Applied once nightly;
Irritation (redness and
strengths of 0.025-0.1%
scaling)
available
Adapalene
Applied once daily, at night Minimal irritation
or in the morning
Tazarotene
Applied once nightly
Irritation
Antimicrobials
Benzoyl peroxide,
alone or with zinc,
2.5-10%
Clindamycin,
erythromycin
Combination benzoyl
peroxide and
clindamycin or
erythromycin

Other topical agents

Azelaic acid, sodium
sulfacetamidesulfur, salicylic acid

6-2F

Applied once or twice daily

Benzoyl peroxide can bleach

clothing and bedding

Applied once or twice daily

Propensity to resistance

Applied once or twice daily

Applied once or twice daily

Well tolerated

Other Considerations

Generics available

Limited data suggest tazarotene more

effective than alternatives
Available over the counter; 2.5-5%
concentrations as effective as less
drying than 10% concentrations
Most effective for inflammatory lesions
(rather than comidones); resistance
a concern when used alone
Combination more effective than topical
antibiotics alone; limits development
of resistance; use of individual
products in combination less
expensive and appears similarly
effective
Good adjunctive or alternative
treatments

Steroid Steroid Steroid

6-2

307

3:

1.
Hydrocortisone acetate
Prednisolone
2.
Triamcinolone acetonide
3.
Triamcinolone acetonide
Prednicarbate
Clobetasone butyrate
Fluocinolone acetonide
Betamethasone valerate
Mometasone furoate
4.
Amcinonide
Desoximetasone
Betamethasone dipropionate
5.
Betamethasone dipropionate
Clobetasol propionate

Hytisone
Prednisil
Aristocort
Aristocort A
Dermotop
Eumovate
Synalar
Betnovate
Elomet
Visderm
Esperson
Diprosone
Diprotop
Dermovate

0.1%
0.5 %
0.02%
0.1%
0.25%
0.025%
0.1%
0.1%
0.1%
0.1%
0.25%
0.5%
0.05%
0.05%

Cream
Cream
Cream
Cream
Cream
Cream
Cream
Cream
Cream/oint.
Cream
Cream
Cream/oint.
in 10% PG oint
Cream

Steroid + Salicylic acid/urea barrier

Steroid + Antibiotic/Antifungal
1
Steroid
1.

2.

3.

4.
5. steroid
Topical steroids
1. 3-4
2. corticosteroids
3. stratum corneum

4. epidermis
5. steroid (occlusion)
6. propylene glycol, salicylic acid, urea
7.
8.

4:

308

6-2

309

References
[1] . Superficial and cutaneous mycoses. (Dermatology 2010).
, . 1. : , 2548
[2] . . : .
1. : (),2549. 249-283
[3] . . 2. : .., 2549
[4] . . , 2548
[5] . : . 3 (). :
, 2544
[6] Ellsworth A, Smith RE. Dermatotherapy and drug induced skin disorders.In Applied therapeutics : the clinical use of drugs.
Mary Anne Koda-Kimble, editor. 8th ed. Philadelphia : Lippincott Williams & Wilkins, 2005.
[7] Gnann JW Jr, Whitley RJ. Herpes Zoster. N Engl J Med. 2002;347:340-6.
[8] James WD. Acne. N Engl J Med. 2005;352:1463-72.

310

6-3

6-3A

Topical Corticosteroids

Hydrocortisone Glucocorticoids
steroid C1-C2
B D C17
21

24

22
20

HC
12 3
19

2
3

10
5

23
17

11

H 3C

C
H

13

26
25

18

D
14

16

27

15

8
7

1: Basic steroid structure and numbering system

1111-OH
one 11-OH hydrocortisone
cortisone hydrocortisone
1-ene Prednisolone Prednisone 4
salt retention A C1C2 Prednisolone cortisol
9-halo derivative 11-OH

halogen 11-OH 11-one

9-Fluoro Hydrocortisone salt retention

6-methyl
16-methyl methyl C-16 salt retention
2
16-hydroxy hydroxylation C-16 salt retention
17-hydroxy 17-methyl salt retention glucocorticoids
21-htdroxy
1: SAR steroid
salt retention

glucocorticoids mineralocorticoid

16-hydroxy
16, 17-ketal
6-methyl
16- 16-methyl

1-ene (1-dehydro)
9-fluoro
9-chloro
21-hydroxy

6-3

311

16-methyl
16-hydroxy salt retention glucocorticoid

2: Glucocorticoid Mineralocorticoid
Antiinflammatory
Functional group
Glycogen deposition
Activity
10
7-10
9-fluoro
3-5
3-4
9-chloro
3-4
3-4
1-dehydro
2-3
1-2
6-methyl
0.4-0.5
0.1-0.2
16-hydroxy
1-2
4
17-hydroxy
4-7
25
21-hydroxy

Effects on
Urinary sodium
+++
++
-----++

Topical Corticosteroids

Wilson and Gisvolds Textbook of Organic Medicinal
and Pharmaceutical Chemistry 5 Very high potency, High potency,
Medium potency, Low potency Lowest potency Foye's principles of medicinal chemistry
4 Very high potency, High potency, Medium potency Low potency
3: Topical Corticosteroids
Wilson and Gisvolds Textbook of
Organic Medicinal and Pharmaceutical Chemistry
1. Very high potency
Augmented Betamethasone dipropionate, 0.05%
Clobetasol propionate, 0.05%
Diflorasone diacetate ointment, 0.05%
2. High potency
Amcinonide, 0.1%
Betamethasone dipropionate ointment, 0.05%
Desoximetasone, 0.1%
Diflorasone diacetate cream, 0.05%
Fluocinonide, 0.05%
Halocinonide, 0.1%
Halbetasol propionate, 0.05%
Triamcinolone acetonide, 0.5%

3. Medium potency
Betamethasone valerate, 0.1%
Clocortolone pivalate, 0.1%
Desoximetasone, 0.05%
Fluocinolone acetonide, 0.025%
Fluticasone propionate, 0.005%
Hydrocortisone butyrate, 0.1%
Hydrocortisone valerate, 0.2%
Mometasone furoate, 0.1%
Prednicarbate, 0.1%
Triamcinolone acetonide, 0.1%

Foye's Principles of Medicinal Chemistry.

1. Very high potency
Augmented Betamethasone dipropionate ointment, 0.05%
Clobetasol propionate, 0.05%
Diflorasone diacetate, 0.05%
Halobetasol propionate, 0.05%
2. High potency
Amcinonide, 0.1%
Augmented Betamethasone dipropionate cream, 0.05%
Betamethasone dipropionate, 0.05%
Betamethasone valerate ointment, 0.1%
Desoximetasone cream, ointment, gel, 0.1%
Diflorasone diacetate cream, 0.05%
Fluocinolone acetonide, 0.2%
Fluocinonide, 0.05%
Halocinonide, 0.1%
Triamcinolone acetonide, 0.5%
3. Medium potency
Betamethasone benzoate, 0.025%
Betamethasone dipropionate lotion, 0.05%
Betamethasone valerate cream, 0.1%
Clocortolone pivalate, 0.1%
Desoximetasone cream, 0.05%
Fluocinolone acetonide, 0.025-0.2%
Flurandrenolide 0.025-0.05%
Fluticasone propionate, 0.005-0.05%
Hydrocortisone butyrate, 0.1%
Hydrocortisone valerate, 0.2%
Mometasone furoate, 0.1%
Prednicarbate, 0.1%
Triamcinolone acetonide, 0.025-0.1%
Continued next page

312

Wilson and Gisvolds Textbook of

Organic Medicinal and Pharmaceutical Chemistry

Foye's Principles of Medicinal Chemistry.

4. Low potency
Alclometasone dipropionate, 0.05%
Desonide, 0.05%
Fluocinolone acetonide, 0.01%
Triamcinolone acetonide cream, 0.1%

4. Low potency
Alclometasone dipropionate, 0.05%
Desonide, 0.5%
Dexamthasone, 0.01-0.04%
Dexamethasone sodium phosphate cream 0.1%
Fluocinolone acetonide, 0.025-0.2%
Hydrocortisone, 0.25-2.5
Hydrocortisone acetate, 0.5-1%
Prednicarbate cream 0.1%

5. Lowest potency
Hydrocortisone, 1.0%
Hydrocortisone, 2.5%

Topical Corticosteroids
..2549 Topical Corticosteroids

6. Fluocinolone acetonide
1. Amcinonide
7. Hydrocortisone acetate
2. Betamethasone dipropionate
8. Momethasone furoate
3. Betamethasone valerate
9. Prednicarbate
4. Desoximetasone
10. Triamcinolone acetonide
5. Clobetasol propionate
O
O
OH

CH3

O
O

HO

OCO(CH2)3CH3
CH3

H3 C

HO

H3C

Amcinonide

Betamethasone dipropionate
O

O
H

HO

HO
CH3

Betamethasone valerate

Cl

OH

CH3
F

CH3

Desoximetasone

Clobetasol propionate

Fluocinolone acetonide

O
Cl

H 3C

O
O

HO

OH

HO

HO

O
Cl

CH3

O
O
O

CH3

CH3

Hydrocortisone acetate

Momethasone furoate

Prednicarbate

OH
O
CH3

HO

CH3
O

F
O

Triamcinolone acetonide

2: steroid

 4: Topical Corticosteroid

6-3

313

4: Topical Corticosteroid ()

314

 4: Topical Corticosteroid ()

6-3

315

316

6-3B

Imidazoles

Imidazoles nitrogen-carbon
amidine nitrogen atom (N-3 imidazole triazone N-4) iron heme
Cytochrome P-450 steroids
antifungal azoles aromatic 2 3 1 2-3
halogen 2,4-dichlorophenyl, 2,4-difluorophenyl halogen
fluorine
steroids substrate lanosterol
14-demethylase
antifungal azoles (lipophilicity) free
base ethanol ( fluconazole
triazoles free base )
Imidazoles
..2549
1. Cotrimazole
Ar
X
Cl
2. Econazole nitrate
3. Isoconazole nitrate
N
Cl
4. Ketoconazole
N
5. Miconazole nitrate
6. Ticonazole
Cl

Cl

Cl
N

Cl
O

Cl
N C

Cl

Cl

Cl

Clotrimazole
1-(o-Chloro-,-diphenylbenzyl)-imidazole

Econazole
1-[2-[(4-Chlorophenyl)methoxy]-2-(2,4dichlorophenyl)ethyl]-1H-imidazole

Isoconazole nitrate

Cl

N
O

CH 3

Cl

Cl

O
N

Cl

O
H Cl

Cl

Ketoconazole
1-Acetyl-4-[4-[[2-(2,4-Dichlorophenyl)-2(1Himidazole-1-ylmethyl)-1,3-dioxolan-4yl]methoxy]phenyl]piperazine

S
O

Cl

Cl

Cl

Miconazole nitrate
1-[2-[(2,4-Dichlorophenyl)-2-[2,4dichlorophenyl)methoxy]ethyl]-1Himidazole

Ticonazole
1-[2-[(2-chloro-3-thienyl)methoxy]2(2,4-dichlorophenyl)ethyl]-1Himidazole

3: imidazoles

 5: Imidazoles

6-3

317

5: Imidazoles ()

318

[1]
[2]
[3]
[4]

. . 1. : , 2528. 34
Block, JH and Beale, JM. Wilson and Gisvold's textbook of organic medicinal and phamaceutical chemistry. 11th ed. Philadelphia: Lippincott Williams & Wilkins, 2004.
MIMS Thailand 102nd edition 2006.
Williams DA, Lemke TL. Foye's principles of medicinal chemistry. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2002.

References

5: Imidazoles ()

6-3

319

320

6-4

6-4A

Clinacanthus nutans (Burm. f.) Lindau

Acanthaceae
()
()

, ()
() (-)

1-3

0.5-1.5 . 2.5-13 .
5
2

:
lupeol, -sitosterol, stigmasterol
flavonoids
: betulin, lupeol, -sitosterol, stigmasterol
: lupeol
()

- ( )

- :
-
10-15
1

6-4

321

1.
(anti-inflammatory)



(anti-writhing)
270
100
1 flavonoid

15

Herpes simplex virus Varicella zoster virus (anti-viral activity)

(Herpes simplex virus Type-2; HSV2) (Acyclovir) Plague reduction assay
HSV-2 viro cell HSV-2
HSV-2

(Varicella zoster virus)

2.

(5%) Acyclovir
Acyclovir 3 7
Acyclovir
Acyclovir
(5%) 5
1-3 7-10 4-7
10-14

herpes apthus ulcer

322

3.

1.3
5.44

0.01, 0.1 1.0

0.042, 0.42 4.18 90
1

1:

Clinacanthus nutans
,
(Burm. f.) Lindau

4-5%

2.5-4%

1.25-4%

3-5
3-5
3-5

4.
(GPO)


""

1 40


4 5
5

6-4

()
()

()
()

323

(13144: 7460)
(13664: 7460)
130/149 .3 .- .- . . . 13170
. 0-3572-1745, 0-3572-1445-7
G 454/41

PHAYA YO GLYCERINE

(13144 : 7460)
(13664 : 7460)
130/149 .3 .- .- . . . 13170
. 0-3572-1745, 0-3572-1445-7
G 383/42

4 .. 2549

()
()

()
()

PHRAYAYAW OINTMENT

(2702: 1245)
(2569: 1245)
5/184 .10 . . .9
. 10260 . 0-2743-0286
G 410/43

PA YA YOR OINTMENT TRA NGAMRAHONG

(2601: 1209)
(2480: 1209)
89/1 .1 .- . 1 .
. 10520 . 0-2737-8342-3
G 66/42

324

6-4B

(Garlic)

6-4C

6-4D

Rhinacanthus nasutus (Linn.) Kurz.

Acanthaceae

30-50% 7 3-4
7
1 3

(Galangal, False Galangal, Greater Galangal)

6-4E

Allium sativum Linn.

Alliaceae

Allicin

70% 10-15

Alpinia nigra (Gaertn.) B. L. Burtt

Leguminosae

1
70% 10-15
3-4

(Candelabra Bush, Candle Bush, Ringworm Bush)

Cassia alata Linn.

Zingiberaceae


3-4
3-4 2-3
1

6-4

6-4F

325

(Betel Vine, Betel Peper)

Piper betle Linn.

Piperaceae

1.

3-4

2.

3-4 3-4

6-4G

(Sugar Apple)

Annona squamosa Linn.

Annonaceae

8-12 10
1:2
1-2
1 2-3

References
[1] . .. 2542 ()
[2] , . . , . 1 . :
, 2544
[3] . . [Homepage on the internet], Available from:
URL: http://herbal.pharmacy.psu.ac.th/data/herbal/Clinacanthus-nutans.html [Accessed Mach 4, 2006]
[4] . . [Home
Page on the internet], Available from: URL: http://www.medplant.mahidol.ac.th/pubhealth/index.html [Accessed May 20,
2006]
[5] . . [Homepage on the internet], Available from: URL: http://www.gpo.or.th/herbal/nutan/nutan.htm
[Accessed Mach 4, 2006]
[6] . . [Homepage on the internet], Available from: URL: http://www.gpo.or.th/herbal/
herbal.htm [Accessed Mach 4, 2006]