Pharmacology Notes

Clinical Pharmacology and
Therapeutics (CPT) Revision

Notes
By Dr Garry KJ Pettet MBBS/BSc
Revision 2 (January 2006)
Contents
......................................................................... Preface 1
......................................................... Drug development 2
................................................... Adverse drug reactions 5
........................................................... Drug interactions 7
.............................. Pharmacodynamics/pharmacokinetics 9
.................................. Prescribing in renal / liver disease 12
............................................................. Rheumatology 16
......................................................... Gastroenterology 22
.................................................................... Antivirals 27
........................................................... Asthma / COPD 30
.................................................................. Analgesics 35
.......................................................... The failing heart 38
.............................................................. Endocrinology 46
......................................................................... Lipids 57
...................................................................... Clotting 60
............................................................ Mood disorders 68
.................................................. Anti-arrhythmic drugs 74
............................................................... Hypertension 81
........................................................ Antibiotic therapy 83
.................................................................. Antibiotics 86
..................................................................... Diabetes 95
Copyright Dr Garry KJ Pettet 2005 - 2009
www.garrypettet.com
.................................................................... Epilepsy 101
................................................................... Migraine 107
....................................................... Multiple sclerosis 109
.................................................... Parkinsons disease 110
............................... Drug-induced movement disorders 115
...................................................... Myasthenia gravis 117
................................................................... Diuretics 119
........................................................ Muscle relaxants 122
.............................................................. Anti-emetics 124
.................................................................... The eye 127
....................................... Antipsychotics (neuroleptics) 130
........................ Drugs in the elderly, young or pregnant 134
............................................. Cytotoxic chemotherapy 137
............................................................ Anti-malarials 141
www.garrypettet.com
Preface
I wrote these notes as a final year medical student in the UK as I found it
very difficult to find a good single text to use for my CPT revision.
I used the following textbooks in writing these notes:
- British National Formulary (BNF 47 March 2004)
- Clinical medicine 5
th
edition (Kumar, Clark)
- Hands-on-guide to clinical pharmacology (Chatu, Milson & Tofield)
- Medical pharmacology at a glance 4
th
edition (Neal)
- Oxford handbook of clinical medicine 6
th
edition (Longmore, Wilkinson
& Rajagopalan)
- Pharmacology 4
th
edition (Rang, Dale, Ritter)
I have made sure that everything that has been mentioned in our lectures is
in these notes. We must thank the following lecturers, as some of their
material may well be in these notes:
- Dr Chris Bench
- Dr Neil Chapman
- Dr Anton Emmanuel
- Dr Michael Feher
- Dr Alun Hughes
- Prof Sebastian Johnston
- Prof John MacDermot
- Dr Janice Main
- Dr Vias Markides
- Dr Jamil Mayet
- Dr Andrew Rice
- Dr Stephen Robinson
- Dr Mike Schachter
- Dr Tom Sensky
- Prof Peter Sever
- Dr Colin Tench
- Dr Simon Thom
- Dr Roxaneh Zamegar
I would also like to thank Dr Wajid Hussain for proofreading the section on
anti-arrhythmics.
Although every effort has been made to ensure the accuracy of these notes, I
take no responsibility for errors within (but please let me know as I have to
revise from these as well!).
Dr Garry Pettet
1
www.garrypettet.com
Drug development
Surrogate markers:
A biological measurement which substitutes for the therapeutic end-

point
Examples:
o
BP and stroke
o
Cholesterol and coronary disease
Characteristics of a good surrogate:

o
Biological feasibility
o
Dose-related response to intervention
o
Easy to measure
o
Reproducible
o
Specific / sensitive
o
High predictive value
o
Acceptable by experts / regulatory authorities
Types of clinical trials:
Open:
o
Subject and researcher know what they are getting
Single-blind:
o
The subjects do not know what they are getting
Double-blind:
o
No one knows what they are getting (during the trial)
PROBE:
o
Prospective
o
Randomised
o
Open-labelled
o
Blinded
o
End-point
o
This is used for large, complex studies with several treatments.
It is an open trial where those who analyse the results do not
know who got what treatment
The phases of a clinical trial:
Phase 1:
o
Healthy volunteers (not for cancer / HIV trials)
o
Few subjects (< 50)
o
Looks at pharmacokinetics / pharmacodynamic activity / safety
Phase 2:
o
Patients with the target disease
o
More subjects (100 200)
o
Usually single-blind trials
o
Looks again at pharmacokinetics / safety (note, these may be
different than in healthy volunteers)
Phase 3:
o
Patients
o
Much larger (> 1000)
2
www.garrypettet.com
o
Usually double-blind or PROBE
o
May be parallel or crossover
o
Multi-centre
o
May use either hard (e.g. MI) or surrogate end-points
Phase 4:
o
Post-marketing
o
Surveillance for:
! Adverse drug reactions
! Rare side-effects
! Drug interactions
Parallel vs crossover studies:
Parallel study:
o
Most randomised controlled trials (RCTs) are parallel
Crossover study:
o
Need fewer subjects
o
Should normally be used in chronic stable diseases and the
interventions should have a rapid onset and short duration
o
Beware of order effects:
! Carry-over effects
! Period effects:
Changes in the patients disease over time

Power:
Is the study large enough to answer the studys question?
Type 1 error (!):

o
Chance of finding 2 treatments are different when they are not
o
Usually:
! ! = 0.05 (i.e. p < 0.05)
Type 2 error ("):

o
Chance of finding 2 treatments are equal when they are not
o
Usually:
! " = 0.1 or 0.2 (arbitrary)
Power = 1 - " (i.e. 80 90% usually)
The higher we set " (i.e. the greater our power) the more expensive
the trial becomes as we need more subjects
3
www.garrypettet.com
A
B
A
B
Intention to treat vs per protocol analysis:
Intention to treat:
o
Ignore whether the subjects actually take the medication (i.e.
just assume they did)
Per protocol:
o
Only analyse data from subjects who actually took the
medication
4
www.garrypettet.com
Adverse drug reactions
Significance:
3 40% of inpatient admissions
Affects 10 20% of hospital patients
4
th
most common cause of death in US hospital patients
Up to 30 60% are preventable

Types of adverse drug reaction (ADR):
Type 1:
o
Predictable reactions
o
Common
o
Dose-related
o
A consequence of the known pharmacology of the drug
Type 2:
o
Idiosyncratic reactions
o
Rare
o
Usually not dose-related
o
Allergies
o
Pharmacogenetic variations
Classification of ADRs:
Augmented pharmacological effect
Bizarre
Chronic
Delayed
End-of-treatment
Determinants of ADRs:
Drug:
o
Pharmacodynamics
o
Pharmacokinetics
o
Dose
o
Formulation
o
Route of administration
Patient:
o
Age
o
Co-morbidity
o
Organ dysfunction
o
Genetic predisposition
Environment:
o
Mistakes
Allergies vs psuedoallergies:
Allergies:
o
Type I (anaphylaxis):
5
www.garrypettet.com
! Penicillins
! Contrast media (anaphylactoid)
o
Type II (cytotoxic antibodies blood dyscrasias):
! Haemolytic anaemia:
Methyldopa
Penicillin
Sulphonamides
! Agranulocytosis:
Carbimazole
Clozapine
! Thrombocytopenia:
Quinidine
Heparin
o
Type III (immune complex formation):
! Penicillin
! Sulphonamides
o
Type IV (cell mediated):
! Topical antibiotics
Pseudoallergies:
o
Looks like an allergy but is not immune-mediated
o
Examples:
! Aspirin - bronchospasm
! ACE inhibitors cough
Long-term ADRs:
Withdrawal:
o
Opiates
o
Benzodiazepines
o
Corticosteroids
Rebound:
o
Clonidine
o
"-blockers
Adaptive:
o
Neuroleptics
6
www.garrypettet.com
Drug interactions
Liver enzyme inducers (cytochrome P450):
Carbamazepine
Phenobarbitone
Phenytoin
Rifampicin
Liver enzyme inhibitors (cytochrome P450):
Cimetidine
Ciprofloxacin
Grapefruit juice
Macrolide antibiotics:
o
Erythromycin
Omeprazole
Important drugs metabolised by the liver (cytochrome P450):
Carbamazepine
Cyclosporin A
Combined oral contraceptive (COC) pill
Phenytoin
Theophylline
Warfarin
Some important drugs interacting with warfarin:
Drugs increasing the effect of warfarin:

o
Alcohol
o
Amiodarone
o
Antibiotics (many reduced vitamin K absorption)
o
Cimetidine
o
Omeprazole
o
Simvastatin
Drugs decreasing the effect of warfarin:

o
Carbamazepine
o
COC pill
o
Rifampicin
Interactions with diuretics:
General:
o
Potentiate:
! ACE inhibitors
! Lithium
o
Metabolic:
! Hypokalaemia enhances digoxin efficacy
! "-blockers potentiate hypokalaemic effects of diuretics
Loop:
o
Increased risk of ototoxicity with the aminoglycosides
Potassium-sparing:
7
www.garrypettet.com
o
Risk of hyperkalaemia with ACE inhibitors
Drugs affecting gastric emptying and hence drug absorption:
Increase emptying:
o
Metoclopramide
Decrease emptying:
o
Atropine
Impairment of drug excretion:
Probenicid:
o
Competes with Penicillins for renal tubular excretion, leads to
increased concentration of penicillins (can be beneficial)
8
www.garrypettet.com
Pharmacodynamics/pharmacokinetics
Half-life (t1/2):
The time taken for the concentration of drug in plasma (or blood) to
fall to half its original value
Drugs with a short t1/2 may have a long duration of action:

o
So-called cell-trapping
o
E.g. omeprazole
Volume of distribution (Vd):
This is the apparent volume into which the drug is distributed

Vd = dose / (initial apparent plasma concentration)
Is used to calculate the clearance of a drug
Is high for lipid-soluble drugs
Is low for water-soluble drugs
Values of Vd:
o
< 5L drug retained within the vascular system
o
< 15L drug is restricted to the extracellular fluid (ECF)
o
> 15L indicates the drug is distributed throughout the
total body water
Clearance:
The volume of plasma (or blood) cleared of drug per unit time
Depends on drug lipid solubility
Clearance (but not t1/2) provides an indication of the ability of the liver
and kidneys to dispose of the drug
First vs zero order kinetics:
First-order kinetics:
o
A metabolic process that depends on the drug concentration at
any given time is called a first-order process
o
I.e. a non-saturable process
Zero-order kinetics:
o
If any enzyme system responsible for drug metabolism becomes
saturated, then the rate of elimination proceeds at a constant
rate and is unaffected by an increase in the concentration of the
drug
o
I.e. a saturable process
o
Examples include:
! Phenytoin
! Ethanol
o
The importance of zero-order kinetics is that you could double
the dose, but the plasma concentration would not double (may
increase to an enormous extent)
Bioavailability:
The proportion of administered drug reaching the systemic circulation
IV drugs have 100% bioavailability

9
www.garrypettet.com
Drugs with high bioavailability:

o
Ciprofloxacin (near 100%)
Drugs with low bioavailability:

o
Bisphosphonates (~15%)
First-pass metabolism:
Also known as pre-systemic metabolism
This is drug metabolism that occurs before the drug reaches the
system circulation
Occurs in the liver and gut wall
Some drugs undergo extensive first-pass metabolism:

o
Levodopa
o
Lignocaine
o
Morphine
o
Nitrates (e.g. GTN)
o
Propranolol
o
Verapamil
Is generally a nuisance for two reasons:

o
A larger dose is needed when it is given orally
o
Marked individual variations occur
Post-systemic metabolism:
The main purpose is to increase water-solubility of the drug
Phase I:
o
Three types of reaction:
! Oxidation:
Most important are the P450 enzymes
Xanthine oxidase metabolises 6-mercaptopurine
Monoamine oxidase inactivates 5-HT, NA, tyramine

! Reduction / Hydrolysis
o
Usually produces a more reactive compound that will be acted
on by phase II components
o
May activate a prodrug examples:
! Levodopa " dopamine
! Enalapril " enalaprilat
! Azathioprine " 6-mercaptopurine
! Methlydopa " !-methyl-noradrenaline
! Carbimazole " methimazole
Phase II:
o
Conjugation of a drug or phase I metabolite with an
endogenous substance to form a more polar, easily excreted,
compound
o
May be either:
! Glucuronidation
! Sulphation
! Acetylation (does not alter water-solubility)
10
www.garrypettet.com
! Glutathione
Loading doses:
In practice, a steady state concentration is effectively achieved after

three plasma half-times
Faster attainment of the steady state is achieved by starting with a

larger dose a loading dose
Therapeutic drug monitoring:
Why?
o
To investigate lack of drug efficacy
o
Possible poor compliance
o
Suspected toxicity
o
Prevention of toxicity
Type of drugs:
o
Narrow therapeutic index (TI)
o
Uncertain dose / concentration relationship
o
Defined plasma concentrations with no active metabolites
Examples:
o
Not warfarin (this measures the INR, not drug concentration!)
o
Antibiotics (aminoglycosides, vancomycin)
o
Anticonvulsants (carbamazepine, phenytoin)
o
Aminophylline / theophylline
o
Cyclosporin A
o
Digoxin
o
Lithium
11
www.garrypettet.com
Prescribing in renal / liver disease
Important drugs whose elimination is affected by renal impairment
Half-lives are approximate ranges when renal impairment present
Amoxicillin (t1/2 2 14 hours):

o
Applies to most penicillins
o
Toxic effects:
! Seizures (especially in meningitis)
! Rashes are more common in renal impairment
Atenolol (t1/2 6 100 hours):

o
Contraindicated in:
! Asthmatics
! Severe heart failure
! Peripheral vascular disease
o
Toxic effects:
! Bradycardia
! Confusion
! Hypotension
Captopril (t1/2 2 14 hours):

o
Toxic effects:
! # GFR
! Angioedema
! Cough:
Probably due to a direct effect on sensory afferents
Not bradykinin
! GI disturbances
! Hypotension
! Taste disturbances
Digoxin (t1/2 36 90 hours):

o
Requires therapeutic drug monitoring (TDM)
o
Toxic effects:
! Dysrhythmias (VT, heart block)
! Gynaecomastia
! Nausea (severe) / vomiting
! Xanthopsia (distortion of yellow colour vision)
Gentamicin (t1/2 2! - >50 hours):

o
Increased risk of toxicity when:
! Dehydrated (important as septic patients usually are)
! Hyponatraemic
o
Toxic effects:
! Nephrotoxicity (renal tubular damage)
! Ototoxicity (can be irreversible)
Vitamin D and the kidney:
Vitamin D has to undergo two hydroxylation reactions within the body

to become active
12
www.garrypettet.com
Kidney forms the 1-hydroxy form of vitamin D and requires the

enzyme 1!-hydroxylase
In renal impairment, the above step may not happen
Bone di sease caused by renal di sease i s t ermed renal

osteodystrophy:
o
Loss of vitamin D activity
o
$ PTH activity
Replacing vitamin D:
o
Alfacalcidol (the 1-hydroxylated form, thus negating need for
1!-hydroxylase)
o
Calcitriol (the active 1, 25-hydroxylated form) rarely used
Nephrotoxic drugs:
ACE inhibitors:
o
# GFR (if the arterial perfusion pressure is low):
! Renal artery stenosis (especially bilaterally)
! Coarctation of the aorta
Cyclosporin A:
o
Used in renal transplants
o
Is a substrate for P450 (levels may be increased by other drugs)
o
# GFR
o
Damages tubular function
Gentamicin:
o
Renal tubular damage
Lithium:
o
Nephrogenic diabetes insipidus
o
Renal tubular damage
NSAIDs:
o
# GFR
o
Papillary necrosis:
! Loss of PG-mediated vasodilatation
o
Na
+
retention
Others:
o
Urate stones:
! Anticancer drugs (tumour lysis syndrome)
o
Myoglobinuria:
! Alcohol
! Statins
Drugs to watch when patient has impaired hepatic synthetic function:
Hypoalbuminaemia:
o
Drugs which bind to albumin and are cleared by the liver:
! Diazepam
! Phenytoin
! Tolbutamide
A1-acidic glycoprotein deficiency:

o
Binds basic drugs:
! Chlorpromazine
! Imipramine
13
www.garrypettet.com
! Quinidine
Reduced synthesis of clotting factors:

o
Warfarin:
! If the liver is synthesising even less of factors II, VII, IX
and X then warfarins effects will be potentiated
o
Antibiotics:
! Interfere with vitamin K production in the gut by bacteria
! May compound the above problem
Drugs to watch in a patient with current / recent hepatic encephalopathy:
Antidepressants:
o
Tricyclic antidepressants (TCAs) are safest (but use a # dose)
o
Avoid monoamine oxidase inhibitors (MAOIs):
! Idiosyncratic hepatotoxicity
Anti-psychotics:
o
Chlorpromazine
Anxiolytics / hypnotics:
o
Oxazepam / temazepam are the safest
o
Avoid chlormethiazole (especially IV)
Opiates:
o
Can precipitate coma
o
Even low levels are dangerous
Drugs with a high first-pass metabolism:
These drugs will not be metabolised as much in liver impairment (if

given orally), thus the dose should be #
Chlorpromazine
Chlormethiazole
Imipramine
Morphine / pethidine
Propranolol
Verapamil
Hepatotoxic drugs:
Cholestasis:
o
Chlorpromazine (reversible cholestasis)
o
Sulphonylureas (e.g. glibenclamide)
o
Carbimazole
Hepatocellular necrosis:
o
Antibiotics:
! Isoniazid
! Rifampicin
! Nitrofurantoin
o
Anticonvulsants:
! Can cause liver damage at normal doses in some patients
! Carbamazepine
! Phenytoin
! Valproate
14
www.garrypettet.com
o
Anti-hypertensives:
! Hydralazine:
Also causes a SLE-like syndrome (ssDNA Abs)

! Methyldopa
o
Halothane (repeated exposures)
o
Paracetamol (overdose)
15
www.garrypettet.com
Rheumatology
Drug treatment of osteoarthritis (OA):
Simple analgesics:
o
Paracetamol (as good as Ibuprofen in early disease)
Topical therapy:
o
NSAIDs (e.g. ibuleve)
o
Capsaicin:
! Potent pain-producing agent
! After a few applications, the pain-producing effect
disappears and nociceptive responses to other stimuli
disappear as well hence its use here
Glucosamine
Systemic NSAIDs
Drug treatment of rheumatoid arthritis (RA):
NSAIDs
COX-II inhibitors:
o
Indications:
! Age >65 years
! Previous history of DU / GU or GI bleed
! Large doses of NSAID required to control pain
o
Absolute contraindications:
! Established IHD
! Cerebrovascular disease
! Heart failure (NYHA II IV)
Gastroprotection (if on NSAID / long-term steroids):

o
H2-receptor antagonists
o
Proton pump inhibitors (PPIs)
o
Misoprostol
Disease modifying anti-rheumatic drug (DMARD):

o
Persisting synovitis >6 weeks
o
Several may have to be tried to find the right one:
! Methotrexate
! Sulphasalazine
! Gold
! Penicillamine
! Hydroxychloroquine
Anti-TNF! therapy:
o
Progressive RA after 2 DMARD failures
Steroids are controversial but useful in acute flares

Drug treatment of osteoporosis:
Bisphosphonates:
o
Are the mainstay of treatment
Calcium supplements
Vitamin D
Calcitonin (may be considered)
HRT no longer has role

16
www.garrypettet.com
Glucosamine:
Unclear mechanism of action
Probably similar efficacy to simple NSAIDs
Better tolerated than NSAIDs but not free of side-effects:

o
Headache
o
Rash
o
Drowsiness
Non-steroidal anti-inflammatory drugs (NSAIDs):
(Non- selectively) inhibit cyclo-oxygenase (COX)
COX converts arachidonic acid (derived from membrane phospholipids)

into endoperoxides
The endoperoxides are further converted into:

o
Prostaglandins (PGs):
! Potentiate the activity of other pain mediators
! Vasodilatation
o
Thromboxane A2:
! Platelet aggregation
! Vasoconstriction
o
Prostacyclin:
! Inhibits platelet aggregation
! Vasodilatation
There are 2 isoforms of COX - COX-I and COX-II:

o
COX-I is a constitutional enzyme and is important in the
maintenance of the protective GI mucus barrier in the stomach
and of renal blood flow
o
COX-II is expressed at sites of inflammation
NSAIDs are:
o
Analgesic
o
Antipyretic (inhibits the rise in brain PGs that cause pyrexia)
o
Anti-inflammatory (at higher doses)
Adverse effects:
o
GI:
! Peptic ulceration (major adverse effect)
o
Renal:
! Reduced renal blood flow
! Sodium retention - hypertension
! Interstitial nephritis
! Hyperkalaemia
! Papillary necrosis (chronic use)
o
Other:
! Bronchospasm (especially in asthmatics)
! Allergies
Aspirin as a NSAID:
Aspirin is a NSAID but the large doses required to control the

inflammation in the arthritides led to an unacceptable number of
adverse effects
17
www.garrypettet.com
It irreversibly inactivates COX activity returns only when new

enzyme is synthesised:
o
Hence its effectiveness in platelets (cannot synthesise new
enzyme)
Paracetamol as a NSAID:
Like aspirin, paracetamol is a NSAID
Its mechanism of action is not fully understood and it has no anti-

inflammatory activity
It works, act least partly, by reducing COX tone:

o
This activity is only seen in areas of low peroxide concentration
o
Hence, paracetamol works best when there is little or no
leucocyte infiltration (as leucocytes produce high levels of
peroxide)
Relative risk of GI toxicity with NSAIDs:
From least toxic to most toxic:

o
Ibuprofen
o
Diclofenac
o
Aspirin
o
Naproxen
o
Indomethacin
o
Ketoprofen
COX-II inhibitors:
E.g. Celecoxib (Rofecoxib (Vioxx) has been withdrawn in the UK))
No better at improving symptoms of pain / inflammation than NSAIDs
50% reduction in GI:

o
Ulceration
o
Perforation
o
Bleeds
(Probable) increased risk of:

o
Myocardial infarction
o
Stroke
Methotrexate:
Indications:
o
Malignancy
o
Psoriasis (when conventional therapy fails)
o
Rheumatoid arthritis
18
www.garrypettet.com
Mechanism of action:
o
Inhibits dihydrofolate reductase
o
Leads to a reduction in the production of tetrahydrofolic acid
(which is essential for nucleic acid synthesis)
o
Prevents cells from dividing
Administer concurrent folic acid to minimise symptoms
Adverse effects:
o
Nausea
o
Fatigue
o
Pneumonitis (rare but can be life-threatening)
Contraindications:
o
Renal / hepatic impairment
o
Pregnancy
Interactions:
o
NSAIDs / probenicid:
! Reduce the excretion of methotrexate
Sulphasalazine:
Mechanism of action in RA is unknown
Adverse effects:
o
Nausea / abdominal discomfort
o
Reduced sperm count
o
Marrow suppression
Contraindications:
o
Salicylate allergy
o
Renal impairment
Gold:
Adverse effects:
o
Marrow suppression
o
Proteinuria
o
Hepatitis
Penicillamine:
Adverse effects:
o
Marrow suppression
o
Proteinuria
o
Reduction in taste
o
SLE
Contraindications:
o
Penicillin allergy
o
SLE
Hydroxychloroquine:
Adverse effects:
o
Rash
o
Retinopathy (rare)
o
Tinnitus
Cautions:
19
www.garrypettet.com
o
Hepatic impairment
Very toxic in overdose

Anti-TNF! therapy:
TNF! is the major mediator of inflammation
Used in RA when patient has failed to respond to >=2 DMARDs

(including methotrexate)
Can be either:
o
Soluble TNF! receptors (etanercept)
o
Anti-TNF! receptors (infliximab)
Reduce inflammation, inhibit progression and improve radiological

Sharp score (a measure of radiological RA severity)
Adverse effects:
o
Local reactions
o
Increased risk of infections:
! Especially tuberculosis (need to screen before therapy)
o
Demyelination syndromes
o
SLE-like syndrome:
! Avoid in SLE-sufferers
o
Worsening of pre-existing heart failure
Other disease indications:

o
Ankylosing spondylitis
o
Psoriatic arthritis
o
Crohns disease
Bisphosphonates:
E.g. alendronate, pamidronate
Are enzyme-resistant analogues of pyrophosphate
Bind to hydroxyapatite crystals and reduce bone resorption (via

inhibition of osteoclasts)
Indications:
o
Osteoporosis (both primary and steroid-induced)
o
Pagets disease
o
Malignant hypercalcaemia
Adverse effects:
o
Alendronate can cause oesophagitis:
! Swallow the tablet whole with a full glass of water on an
empty stomach and remain upright for at least 30 mins
Vitamin D supplementation:
Usually given as ergocalciferol (vitamin D2 the usual dietary source

of vitamin D)
Is a fat-soluble vitamin so bile salts are necessary for absorption
Adverse effects:
o
Hypercalcaemia
Interactions:
20
www.garrypettet.com
o
Some anticonvulsants (carbamazepine, phenytoin) increase the
requirement of vitamin D
21
www.garrypettet.com
Gastroenterology
Drug treatment of GORD / PUD:
Antacids
Acid suppression:
o
H2-receptor antagonists
o
Proton pump inhibitors (PPIs)
Helicobacter pylori eradication

Drug treatment of constipation (laxatives):
Bulk laxatives
Stimulant laxatives
Osmotic agents
Stool softeners
Suppositories / enemas
Novel:
o
Motilin analogues (e.g. erythromycin)
o
5-HT4 antagonists (e.g. tegaserod)
o
Probiotics
Drug treatment of diarrhoea:
General:
o
Opioids (e.g. loperamide)
Autonomic neuropathy (e.g. diabetes):

o
Clonidine
o
Octreotide (for secretory diarrhoea)
Bacterial overgrowth:
o
Treat underlying cause
o
Cyclical antibiotics if above fails (e.g. neuropathy)
Pancreatic insufficiency (e.g. diabetes, chronic pancreatitis):

o
Pancreatin + acid-suppressant (e.g. PPI)
Drug treatment of Crohns disease:
Acute exacerbations:
o
Steroids (oral / rectal / IV)
o
Elemental diet
o
Anti-TNF! therapy (infliximab):
! Severe (especially fistulating) disease
Maintenance:
o
5-Aminosalicylic acid (5-ASA) compounds
o
Azathioprine (if 5-ASA fails)
o
Methotrexate (if azathioprine intolerant)
Drug treatment of ulcerative colitis:
Acute exacerbations:
22
www.garrypettet.com
o
Rectal 5-ASA (evidence shows benefit over steroids)
o
Steroids (oral / rectal / IV)
Maintenance:
o
5-ASA compounds
Antacids:
Increase gastric pH (this increases rate of emptying thus action is

short)
All antacids can interfere with drug absorption should be taken

separately
Sodium bicarbonate:
o
Only useful water-soluble antacid
o
May cause metabolic alkalosis
Magnesium hydroxide:
o
May cause diarrhoea
Aluminium hydroxide:
o
May cause constipation
Alginate-containing compounds (e.g. Gaviscon):

o
Form a raft on top of stomach contents and prevent reflux
H2-receptor antagonists:
E.g. ranitidine, cimetidine
Block histamine receptors on the gastric parietal cell membrane and

reduce acid secretion
Indications:
o
GORD
o
PUD
Adverse effects (mainly cimetidine):

o
Liver enzyme inhibitor (increases levels of):
! Anticonvulsants (carbamazepine, phenytoin, valproate)
! Theophylline
! Warfarin
o
Hyperprolactinaemia
o
Anti-androgenic activity (gynaecomastia)
Proton pump inhibitors (PPIs):
E.g. omeprazole, lansoprazole
Inactive at neutral pH but are activated in the stomach and irreversibly

inhibit the H
+
/K
+
-ATPase (proton pump)
Are more effective than H2-receptor antagonists and more cost-

effective
Indications:
o
GORD
o
PUD
o
Zollinger-Ellison syndrome
Adverse effects:
o
Liver enzyme inhibitor (increases levels of):
23
www.garrypettet.com
! Phenytoin
! Warfarin
Cautions:
o
Achlorhydria is associated with gastric cancer unsure of long-
term effects of acid suppression
H. pylori eradication therapy:
One PPI and two antibiotics for two weeks
Usual combination (but there are many):

o
Omeprazole
o
Clarithromycin
o
Amoxicillin (or metronidazole)
Resistance to metronidazole is common

Bulk laxatives:
E.g. bran, ispaghula
Only good for mild constipation
Are usually indigestible polysaccharides
Increase the volume of the intestinal contents thus stimulating

peristalsis by stretching mechanoreceptors
Gradual onset of action (~1 week)
Increase stool output as a function of initial stool weight:

o
If stool volume is low initially then wont see much of an
increase
Adverse effects:
o
Exacerbates bloating in slow-transit constipations
Stimulant laxatives:
E.g. bisacodyl, picosulphate, senna
Are inactive glycosides that are activated in the colon by bacteria
Once in colon have direct stimulant effect on the myenteric plexus:

o
Smooth muscle contraction (peristalsis)
Also increase secretion of water and electrolytes
Rapid onset of action (~8 hours) give in evening for morning stool
Adverse effects:
o
Colic
o
Colonic atony
o
Hypokalaemia
o
Pseudomelanosis coli (colonic pigmentation with chronic use)
o
Unpredictable effect
Osmotic agents:
E.g. Lactulose, magnesium salts
Poorly absorbed solutes that maintain a large stool volume by osmosis
Lactulose:
o
Is a disaccharide (fructose-galactose)
o
Cannot be cleaved by human disaccharidases is cleaved by
bacteria in the colon
24
www.garrypettet.com
o
These sugars are poorly absorbed by the colon and act as
osmotic laxatives
Onset of action:
o
Salts hours
o
Lactulose 2 or 3 days
Adverse effects:
o
Cramps
o
Flatulence
o
Hypermagnesaemia (especially in renal impairment) with Mg
salts
Stool softeners:
E.g. sodium docusate, arachis oil
Act like detergents in the colon and facilitate mixing of fat and water
in the stool
Adverse effects:
o
Passive faecal leakage
Not effective enough to be used on their own

Suppositories / enemas:
E.g. glycerine suppositories, phosphate enemas
Probably as effective as oral osmotic laxatives

Opioids and diarrhoea:
E.g. loperamide, codeine, morphine
Sti mul ate -receptors on myenteri c neurones and l ead to

hyperpolarization:
o
Inhibits Ach release from myenteric plexus and reduces
peristalsis
Loperamide is most appropriate as it does not cross the blood-brain

barrier and is unlikely to cause dependence
Pancreatin:
Pancreatic enzyme supplement of porcine origin
Must be taken with an anti-acid drug (usually a H2-receptor

antagonist) to prevent its destruction in the stomach
Is inactivated by heat caution if mixing pancreatin in with food
Indications:
o
Cystic fibrosis
o
Chronic pancreatitis
o
Diabetes mellitus
o
Pancreatectomy
Adverse effects:
o
Nausea / vomiting
o
Abdominal discomfort
o
Irritation of buccal / perianal mucosa
5-Aminosalicyclic acid (5-ASA) compounds:
E.g. mesalazine, olsalazine, sulphasalazine

25
www.garrypettet.com
Unknown mechanism of action
Indications:
o
Induction of remission in UC (rectal preparation)
o
Maintenance of remission in UC and CD:
! 1 year relapse rate (73% placebo vs 21% sulphasalazine)
Probably reduce the cancer risk associated with UC
Drug structures:
o
Olsalazine:
! Two 5-ASA molecules joined by an azo bond that is
cleaved by bacteria in the colon
o
Sulphasalazine:
! 5-ASA with sulphapyridine (a sulphonamide)
! The sulphapyridine carries the 5-ASA to the colon
! Most of the adverse effects are caused by sulphapyridine
Adverse effects:
o
Few with the newer agents (lacking sulphapyridine)
Infliximab:
An anti-TNF! monoclonal antibody
Indications:
o
Crohns disease not controlled by steroi ds and a
conventional immunosuppressant
o
Refractory fistulating Crohns disease
65% of patients initially respond to infliximab
30% will go on to remission
Of those that respond to a single treatment 50% maintain remission

when treated for 1 year
Infliximab closes 50% of refractory fistulas within 2 weeks and

improves healing in 65%:
o
However, only 30% of those who heal remain healed at 1 year
Adverse effects:
o
Local reactions
o
Increased risk of infections:
! Especially tuberculosis (need to screen before therapy)
o
Demyelination syndromes
o
SLE-like syndrome:
! Avoid in SLE-sufferers
o
Worsening of pre-existing heart failure
26
www.garrypettet.com
Antivirals
Treatment of herpes simplex virus (HSV) and varicella zoster virus (VZV):
Aciclovir (topical / oral / IV)
Second-line:
o
Famciclovir (good for genital herpes)
o
Valaciclovir
Treatment of cytomegalovirus (CMV):
Ganciclovir (IV) (can cause myelosuppression)
Second-line:
o
Valaciclovir
o
Foscarnet
Treatment of human immunodeficiency virus (HIV):
Highly active anti-retroviral therapy (HAART):

o
Two NRTIs plus either an NNRTI or a PI
NRTI = nucleoside reverse transcriptase inhibitor
NNRTI = non- nucleoside reverse transcriptase inhibitor
PI = protease inhibitor
Treatment of opportunistic infections

Drugs treatment of chronic hepatitis B (HBV) infection:
40% success rate
Interferon-! (IFN-!) given as a subcutaneous injection
Lamivudine
Second-line:
o
Famciclovir
Drug treatment of chronic hepatitis C (HCV) infection:
Combination therapy (most effective, up to 60% cured):

o
Peginterferon-! ($ bioavailability once weekly)
o
Ribavirin
Treatment depends on HCV genotype:

o
Genotypes 2, 3:
! Better prognosis
! Treat for 6 months
o
Genotypes 1, 4:
! Worse prognosis
! Treat for 12 months
If HCV RNA has not decreased after 12 weeks treatment to <1% of

initial level then consider discontinuing
Drug treatment of influenza:
Influenza A only:
27
www.garrypettet.com
o
Amantadine
Influenza A and B:
o
Neuraminidase inhibitors:
! Olseltamivir
! Zanamivir
Only used in at-risk adults who can start treatment within 48 hours of
the onset of symptoms
At-risk adults:
o
Chronic respiratory disease
o
Significant cardiovascular disease (excluding hypertension)
o
Chronic renal disease
o
Immunocompromised
o
Diabetes mellitus
Aciclovir:
Is a guanosine analogue and an example of a prodrug
Aciclovir is converted to the monophosphate by thymidine kinase
Viral thymidine kinase has a much greater affinity for aciclovir than the
human enzyme
Aciclovir is therefore only activated in virally-infected cells, where it is

converted to the triphosphate:
o
Inhibits viral DNA polymerase and terminates the nucleotide
chain
Adverse effects:
o
Rash (topical preparations)
o
Drip site inflammation
o
Renal damage
o
Bone marrow suppression (with parenteral administration
Interactions:
o
Probenicid decreases excretion of aciclovir
Adverse effects of the NRTIs:
All of these drugs have many side-effects, only important ones for
each are listed here
Abacavir:
o
Hypersensitivity (rash, Stevens-Johnson syndrome)
o
Hepatic impairment (lactic acidosis, hepatomegaly)
Didanosine:
o
Pancreatitis
Lamivudine:
o
Well tolerated
o
Caution in hepatic disease
Stavudine:
o
Lipodystrophy
o
Peripheral neuropathy
Zalcitabine:
o
Pancreatitis
o
Peripheral neuropathy
28
www.garrypettet.com
Zidovudine (AZT):
o
Bone marrow suppression (initially developed as an anti-
cancer agent)
Adverse effects of the NNRTIs:
All of these drugs have many side-effects, only the important ones for
each are listed here
Efavirenz:
o
Psychiatric manifestations
Nevirapine:
o
o
Many drug interactions:
! E.g. methadone is metabolised much faster
Adverse effects of the PIs:
o
Many side effects although an important one is lipodystrophy
Amprenavir:
o
Indinavir:
o
Renal calculi
Ritonavir:
o
Peripheral and circumoral paraesthesia
Saquinavir:
o
Liver impairment
Combination:
o
Kaletra (lopinavir + ritonavir):
! The ritonavir $ the concentration of the lopinavir
! Diarrhoea
Lipodystrophy:
Also known as the fat redistribution syndrome
A common side effect of the PIs and stavudine
Features:
o
Decreased subcutaneous fat
o
Buffalo hump
o
Breast enlargement
o
Hyperlipidaemia
o
Insulin resistance - hyperglycaemia
Amantadine:
Indications:
o
Influenza A in at-risk adults within 48 hours of symptoms
o
Parkinsons disease
Its anti-viral actions arise from its ability to inhibit a viral ion-channel
The putative mechanism in Parkinsons disease is an increase in

dopamine release
29
www.garrypettet.com
Asthma / COPD
Severe asthma:
Unable to complete sentences
Respiratory rate >25/min
Pulse >110/min
PEFR <50% best or predicted

Life-threatening asthma:
PEFR <33% best or predicted
Bradycardia
Hypotension
Silent chest
Feeble respiratory effort
Confusion
Blood gases:
o
pCO2 > 5kPa
o
pO2 <8kPa
o
pH <7.35
BTS guidelines for the management of acute severe asthma in adults
Initial management:
o
100% High flow oxygen
o
Nebulised salbutamol (5mg) or terbutaline (10mg)
o
Add in nebulised ipratropium bromide (0.5mg) if poor
response
o
IV hydrocortisone (100mg)
No improvement:
o
Consider ITU referral
o
Continue repeating nebulised salbutamol
o
IV magnesium sulphate (1.2-2g over 20 mins)
o
Aminophylline:
! Omit loading dose if patient is taking theophylline
o
IV Salbutamol (but not with Aminophylline)
BTS 5 steps approach to the management of asthma:
Step 1 (mild intermittent asthma):

o
Inhaled short-acting "2-agonist as required
Step 2 (regular preventer therapy):

o
Step 1 + low dose inhaled steroid
Step 3 (add-on therapy):

o
Step 2 + long-acting "2-agonist (LABA)
o
If partial response to LABA then:
! Continue with LABA and increase dose of inhaled steroid
o
If no response to LABA then:
! Stop LABA and increase dose of inhaled steroid
! Consider adding in leukotriene antagonist or theophylline
Step 4 (persistent poor control):

30
www.garrypettet.com
o
Step 3 + either:
! High-dose inhaled steroid
! Leukotriene antagonist (if not on one already)
! Oral theophylline
Step 5 (continuous or frequent use of oral steroids):

o
Step 4 + daily oral steroids
o
Refer patient for specialist care
General principles of drug treatment of COPD:
Discontinue drugs which may worsen COPD:

o
E.g. "2-blockers for hypertension
Maintenance therapy:
o
Inhaled bronchodilators:
! "2-agonists (short-/long-acting)
! Anti-muscarinics (short-/long-acting):
These are more important than in asthma

o
Inhaled corticosteroids:
! If FEV1 <50% predicted
! Repeated exacerbations
o
Theophylline
Exacerbations:
o
Oral steroids
o
Antibiotics (if infection suspected)
Vaccination:
o
Influenza (definite benefit shown)
o
Pneumococcal (probable benefit)
Drug treatment of COPD by stage:
Stage 0:
o
No COPD (but at risk)
Stage 1 (mild COPD):

o
FEV1 <80% predicted
o
Short-acting "2-agonist
Stage 2:
o
FEV1 50-80% predicted
o
Long-acting "2-agonist
Stage 3:
o
FEV1 <50% predicted
o
Inhaled steroids (1000 - 2000g daily)
Stage 4:
o
FEV1 <30% predicted
o
Risk of cor pulmonale
o
May need oxygen therapy if hypoxic at rest
Inhaled "2-agonists:
Short-acting (last 4-6 hours):

o
Salbutamol
31
www.garrypettet.com
o
Terbutaline
Long-acting (last ~12 hours):

o
Salmeterol
Indications:
o
Asthma
o
COPD with reversible component
o
Stimulate "2-receptors on airway smooth muscle
o
Leads to $ cAMP which # intracellular Ca
2+
, leading to smooth
muscle relaxation
Adverse effects:
o
Tachycardia
o
Tremor
Interactions (Hypokalaemia with high doses of):

o
Corticosteroids
o
Diuretics (loop and thiazide)
o
Theophylline
Inhaled anti-muscarinics:
Short-acting (last 3-6 hours):

o
Ipratropium bromide (Atrovent)
Long-acting (once daily):

o
Tiotropium (Spiriva)
Indications:
o
Asthma
o
COPD with reversible component (especially tiotropium)
o
Inhibits the parasympathetic nervous supply of the bronchioles
by binding to muscarinic receptors
Adverse effects (uncommon as poorly absorbed systemically):

o
Dry mouth
o
Constipation
Cautions:
o
Glaucoma
o
Prostatic hypertrophy
Inhaled corticosteroids:
E.g. beclomethasone, budesonide, fluticasone
Indications:
o
Asthma (from BTS step 2 onwards)
o
Decrease formation of numerous cytokines important in asthma
o
Inhibit generation of prostaglandins / leukotrienes
o
Inhibit the allergen-induced influx of eosinophils into the lung
o
Up-regulate "2-receptors
Take up to 12 weeks to reach maximum efficacy
Reduce morbidity and mortality of asthma
Improve quality of life
Prevent long-term decrease in airway function

32
www.garrypettet.com
Inhaled steroids work best at a moderate dose combined with

bronchodilators
Adverse effects (fewer than systemic corticosteroids):

o
High dose:
! Adrenal suppression (give patients steroid card)
! Cataracts
! Glaucoma
! Growth suppression (probably just initial growth
velocity)
! Osteoporosis
o
Low dose:
! Candidiasis (reduced by using a spacer device)
! Hoarse voice
Interactions:
o
Very few when inhaled
Cautions:
o
Active or quiescent TB
o
Oral steroids may be required during times of high stress if on
long-term high dose inhaled steroids
Methylxanthines:
E.g. Aminophylline, theophylline
Aminophylline is a soluble form of theophylline:

o
If given IV, must be by very slow IV injection
Indications:
o
Asthma (BTS step 3 onwards) as theophylline
o
Severe acute asthma (as aminophylline)
o
Are phosphodiesterase inhibitors and lead to an $ cAMP and
hence bronchial smooth muscle relaxation
o
May also increase cGMP levels and cause smooth muscle
relaxation
Adverse effects:
o
Nausea / vomiting
o
Hypokalaemia
o
CNS stimulation
Interactions (many is metabolised by liver enzymes):

o
Adenosine:
! Actions of adenosine are inhibited by the methylxanthines
o
Plasma concentration increased by:
! COC pill
! Erythromycin
! Cimetidine
! Verapamil
o
Plasma concentration decreased by:
! Carbamazepine
! Phenytoin
! Rifampicin
Caution:
33
www.garrypettet.com
o
Half-life is increased by:
! Cardiac failure
! Liver disease
! Viral infections
o
Half-life is decreased by:
! Alcoholism
! Smoking
Leukotriene antagonists:
E.g. montelukast
Taken orally
Indications:
o
Asthma (BTS step 3 onwards)
o
Block the effects of cysteinyl leukotrienes (e.g. LTC4, LTD4 and
LTE4) in the airways
Advantages:
o
Improved compliance (oral and dont have the steroid stigma)
o
Some patients respond well to them
o
Well tolerated
Disadvantages:
o
Poor efficacy compared to inhaled steroids
o
Unpredictable response
o
Expensive
Adverse effects:
o
GI disturbances
o
Drug-induced Churg-Strauss syndrome
34
www.garrypettet.com
Analgesics
Taxonomy of opioids:
Opioid:
o
A compound acting at an opioid receptor
Opiate:
o
An alkaloid derived from opium
Adverse effects of opioids:
CNS:
o
Respiratory depression:
! Decreased respiratory rate
! Relief of dyspnoea
o
Sedation
o
Euphoria
o
Meiosis
o
Anti-tussive
o
Nausea / vomiting
Non-CNS:
o
Pruritis
o
Constipation
o
Urinary retention
Opiates only:
o
Histamine release:
! Not opioid receptor mediated
Mechanism of action of opioids:
Mimic endogenous opioids by acting on , % and & receptors in the:

o
Dorsal horn
o
Peri-aqueductal grey matter
o
Midline raphe nuclei
Contraindications to the use of strong opioids:
Severe respiratory disease (e.g. COPD)
Head injury / raised intracranial pressure:

o
Interfere with neurological assessment
Hepatic failure
Acute alcohol intoxication

WHO analgesic ladder:
Step 1:
o
Non-opioid analgesics:
! Aspirin
! Paracetamol
! NSAIDs
Step 2:
o
Weak opioids /partial opioid agonists:
35
www.garrypettet.com
! Codeine
! Tramadol
Step 3:
o
Strong opioids:
! Morphine
! Diamorphine
Paracetamol (acetaminophen):
Indications:
o
Mild to moderate pain
o
Pyrexia
Adverse effects:
o
Dangerous in overdose
Overdose:
o
Signs / symptoms:
! None (generally)
! Abdominal pain
! Hypoglycaemia
! Vomiting
o
Investigations:
! ABG, FBC, glucose, LFTs (ALT), INR, U&Es
o
Treatment:
! Remove the drug:
If >12g and <1 hr since ingestion - gastric lavage
If <8 hrs since ingestion - activated charcoal

! Find the time vs paracetamol concentration graph in A&E:
If above treatment line start N-acetylcysteine

o
Rule of thumb:
! If PT (secs) > time since od (hrs) then bad prognosis
o
Criteria for transfer to specialist liver unit:
! Encephalopathy / $ ICP
! INR > 2.0 at < 48 hrs or INR >3.5 at 72 hours:
If INR is normal at 48 hours, patient can go home

! Renal impairment (creatinine >200mol/L)
! Blood pH <7.3
! Systolic BP <80mmHg
Cautions:
o
Hepatic / renal impairment
o
Alcohol dependence
Codeine phosphate:
Indications:
o
Cough suppression
o
Diarrhoea
o
Half-life of 3.5 hours
Adverse effects:
o
Constipation (prominent)
o
See adverse effects of opioids
36
www.garrypettet.com
Tramadol:
Synthetic analogue derived from codeine
Indications:
o
Moderate to severe pain
o
-receptor agonist (like most opioids)
o
Inhibits uptake of noradrenaline and 5-HT
Advantages over other opioids:

o
Does not depress respiration
Disadvantage over other opioids:

o
Can cause seizures
Morphine:
Indications:
o
Pain:
! Acute (e.g. myocardial infarction)
! Chronic (e.g. chronic pancreatitis)
! Terminal (e.g. malignancy)
o
Acute pulmonary oedema
o
Intractable cough in terminal care
Half-life of 3 hours
Tolerance to morphine occurs after about 2 weeks of continuous use
Titration of morphine dose:

o
Assess individual 24 hour requirement to relieve pain at rest and
on movement
o
Convert to modified release morphine (MST) bd with rapid
release morphine prn for breakthrough pain
o
Increase the dose of MST based on the basis of breakthrough
requirements
37
www.garrypettet.com
The failing heart
Heart failure:
Acute:
o
Myocardial infarction (MI):
! Acute
! Post-MI
o
Pulmonary oedema without MI
Chronic:
o
Chronic stable angina
o
Heart failure
Drug treatment of acute myocardial infarction:
Oxygen
Aspirin 300mg (chewed) or clopidogrel (if aspirin contraindicated)
Morphine 5-10mg IV + metoclopramide 10mg IV
GTN 2 puffs or 1 tablet prn
"-blocker (e.g. atenolol 5mg IV) unless contraindicated
Thrombolysis:
o
Indications:
! Presentation within 12 hours of chest pain and
! ST elevation >2mm in 2 or more chest leads or
! ST elevation >1mm in 2 or more limb leads or
! New left bundle branch block or
! Posterior infarction
o
Contraindications:
! Bleeding
! Prolonged / traumatic CPR
! Trauma / surgery (within 2 weeks)
! Recent haemorrhagic stroke
! Severe hypertension (>200/120mmHg)
! Pregnancy
! Suspected aortic dissection
o
Thrombolytic agent:
! Streptokinase (SK):
1.5 million units in 100mls 0.9% saline over 1 hour
Usual first choice
Risk of allergy / anaphylaxis

! Tissue plasminogen activator (tPA):
Give if patient already received SK
Alteplase " infusion
Tenecteplase " bolus injection
Heparin:
o
DVT / PE prophylaxis
Drug treatment post-myocardial infarction:
Aspirin 75mg od
38
www.garrypettet.com
"-blocker (e.g. atenolol) or verapamil if contraindicated
ACE inhibitor (especially if evidence of heart failure)
Statin (e.g. benefit shown even if normal cholesterol levels)
Treat other risk factors:

o
Diabetes mellitus
o
Hypertension
Think of the 4 As (Aspirin, Atenolol, ACE inhibitor and Atorvastatin)

Drug treatment of acute pulmonary oedema:
Sit patient upright
Oxygen
Furosemide (40 80mg slow IV)
Diamorphine (2.5 5mg slow IV)
GTN 2 puffs or 2x0.3mg tablets
If systolic BP >100mmHg start nitrate infusion (keep >90mmHg)
If patient worsening:
o
Repeat furosemide 40 80mg slow IV
o
Consider ventilation
o
Consider increasing nitrate infusion
Drug treatment of chronic stable angina:
Aspirin
Nitrates:
o
Relief:
! GTN
o
Prevention:
! Long-acting nitrates
"-blockers (e.g. atenolol 50-100mg/24 hours po)
Calcium-channel blockers:
! Caution with concomitant use of "-blocker
o
Dihydropyridines:
! Amlodipine
o
Non-dihydropyridines:
! Diltiazem
! Verapamil (caution with "-blockers)
Potassium channel activator:

o
Nicorandil
Drug treatment of chronic heart failure:
Diuretics:
o
Furosemide (symptomatic only)
o
Spironolactone:
! Potassium-sparing
! Shown to reduce mortality
o
Metolazone:
! Thiazide diuretic
! Synergistic with furosemide for refractory oedema
ACE inhibitors:
o
Shown to reduce mortality
39
www.garrypettet.com
"-blockers:
o
Shown to reduce mortality (probably via # arrhythmias)
o
Synergistic with ACEIs
o
Start low, go slow needs careful titration
Digoxin:
o
Can be used even if the patient is in sinus rhythm
o
No reduction in mortality
o
# in hospital admissions
Angiotensin II receptor antagonists:

o
Probably similar to ACEIs but little conclusive evidence
Nitrates:
o
Probably reduce mortality (but less so than ACEIs)
o
Used in those in whom ACEIs are contraindicated
Nitrates:
All function as nitric oxide (NO) donors
Cause mainly venous dilatation (hence # preload)
Mechanism of action of NO:

o
NO stimulates guanylyl cyclase which leads to an $ cGMP
o
$ cGMP leads to smooth muscle relaxation
Glyceryl trinitrate (GTN):

o
Onset is rapid and lasts for ~30 mins
o
Usually given sublingually
Long-acting nitrates (isosorbide mono-/dinitrate):

o
More stable than GTN and last several hours
o
Isosorbide mononitrate is the active metabolite of isosorbide
dinitrate:
! The mononitrate avoids the unpredictable first-pass
metabolism of the dinitrate
o
Tolerance develops after as little as 24 hours avoid by
omitting the evening dose (permits an 8 hour drug-free interval)
Adverse effects:
o
Headaches (frequently dose-limiting)
o
Hypotension / fainting
o
Reflex tachycardia (prevented by administration of a "-blocker)
Contraindications:
o
Constrictive pericarditis
o
Hypotension
o
Head trauma
o
Hypertrophic obstructive cardiomyopathy (HOCM)
o
Valvular stenosis (aortic / mitral)
Interactions:
o
Sildenafil (Viagra):
! Profound hypotension
"-blockers:
Non-selective:
o
Propranolol:
! Is a full antagonist
o
Pindolol / oxprenolol:
40
www.garrypettet.com
! Are partial agonists
o
Labetolol:
! " and ! antagonist (" > !)
Cardio-selective ("1-antagonists):
o
Atenolol
o
Metoprolol
Indications:
o
Angina
o
Heart failure
o
Hypertension
o
Post-MI
o
Prevention of variceal bleeding in liver disease (propranolol)
o
Prophylaxis of migraine
o
Stress-induced arrhythmias
o
Most do not affect resting parameters (e.g. heart rate) but
prevent the exercise-induced cardiovascular changes caused by
sympathetic stimulation
o
Anti-hypertensive action probably arises from an alteration in
the CNS set-point
Adverse effects:
o
Lethargy / fatigue (usually improves with use)
o
Bradycardia
o
Cold hands / feet
o
Hypotension
o
Bronchospasm (including cardio-selective agents)
o
Nightmares
o
Worsened / precipitated heart failure
Contraindications:
o
Asthma / COPD
o
Bradycardia / heart block
Interactions:
o
Diltiazem / verapamil:
! $ risk of bradycardia / AV block
o
Insulin / oral anti-diabetic agents:
! "-blockers mask the signs of hypoglycaemia
Calcium-channel blockers:
Two classes:
o
Dihydropyridines:
! Nifedipine (short-acting)
! Amlodipine (longer-acting)
o
! Diltiazem
! Verapamil
Indications:
o
All:
! Angina (especially vasospastic angina)
41
www.garrypettet.com
! Hypertension
o
Nifedipine:
! Raynauds phenomenon
o
Verapamil:
! Supraventricular arrhythmias:
Adenosine has largely replaced in acute situation
Can be used as prophylaxis against SVTs
o
Block L-type voltage-sensitive Ca
2+
channels in:
! Arterial smooth muscle (vasodilatation):
Both classes
Can cause a reflex tachycardia

! Myocardial conduction system (negative inotropism):
Non-dihydropyridines (as they have a high

affinity for channels in the activated state
Amlodipine causes less tachycardia than nifedipine
Verapamil (and to a lesser extent diltiazem) depress the sinus node:

o
Mild resting bradycardia
Verapamil slows conduction at the AVN
Diltiazem has actions in between verapamil and nifedipine:

o
Popular in treatment of angina does not cause tachycardia
Adverse effects:
o
Fluid retention (ankle oedema):
! Can be severe enough to merit withdrawal
! Is a local effect that has nothing to do with Na
+
retention
o
Headaches
o
Hypotension
o
Flushing
o
Gum hypertrophy
Contraindications:
o
All:
! Cardiogenic shock
o
Dihydropyridines:
! Severe aortic stenosis / HOCM
! Unstable angina
o
! Myocardial conduction defects (e.g. bradycardia)
! Heart failure:
Further depression of cardiac function

o
Nifedipine:
! Angina (short-acting preparation may $ mortality)
o
Verapamil:
! Ventricular tachycardia (potentially lethal)
! AF with Wolff-Parkinson-White syndrome
Interactions:
o
Diltiazem:
! Digoxin:
Diltiazem $ plasma concentration of digoxin

42
www.garrypettet.com
! Carbamazepine:
Diltiazem $ plasma concentration of carbamazepine

! Phenytoin:
Diltiazem $ plasma concentration of phenytoin

o
Nifedipine:
! Diltiazem:
$ plasma levels of nifedipine

! Phenytoin:
Nifedipine $ plasma levels of phenytoin

! Grapefruit juice:
$ pl asma l evel s of ni f edi pi ne (and other

dihydropyridines but not Amlodipine)
o
Verapamil:
! "-blockers (asystole, severe hypotension, heart failure)
! Digoxin:
Verapamil $ plasma concentration of digoxin

! Cyclosporin:
Verapamil $ plasma concentration of cyclosporin

Angiotensin converting enzyme inhibitors (ACEIs):
E.g. captopril, enalapril, lisinopril
Indications:
o
Diabetic nephropathy
o
Hypertension
o
Heart failure
o
Post-MI
Inhibit ACE, thus reduce circulating angiotensin II
Actions of angiotensin II (mediated via the AT1 receptor):

o
Potent vasoconstrictor
o
Aldosterone secretion:
! Na
+
retention
! K
+
excretion
Advantages:
o
Do not affect blood lipids
o
May improve cardiac remodelling
Adverse effects:
o
Postural hypotension:
! Usually first-dose
! More common in sodium-depleted patients
o
Dry cough (Chinese are more susceptible)
o
Hyperkalaemia
o
Angioedema (in 1 2% of patients)
Contraindications:
o
Poor renal arterial perfusion pressure:
! Renal artery stenosis / coarctation of the aorta:
Loss of renal efferent arteriole tone (caused by the

ACEI) and # afferent arteriole pressure leads to
renal ischaemia
43
www.garrypettet.com
o
Aortic stenosis
o
Pregnancy
Interactions:
o
NSAIDs:
! $ risk of renal impairment
o
Potassium-sparing diuretics:
! $ risk of hyperkalaemia
o
Lithium:
! ACEIs # excretion of lithium
o
Diuretics:
! $ risk of hypotension
Angiotensin II (AII) receptor antagonists:
E.g. losartan, irbesartan, candesartan
Indications:
o
Diabetic nephropathy
o
Hypertension
o
Heart failure (unlicensed indication)
o
Block the AT1 receptor, inhibiting the actions of angiotensin II
o
As they do not block ACE, they do not affect the metabolism of
bradykinin possibly why they do not cause a cough
Adverse effects/contraindications/interactions as for ACE inhibitors

Digoxin:
Indications:
o
Supraventricular dysrhythmias (esp. AF) for ventricular rate
control
o
Heart failure (improves symptoms not mortality)
o
Is a cardiac glycoside extracted from foxglove leaves
o
Inhibits cardiac membrane Na
+
/K
+
-ATPase:
! $ intracellular Na
+
! Secondary $ in intracellular Ca
2+
Clinical effects:
o
$ force of cardiac contraction
o
$ cardiac vagal activity:
! # heart rate
! # AV conductance
! $ AVN refractory period
Common adverse effects:

o
Anorexia
o
Nausea
o
Vomiting
Toxic levels:
o
Digoxin requires therapeutic drug monitoring
o
Risk of toxicity increased with:
! Hypokalaemia (reduced competition for pump binding)
! Hypercalcaemia
44
www.garrypettet.com
! Hypothyroidism
o
May require digoxin specific antibody fragments (Fab)
o
Features:
! Nausea (severe)
! Dysrhythmias:
VT
Heart block
! Xanthopsia (distortion of yellow colour vision)
Contraindications:
o
Complete heart block
o
HOCM
o
Wolff-Parkinson-White syndrome
Caution in renal impairment:

! Digoxin is excreted by the kidneys
Drugs increasing risk of digoxin toxicity:

o
Anti-arrhythmics:
! Amiodarone
! Quinidine
o
Calcium channel blockers (non-dihydropyridines)):
! Diltiazem
! Verapamil
o
Diuretics (loop and thiazide):
! Cause hypokalaemia, thus $ risk of digoxin toxicity
Nicorandil:
Indications:
o
Angina
o
Potassium channel activator with a nitrate component
o
Causes both arterial and venous vasodilatation
Adverse effects:
o
Headache
o
Flushing
o
Oral ulceration (rarely)
Interactions:
o
Sildenafil:
! Profound hypotension avoid concomitant use
45
www.garrypettet.com
Endocrinology
Drug treatment of hyperthyroidism:
Immediate symptom control:

o
Propranolol
Long-term treatment:
o
Thionamides:
! Carbimazole or
! Propylthiouracil
o
Radioiodine (
131
I)
Prior to surgery to decrease thyroid vascularity:

o
Lugols iodine solution
Immediate management of thyrotoxic storm:
IV fluids
Take blood for T3, T4 (and cultures if infection suspected)
Sedate if necessary:
o
E.g. chlorpromazine
Propranolol (oral or IV if no contraindications)
Digoxin:
o
May be needed to slow the heart
Anti-thyroid drugs:
o
Carbimazole
o
Lugols solution
Corticosteroids (IV hydrocortisone or oral dexamethasone)

Drug treatment of hypothyroidism:
Hypothyroidism:
o
Levothyroxine (T4)
Myxoedema coma:
o
Liothyronine (T3)
Drug treatment of Addisons:
Disease:
o
Oral hydrocortisone:
! 20mg in the morning
! 10mg in the evening
! Double during febrile illness, stress or injury
o
Fludrocortisone:
! Only needed if:
Postural hypotension
# Na+, $K+ or $ renin

! Give every second day
Crisis:
o
Hydrocortisone 100mg IV stat
o
IV fluids (colloid to resuscitate then crystalloids)
o
Glucose IV if hypoglycaemic
o
Antibiotics if infection present
46
www.garrypettet.com
Drug treatment of Cushings syndrome:
Treat the underlying cause rarely need drug therapy long-term
Suppression of plasma cortisol level:

o
Aminoglutethemide
o
Ketoconazole
o
Metyrapone
Drug treatment of Conns syndrome:
Definitive treatment is with surgery
Spironolactone
Drug treatment of diabetes insipidus (DI):
Cranial DI:
o
Treat the underlying cause
o
Intranasal desmopressin (DDAVP)
Nephrogenic DI:
o
Treat the underlying cause
o
Bendrofluazide (paradoxically, as this is a diuretic)
Drug treatment of acromegaly:
Best treated with trans-sphenoidal surgery or irradiation
Somatostatin analogues (first line):

o
Octreotide (short-acting)
o
Lanreotide (long-acting)
Dopamine agonists:
o
Bromocriptine
o
Cabergoline
Drug treatment of hypopituitarism:
Need to replace what is missing
ACTH:
o
Hydrocortisone
GH:
o
Recombinant GH is available
FSH, LH:
o
Testosterone - males
o
Oestrogen (via COC pill) - females
TSH:
o
Thyroxine (if hypothyroid, but cant use to TSH to monitor)
No need to replace prolactin

Drug treatment of hypogonadism:
Males:
o
Testosterone
47
www.garrypettet.com
Females:
o
COC pill
Drug treatment of hyperprolactinaemia:
Definitive treatment is surgical
Dopamine agonists:
o
Bromocriptine
o
Cabergoline
Drug treatment of hypercalcaemia:
Treat underlying cause if possible
IV fluids
Bisphosphonates
Salmon calcitonin:
o
Rarely used
o
Faster onset than bisphosphonates
Steroids:
o
E.g. for sarcoidosis
Furosemide (once rehydrated)

Drug treatment of hypocalcaemia:
Mild:
o
Oral calcium supplements (e.g. sandocal)
Severe:
o
10mls 10% calcium gluconate IVI over 30 mins
o
Repeat as necessary
Must correct magnesium levels will never correct Ca

2+
otherwise
Drug treatment of phaeochromocytoma crisis:
Control BP with IV phentolamine (short-acting !-antagonist)
When BP controlled, give phenoxybenzamine (irreversible !-

antagonist)
Give "1-blocker
Arrange for surgery within next few weeks

Thionamides:
E.g. carbimazole, propylthiouracil
Indications:
o
Carbimazole:
! Hyperthyroidism
o
Propylthiouracil:
! Usually reserved for patients intolerant to carbimazole
o
All:
! Inhibition of thyroid peroxidase
! Immunosuppressive properties (controversial)
48
www.garrypettet.com
o
Carbimazole:
! Is a prodrug (converted to methimazole)
o
Propylthiouracil:
!
Inhibits peripheral conversion of T4 " T3
How to use:
o
Aim is to render the patient euthyroid and then give a # dose for
maintenance
o
It is often possible to stop treatment after 1 or 2 years (50%
relapse rate)
Adverse effects:
o
GI disturbances
o
Carbimazole:
! Pruritis
! Rash
o
Agranulocytosis:
! Carbimazole (0.1%)
! Propylthiouracil (0.4%)
! Patients should be told to seek medical attention if they
develop symptoms of infection (e.g. sore throat):
If neutropenia confirmed " stop treatment
Cautions:
o
Pregnancy:
! Low doses should be used as carbimazole crosses the
placenta and can cause neonatal hypothyroidism / goitre
! PTU is less problematic in pregnancy
Radioiodine (
131
I):
Treatment of choice in pts >40 years (can be used in younger pts)
Indications:
o
Hyperthyroidism
o
Disseminated thyroid malignancy
o
The radioactive iodine is localised to the thyroid where it
destroys thyroid tissue via "-radiation
Treatment renders the pt euthyroid within 4-6 weeks, when thyroxine

replacement therapy can be undertaken (lifelong)
Adverse effects:
o
Causes hypothyroidism
o
May precipitate thyroid storm
Contraindications:
o
Children
o
Pregnancy (also, pregnancy must not be allowed to occur
within 3 months)
o
Mothers who are unable to leave their children in others care for
at least 10 days (to avoid exposure)
Thyroxine:
May be either T4 (Levothyroxine) or T3 (liothyronine)
T3 is faster acting than T4 but with a shorter half-life

49
www.garrypettet.com
Adverse effects (mainly in overdose):

o
Angina
o
Dysrhythmias (including AF)
o
MI
o
Tachycardia
o
Hyperthyroid symptoms (even when TSH in normal range)
Cautions:
o
Thyroxine should be introduced slowly in those with IHD
Interactions:
o
Warfarin:
! Thyroxine $ the effect of warfarin
Corticosteroids:
E.g. hydrocortisone, prednisolone, dexamethasone
Indications (many):
o
Anti-inflammatory:
! Topical:
Asthma
Skin disorders (e.g. eczema)

! Systemic:
Anaphylaxis
IBD
Rheumatoid arthritis
o
Immunosuppression:
! Connective tissue diseases (e.g. temporal arteritis)
! Leukaemia
! Sarcoidosis
! Transplant rejection
o
Replacement:
! Addisons disease
! Congenital adrenal hyperplasia
o
Bind to cytoplasmic receptor that diffuses into nucleus and binds
to steroid-response elements on DNA:
! Either increases or decreases transcription with numerous
effects
o
Inhibits phospholipase A2 (thus # production of arachidonic acid)
o
# B and T cell responses to antigens
Adverse effects (many):

o
CNS:
! Depression
! Psychosis
o
Endocrine:
! Adrenal suppression
! Hirsuitism
50
www.garrypettet.com
! Impotence
! Oligo-/amenorrhoea
! Weight gain
o
Eyes:
! Cataracts
! Glaucoma
o
Gastrointestinal:
! Candidiasis
! Peptic ulceration
! Pancreatitis
o
Immune system:
! $ susceptibility to and $ severity of infections
o
Metabolic:
! Hyperglycaemia
! Hypertension
o
Musculoskeletal:
! Growth suppression
! Myopathy
! Osteoporosis
o
Skin:
! Abdominal striae
! Buffalo hump
! Easy bruising
! Poor wound healing
! Thinning
Differences between the different steroids:

o
Hydrocortisone:
! Replacement therapy
! IV in shock / status asthmaticus
o
Prednisolone:
! Orally for anti-inflammatory effects
o
Dexamethasone:
! No salt-retaining properties
! Very potent
! Useful when high doses required (e.g. cerebral oedema)
o
Budesonide / beclomethasone:
! Pass membranes very poorly
! Much more active topically (e.g. aerosol, gut)
Interactions:
o
Enhances activity of warfarin
o
Live vaccines (impairs response)
o
Reduces activity of anticonvulsants (carbamazepine,
phenytoin)
Withdrawal of glucocorticoids withdrawal gradually in the following:

o
Course duration >3 weeks
o
Received >40mg prednisolone (or equivalent) daily
o
Been given repeated doses in the evening
o
Taken a short course within 1 year of taking long-term therapy
Notes:
51
www.garrypettet.com
o
Physiological dose of steroid is ~7.5mg prednisolone
o
Patients should be given a steroid card
Metyrapone:
Indications:
o
Cushings syndrome:
! Especially that not amenable to surgery (e.g. lung ca)
o
Resistant oedema due to aldosterone secretion in:
! Cirrhosis
! Congestive cardiac failure
o
Competitive inhibitor of 11"-hydroxylase
o
Inhibits endogenous production of cortisol (and to a lesser
extent aldosterone) by the adrenals
Contraindications:
o
Adrenocortical insufficiency
o
Pregnancy / breast feeding
Adverse effects:
o
Hypoadrenalism
Desmopressin (DDAVP):
Synthetic vasopressin (ADH) analogue
Indications:
o
Cranial diabetes insipidus (diagnosis and treatment)
o
Haemophilia
o
Persistent enuresis
o
Selectively agonises V2 receptors on renal tubular cells:
! Leads to increased reabsorption of water
! Thus devoid of vasoconstrictor activity (V1)
o
Also increases the plasma concentration of factor VIII
Adverse effects:
o
Dilutional hyponatraemia
o
Fluid retention
Contraindications:
o
Heart failure
Somatostatin analogues:
E.g. octreotide (given tds), lanreotide (given once monthly)
Indications:
o
Acromegaly
o
Carcinoid syndrome
o
Variceal bleeding (octreotide, unlicensed indication)
Mechanism of action in acromegaly:

o
Inhibits GH release from the pituitary gland
o
90% of patients respond and 60% have GH level normalisation
52
www.garrypettet.com
Adverse effects:
o
Gallstones
o
GI disturbances
Interactions:
o
Anti-diabetic agents (oral and insulin):
! Octreotide may # requirements for these drugs
Dopamine agonists:
E.g. bromocriptine (short-acting), cabergoline (long-acting)
Indications:
o
Acromegaly
o
Hyperprolactinaemia
o
Idiopathic Parkinsons disease
o
Suppression of lactation
o
Cyclical benign breast disease
o
Directly stimulate dopamine receptors in the CNS (anti-
Parkinsons effect)
o
Inhibits release of prolactin from anterior pituitary
o
Inhibits the release of GH in acromegalics:
! Increases GH levels in non-acromegalics
Lead to a maximum # of GH of 7-60%:

o
Only 10-15% of patients achieve GH normalisation
Adverse effects:
o
Nausea / vomiting
o
o
Drowsiness / confusion
o
Dyskinesia
o
Fibrotic reactions (rare):
! Pericardial / pulmonary and retroperitoneal fibrosis
Domperidone (D2 antagonist):

o
Can be used to relieve the peripheral adverse effects of
bromocriptine (does not cross the BBB so has no effect on CNS
effects)
Interactions:
o
Erythromycin and sympathomimetics (e.g. dobutamine):
! Increase the plasma concentration of bromocriptine
Growth hormone:
E.g. somatrophin
Indications:
o
Adults:
! GH deficiency
o
Children:
! GH deficiency
! Chronic renal impairment
! Turners syndrome
Testosterone:
53
www.garrypettet.com
E.g. restandol (oral), sustanon (IM), andropatch (transdermal patch)
Indications:
o
Male androgen deficiency
Adverse effects:
o
Androgenic effects:
! Fusion of epiphyses in prepubertal boys (stunted
growth)
! Hirsuitism
! Male pattern baldness
! Acne
o
Prostate abnormalities (enlargement malignancy)
o
Cholestatic jaundice
Contraindications:
o
Cancers:
! Male breast
! Primary liver tumour
! Prostate
Interactions:
o
Warfarin:
! Potentiates actions of warfarin
Combined oral contraceptive (COC) pill:
E.g. cilest, microgynon
Are preparations containing both an oestrogen and a progestogen
Indications:
o
Contraception
o
Menstrual cycle control / menorrhagia
o
Mild endometriosis
o
Premenstrual symptoms
o
Exerts a negative feedback on the pituitary and inhibits
gonadotrophin release, and thus inhibits ovulation
Adverse effects:
o
Major:
! $ risk of venous thromboembolism (VTE)
! $ risk of hypertension
! $ risk of breast carcinoma (small)
o
Minor:
! Breast tenderness
! Headaches
! Nausea
! Weight gain
Contraindications:
o
Absolute:
! History of CVA / IHD / VTE
! Migraine (severe / focal)
! Blood clotting disorders
! Active breast / endometrial cancer
o
Relative:
54
www.garrypettet.com
! Age > 40 years
! Obesity
! Smokers
Interactions:
o
Drugs reducing the efficacy of the COC pill:
! Broad-spectrum antibiotics
! P450 inducers:
Carbamazepine
Phenytoin
Rifampicin
o
Warfarin:
! Oestrogens (including the COC pill) reduce the effect of
warfarin
The COC pill should be stopped several weeks prior to an elective

surgical procedure to # risk of VTE
Calcitonin:
E.g. calcitonin (porcine natural), salcatonin (synthetic salmon

calcitonin)
Indications:
o
Hypercalcaemia (rarely)
o
Malignant bone pain
o
Osteoporosis
o
Pagets disease of bone (especially pain relief)
o
Lowers serum calcium:
! Inhibits osteoclast activity
! Increases renal Ca
2+
excretion
Adverse effects:
o
Facial flushing
o
Nausea / vomiting
o
Tingling sensation in the hands
o
Unpleasant taste in the mouth
!1-antagonists:
Non-selective (!1 and !2):

o
Phentolamine (short-acting)
o
Phenoxybenzamine (irreversible, long-acting)
!1:
o
Prazosin
o
Doxazosin
o
Tamsulosin (Flomax)
Indications:
o
Non-selective !-blockers:
! Phaeochromocytoma
o
!1-blockers:
55
www.garrypettet.com
! Hypertension
! Benign Prostatic hypertrophy (doxazosin, tamsulosin)
o
Antagonism of post-synaptic !1-adrenoceptors leads to
vasodilatation
o
!1 blockade also leads to relaxation of the internal urethral
sphincter, resulting in $ urinary flow
Adverse effects:
o
First-dose hypotension
Interactions:
o
Other hypotensive agents - $ risk of hypotension
56
www.garrypettet.com
Lipids
Which patients require lipid-lowering therapy?
Primary prevention:
o
Guidelines are frequently changing
! Total [chol] >5mmol/L and CHD risk >30% over 10yrs or
! 10yr CHD risk >=15%
Secondary prevention:
o
History of CVS event (angina, MI, PVD, CVA)
o
[chol] >=5mmol/L
Choice of drug:
o
First choice therapy:
! Statin
o
Second choice therapy:
! Fibrates
! Anion exchange resins
Note about diet:

o
Diet lowers [cholesterol] only by ~10% (as we endogenously
synthesise cholesterol, not just eat it)
Drugs used to treat obesity:
Orlistat
Sibutramine
Statins:
E.g. simvastatin, atorvastatin, pravastatin
Usually taken at night
Reduce incidence of all cardiovascular events and total mortality
o
Are HMG-CoA reductase inhibitors block the rate-limiting step
in hepatic cholesterol synthesis
o
Due to the # concentration of cholesterol in the hepatocytes,
there is an $ in the number of hepatic LDL receptors
o
This leads to a # in plasma LDL
o
Those with homozygous familial hypercholesterolaemia do not
respond to statins (as they have no LDL receptors)
Adverse effects (all uncommon):

o
Myositis:
o
Patients complain of weakness / aching muscles
! If CK >5x upper limit of normal discontinue
! Can lead to rhabdomyolysis and renal failure
! If this occurs, cannot use a statin again
o
Altered LFTs
Contraindications:
o
Liver disease
o
Pregnancy
Interactions:
o
Drugs increasing the risk of myositis:
57
www.garrypettet.com
! Cyclosporin
! Fibrates
o
Warfarin:
! Statins potentiate the actions of warfarin
Patients should have their LFTs monitored regularly whilst on a statin

Fibrates:
E.g. bezafibrate, gemfibrozil
Actions:
o
Unclear mechanism possibly stimulate lipoprotein lipase
o
# TGs (~30%)
o
# LDL (~10%)
o
$ HDL (10%)
Are first line drugs in patients with hypertriglyceridaemia (who are at

risk of pancreatitis and retinal vein thrombosis)
Adverse effects:
o
GI disturbance
o
Myositis
o
Gallstones
Contraindications:
o
Hepatic / renal impairment
o
Pregnancy
Interactions:
o
Statins:
! $ risk of myositis
o
Warfarin:
! Potentiate the actions of warfarin
Anion exchange resins:
E.g. cholestyramine, cholestipol
o
Bind bile acids in the bowel
o
Forces the liver to synthesise more bile acids causes an
increase in the expression of LDL receptors and lowering of LDL
Adverse effects:
o
GI disturbance:
! Bloating
! Constipation
! Nausea / vomiting
o
May aggravate hypertriglyceridaemia
o
Impairs the absorption of many drugs
o
May impair the absorption of fat soluble vitamins:
! May require supplements of vitamins A, D and K
Omega-3-oils (fish oils):
Can be effective in hypertriglyceridaemia
Adverse effects:
58
www.garrypettet.com
o
Fish-like odour to the patient
Orlistat:
Indications:
o
Adjunct in obesity management:
! BMI >30 if no diabetes
! BMI >27 if diabetic
o
Pancreatic lipase inhibitor
o
Impairs absorption of dietary fat
Adverse effects:
o
GI disturbance:
! Probably why the drug works as patients reduce their fat
intake to reduce the side-effects
o
May impair the absorption of fat soluble vitamins:
! May require supplements of vitamins A, D and K
Contraindications:
o
Cholestasis
o
Pregnancy
Interactions:
o
Warfarin:
! Difficulty in controlling the INR
Sibutramine:
Indications:
o
As for orlistat
o
Centrally acting anorectic
o
Inhibits reuptake of noradrenaline and 5-HT
Adverse effects:
o
Hypertension
o
Many others
Contraindications:
o
Many, mainly cardiovascular
59
www.garrypettet.com
Clotting
Antiplatelet drugs:
Aspirin
Dypyridamole
Clopidogrel
GP IIb/IIIa receptor antagonists:

o
Abciximab
Anticoagulants:
Oral:
o
Warfarin
Parenteral:
o
Unfractionated heparin
o
Low molecular weight heparin (LMWH)
Thrombolytic agents:
Streptokinase
Tissue plasminogen activator (tPA)

Indications for antiplatelet drugs:
Acute coronary syndromes
Primary prevention of cardiovascular events:

o
If 10yr CVD risk >=20% (with a controlled blood pressure)
Secondary prevention of cardiovascular events:

o
CVA / TIA
o
IHD
o
PVD
Heart valve replacements
AF (in those who cannot be anti-coagulated)

Indications for oral anti-coagulants:
AF
Prophylaxis / treatment of VTE:

o
DVT
o
PE
Mechanical heart valve replacements
Dilated cardiomyopathy / left ventricular aneurysm
? TIAs
Indications for parenteral anti-coagulants:
Acute coronary syndromes
Acute arterial obstruction
Treatment of VTE:
o
DVT
o
PE
Indications for thrombolytic agents:
Acute myocardial infarction

60
www.garrypettet.com
Arterial thrombus
Life-threatening PE
Occluded lines / shunts

Aspirin:
Indications:
o
o
Pyrexia
o
Anti-platelet:
! Acute myocardial infarction
! History of:
Angina
Intermittent claudication
Myocardial infarction
Stroke
TIA
! AF (in patients where warfarin is contraindicated)
! Kawasaki syndrome (only childhood indication)
o
Irreversibly inactivates platelet COX
o
Platelets cannot synthesise new COX:
! Takes 4 7 days for new platelets to be synthesised
following a single dose (300mg)
!
Reduction in production of the platelet aggregating
compound thromboxane A2
Adverse effects:
o
Bleeding
o
Bronchospasm
o
GI irritation / bleeding
o
Dangerous in overdose
Overdose:
o
Signs / symptoms:
! Coma
! Dehydration
! Hyperventilation
! Tinnitus
! Seizures
! Sweating
! Vertigo
! Vomiting
o
Investigations:
! Levels (salicylate and paracetamol, may have taken
both):
Levels >700mg/L are potentially fatal

! ABG, FBC, Glucose, LFTs, INR, U&Es
o
Treatment:
! Remove drug:
Gastric lavage if od <1 hour ago

61
www.garrypettet.com
!
Correct acidosis with 1.26% HCO3
-
! >500mg/L:
Consider alkalinization of the urine

! Consider dialysis when:
Levels >700mg/L
Cardiac / renal failure
Seizures
Cautions:
o
Asthma
o
Uncontrolled hypertension
Contraindications:
o
Children <16 years (unless Kawasakis syndrome):
! Risk of Reyes syndrome
o
Active peptic ulceration
o
Bleeding disorders (e.g. haemophilia)
Interactions:
o
Warfarin:
! Increased risk of bleeding
o
Methotrexate:
! Aspirin $ risk of toxic effects of methotrexate
Dipyridamole:
Indications:
o
Secondary prevention of CVA / TIA:
! Some synergistic benefit with aspirin
! Used in those patients who have had a CVA on aspirin
o
Prevention of thromboembolism from prosthetic heart valves:
! Adjunct to oral anti-coagulation
o
Phosphodiesterase inhibitor
o
Leads to an $ in cAMP and potentiation of prostacyclin
No increased risk of bleeding (cf aspirin)
Adverse effects:
o
Headache
Contraindications:
o
Myasthenia gravis (risk of exacerbation)
Interactions:
o
Adenosine:
! Dipyridamole prolong / enhances the effects of adenosine
Clopidogrel:
Indications:
o
Secondary prevention of CVD:
! Within 35 days of MI
! Within 6 months of CVA
o
Acute coronary syndrome (without ST elevation):
! Given with aspirin
! Not for >12 months
o
Coronary artery stents
62
www.garrypettet.com
Mechanisms of action:
o
Irreversibly blocks the action of ADP on platelets leading to a
reduction of platelet aggregation
Adverse effects:
o
Bleeding
o
Bone marrow suppression (rare)
Cautions:
o
First few days following MI / CVA
Interactions:
o
Warfarin:
! Increased risk of bleeding
Abciximab:
Indications:
o
Patients awaiting PTCA:
! Short-term prevention of MI in those with ACS
o
Patients undergoing PTCA:
! Adjunct to aspirin and heparin
o
Monoclonal antibody to GP IIb/IIIa
o
Inhibit platelet aggregation
Adverse effects:
o
Bleeding
o
Thrombocytopenia
Warfarin:
Indications:
o
Prevention / treatment of VTE:
! DVT
! PE
o
Prevention of thromboembolism:
! AF
! Prosthetic heart valves
o
Vitamin K antagonist
o
Inhibits the vitamin K-dependent synthesis of clotting factors II,
VII, IX and X
o
Also inhibits formation of protein C and S:
! Has an initial procoagulant effect
o
Takes at least 23 days to work (due to the half-life of pre-
existing clotting factors in the circulation)
o
Prolongs the prothrombin time (PT)
Pharmacokinetics:
o
Long half-life (40 hours)
o
Takes ~5 days after stopping treatment for INR to normalise
o
Highly protein-bound (albumin)
Dosage:
o
Loading:
! Warfarin therapy begins with a loading dose, usually:
63
www.garrypettet.com
Day 1 - 10mg
Day 2 10mg # measure INR and adjust dose
Day 3 5mg (if still not target INR)

o
Daily dose:
! Daily maintenance is usually 3-9mg daily (taken at same
time each day)
INR (International Normalised Ratio):

o
Prothrombin results can vary depending on the thromboplastin
reagent used
o
The INR is a conversion unit that takes into account the different
sensitivities of thromboplastins
o
Target INRs:
! 2 2.5:
Prophylaxis of DVT
! 2.5:
AF
Treatment of DVT / PE
Rheumatic mitral valve disease

! 3.5:
Recurrent DVT / PE
Mechanical prosthetic heart valves

o
Monitoring the INR:
! The INR should be determined daily (or alternate days) in
the early days of therapy, then at longer intervals
(depending on response) then up to every 12 weeks
Adverse effects:
o
Bleeding / bruising
o
Skin necrosis
o
Alopecia
o
Liver damage
o
Pancreatitis
Management of warfarin-induced haemorrhage:

o
Major bleeding:
! Stop warfarin
! Give vitamin K (phytomenadione) by slow IV injection
! FFP
o
INR >8 (no bleeding or minor bleeding):
! Stop warfarin and restart when INR <5
! Vitamin K (either IV or oral)
o
INR 6-8: (no bleeding or minor bleeding):
! Stop warfarin and restart when INR <5
o
INR <6 but >0.5 units above target value:
! Reduce or stop warfarin and restart when INR <5
Contraindications:
o
Pregnancy:
! Teratogenic (1
st
trimester)
! Foetal haemorrhage (3
rd
trimester)
o
Peptic ulcer
o
Severe hypertension
64
www.garrypettet.com
Interactions (many!):
o
Drugs that $ the efficacy of warfarin:
! Alcohol
! Cimetidine
! Omeprazole
! Simvastatin
o
Drugs that # the efficacy of warfarin:
! Carbamazepine
! COC pill
! Rifampicin
o
Drugs increasing risk of haemorrhage:
! Aspirin
Heparin:
Low molecular weight heparins (LMWHs) include:

o
Enoxaparin
o
Tinzaparin
Indications:
o
Treatment of VTE
o
Unstable angina
o
Acute peripheral arterial occlusion
o
Prophylaxis in surgery
o
Extracorporeal circuits (e.g. cardiac bypass surgery)
o
Heparin potentiates the actions of antithrombin III
o
Antithrombin III inactivates factor IIa (thrombin)
o
Prolongs the APTT
Structure:
o
Both types of heparin are extracted from bovine lung or hog
intestine
o
Unfractionated heparin:
! Mixture of sulphated glycosaminoglycans with a range of
molecular weights up to 40,000
o
LMWH:
! Fragments of heparin with weights 4000 15,000
Unfractionated or LMWH?
o
Unfractionated heparins are best used when there is a high risk
of bleeding as their effect can be terminated rapidly by stopping
the infusion
o
LMWHs do not require monitoring of the APTT and only need to
be given once-daily
o
LMWHs have a more predictable subcutaneous absorption
Adverse effects:
o
Thrombocytopenia:
! Immune-mediated
! Develops ~6 days after starting treatment
o
Hyperkalaemia:
! Heparin inhibits aldosterone activity
o
Haemorrhage
65
www.garrypettet.com
o
Osteoporosis
o
Skin necrosis
o
Hypersensitivity
o
Alopecia
Contraindications:
o
Bleeding disorders (e.g. haemophilia)
o
Thrombocytopenia
o
Peptic ulcer
o
Recent cerebral haemorrhage
o
Severe hypertension
o
Severe liver disease (especially variceal disease)
o
Hypersensitivity
The effects of heparin can be reversed by IV protamine sulphate:

o
A strongly basic protein that forms an inactive complex with
heparin
Streptokinase (SK):
Indications:
o
Acute MI
o
Thromboembolic events:
! PE
! Thrombosed arteriovenous shunts
o
Binds circulating plasminogen and converts it to plasmin
o
Plasmin then lyses fibrin within the thrombus and dissolves it
Adverse effects:
o
Allergic reactions:
! Rash (common)
! Anaphylaxis
o
Hypotension
o
Guillain-Barre syndrome
Contraindications:
o
Bleeding
o
Prolonged / traumatic CPR
o
Trauma / surgery (within 2 weeks)
o
Recent haemorrhagic stroke
o
Severe hypertension (>200/120mmHg)
o
Pregnancy
o
Suspected aortic dissection
Interactions:
o
Warfarin (increased risk of haemorrhage)
Patients develop antibodies to streptokinase:

o
If a patient requires thrombolysis and has received SK in the
past they should be given recombinant tPA
Tissue plasminogen activator (tPA):
E.g. alteplase (requires infusion), tenecteplase (bolus)

66
www.garrypettet.com
Indications:
o
As for SK but in those patients who cannot receive SK
In contrast to SK, co-administration of tPA and heparin produces

added benefit (but increases the risk of stroke)
67
www.garrypettet.com
Mood disorders
Which antidepressant?
No hard and fast rules, although TCAs and SSRIs are generally first
choice
All antidepressants take 2-6 weeks to work
Antidepressants should be continued for 4-6 months after resolution

of symptoms
When to use a TCA:

o
Severe depression
o
When insomnia is prominent symptom
When to use a SSRI:

o
Suicidal patient (safer in overdose)
o
Intolerance to TCAs:
! Prostatism
! Dementia (TCAs can cause confusion)
! Cardiac illness
When to use a MAOI:

o
Atypical depression
o
Depression refractory to first-line drugs
When to use venlafaxine:

o
Severe depression with hypersomnia
Drugs used as mood stabilisers:
Lithium carbonate
Anticonvulsants:
o
Carbamazepine
o
Valproate
Tri-Cyclic Antidepressants (TCAs):
More sedating:
o
Amitriptylline
o
Clomipramine
o
Dothiepin
Less sedating:
o
Imipramine
Indications:
o
Moderate to severe depression
o
Neuropathic pain (amitriptylline unlicensed indication)
o
Nocturnal enuresis (children)
o
Inhibit noradrenaline (NA) and serotonin (5-HT) uptake in
central nerve terminals
o
Most TCAs act on several other neurotransmitter receptors and
this is the reason for their large side-effect profile:
! Anti-muscarinic # most TCAs
! Histamine receptor blockade
Adverse effects:
68
www.garrypettet.com
o
Sedation (some more than others)
o
Confusion
o
Seizures (# seizure threshold)
o
Blurred vision (loss of accommodation)
o
Dry mouth (can lead to # dental hygiene)
o
Heart block
o
o
Constipation
o
Impotence
Contraindications:
o
Dysrhythmias (especially heart block)
o
Epilepsy
o
Severe coronary heart disease
o
Suicidal patient (danger in overdose)
TCA overdose:
o
Clinical features:
! Tachycardia
! Mydriasis
! Convulsions
! Arrhythmias
! Hypotension
o
Management:
! Treat convulsions with diazepam
! Treat SVT / VT with sodium bicarbonate (even in absence
of acidosis)
Interactions:
o
MAOIs:
! Danger of potentially fatal hyperthermia syndrome
o
Anti-arrhythmics:
! Increased risk of ventricular dysrhythmias
o
Anticonvulsants:
! TCAs lower the seizure threshold and thus antagonise the
effect of anticonvulsants
o
Antipsychotics:
! Increased risk of ventricular dysrhythmias
Selective Serotonin Reuptake Inhibitors (SSRIs):
E.g. fluoxetine (prozac), paroxetine (seroxat), citalopram
Indications:
o
Depression:
! High suicide risk
! Those intolerant to TCAs (e.g. Prostatism)
o
Obsessive compulsive disorder (OCD)
o
Eating disorders
o
Selectively block the uptake of 5-HT by central nerve terminal,
thus increasing its concentration
69
www.garrypettet.com
o
Fewer side-effects than the TCAs:
! Less anti-muscarinic effects
! Safer in overdose
Adverse effects:
o
Nausea / anorexia
o
Insomnia
o
Sexual dysfunction:
! Loss of libido
! Failure of orgasm
Contraindications:
o
Children <18 years of age:
! $ risk of self-harm / suicidal behaviour
o
Mania
Interactions:
o
MAOIs:
! Do not start an SSRI until at least 2 weeks after stopping
a MAOI
! Risk of hyperthermia syndrome:
Hyperthermia
Tremor
Collapse
o
Anticonvulsants (e.g. carbamazepine, phenytoin):
! SSRIs $ plasma levels of these drugs
o
Haloperidol:
! SSRIs $ plasma levels of haloperidol
Monoamine Oxidase Inhibitors (MAOIs):
Non-selective (inhibit MAO-A and MAO-B):

o
Phenelzine
MAO-AIs (reversible):
o
Moclobemide
MAO-BIs:
o
Selegiline
Indications:
o
Atypical depression (especially in young patients):
! Weight gain
! Hypersomnia
o
Second-line use in depression (after TCA / SSRI)
o
MAO is found throughout body tissues (including the gut)
o
There are 2 isoforms of MAO - A and B
o
MAO-A has a preference for 5-HT (this is seen to be beneficial in
depression)
o
MAO-B has a preference for dopamine (hence an anti-Parkinson
effect with selegiline)
o
MAO regulates intra-neuronal concentration of its substrates (it
is not involved in the inactivation of released transmitter)
Adverse effects:
o
Hypotension
70
www.garrypettet.com
o
Weight gain
o
Sedation
o
Anti-muscarinic effects
Contraindications:
o
Hepatic impairment
o
Phaeochromocytoma
o
Non-compliant patients (unable to monitor diet)
Interactions:
o
Main hazard is with foods the cheese reaction:
! Caused by foods containing high levels of tyramine:
Hard cheeses
Yeast extracts (e.g. marmite)
Red wine / beer

! MAO in the gut wall usually metabolises tyramine, thus
preventing it reaching the systemic circulation
! In the presence of a MAOI, tyramine reaches the
circulation and acts as a sympathomimetic (triggers the
release of NA) and can lead to severe hypertension
! Treat with:
!1-antagonist (e.g. phentolamine) or
Nifedipine
o
Antidepressants (TCAs, SSRIs):
! Avoid concomitant use (allow washout period in between)
! Potentiation of all side-effects and risk of hyperthermia
syndrome
o
Pethidine:
! Hyperthermia
! CNS depression or excitement
o
Carbamazepine:
! MAOIs can # the plasma levels of carbamazepine
The selective MAO-AIs have a much smaller risk of the cheese

reaction
Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs):
E.g. venlafaxine
Indications:
o
Severe / refractory depression
o
Anxiety disorders
Adverse effects:
o
Nausea
o
Insomnia
o
Hypertension (at high doses)
o
Withdrawal problems common
Interactions:
o
MAOIs:
! Risk of hyperthermia syndrome
Fewer side-effects than the TCAs but no more efficacious

71
www.garrypettet.com
Noradrenaline and Specific Serotenergic Antidepressants (NaSSAs):
E.g. mirtazapine
Indications:
o
Depression (especially with insomnia)
Adverse effects:
o
Drowsiness (even at low doses)
o
$ appetite / weight gain
o
Blood dyscrasias (rarely)
Interactions:
o
Other sedatives (including alcohol)
o
MAOIs
Safe in overdose
Minimal effects on sexual function

Lithium carbonate:
Indications:
o
Acute mania
o
Prophylaxis of bipolar disorder
o
Recurrent depression
o
Aggressive / self-mutilating behaviour
Toxicity:
o
Lithium requires therapeutic drug monitoring:
! Normal range is 0.4 1.0mmol/L
Adverse effects:
o
0.4 1.0mmol/L:
! Nausea
! Diarrhoea
! Polyuria / polydipsia (nephrogenic DI)
! Weight gain
o
1.0 2.0mmol/L:
! Blurred vision
! Anorexia / vomiting
! Ataxia / dysarthria / tremor
! Drowsiness
o
>2.0mmol/L:
! Convulsions
! Hyperreflexia
! Oliguria
! Circulatory failure - death
Long-term effects:
o
Can cause renal tubular damage and hypothyroidism
Contraindications:
o
Pregnancy (although consider relative risks of drug cessation)
o
Renal impairment
o
Thyroid disease
o
Sick sinus syndrome
o
Poor compliance
Interactions:
o
Lithium levels increased by:
72
www.garrypettet.com
! Diuretics (thiazides > loop)
! ACEIs
! NSAIDs
! Alcohol
o
Lithium levels decreased by:
! Xanthines (e.g. theophylline)
! Antacids
! Acetazolamide
73
www.garrypettet.com
Anti-arrhythmic drugs
Vaughan-Williams classification:
Class I:
o
Are all Na
+
channel blockers (local anaesthetics)
o
Ib only works in the ventricles
o
Ia (A, SAN, AVN, V):
! E.g. quinidine, disopyramide, procainamide
! $ AP duration
! Hardly ever used in the UK (but used in the USA)
o
Ib (V only):
! E.g. lidocaine (lignocaine)
! AP duration unaffected or slightly #
o
Ic (A, SAN, AVN, V):
! E.g. flecainide
! AP duration slightly $
! Primarily act by slowing conduction
Class II (A, SAN, AVN, V):

o
"-blockers (e.g. propranolol)
o
# automaticity
o
# AP duration acutely (may prolong it with prolonged use)
o
# refractory period
Class III (A, SAN, AVN, V):

o
E.g. amiodarone, sotalol (a "-blocker)
o
All have effects on various K
+
channels
o
$ AP duration
o
$ refractory period
Class IV (SAN, AVN):

o
Ca
2+
channel blockers (e.g. verapamil)
o
Dihydropyridines (e.g. amlodipine) have no role in arrhythmias
Unclassified:
o
Digoxin (AVN)
o
Adenosine (AVN)
Supraventricular arrhythmias:
Supraventricular tachycardias (SVTs) are often due to re-entry:

o
SNRT (sinus node re-entry tachycardia)
o
AVNRT (atrioventricular node re-entry tachycardia)
o
AVRT (atrioventricular re-entry tachycardia):
! Caused by an accessory pathway
Atrial arrhythmias:
o
Atrial tachycardia
o
Atrial flutter
o
Atrial fibrillation (AF):
! Paroxysmal
! Persistent
74
www.garrypettet.com
! Permanent
Treatment of SVTs:
Vagal manoeuvres
Adenosine:
o
6mg " 12mg " 12mg
If adenosine fails:
o
Cardiovascular instability:
! Synchronised cardioversion
o
No cardiovascular instability:
! Verapamil or
! Digoxin or
! Amiodarone
Prophylaxis:
o
"-blockers
o
Flecainide (AVRT)
o
Verapamil (AVNRT)
Wolff-Parkinson-White (WPW) syndrome:

o
If pt with WPW has AF and fast ventricular rate:
! Adenosine, digoxin and verapamil are absolutely
contraindicated
! Use Flecainide
Treatment of atrial tachycardia:
Treat underlying coronary / structural heart disease if present
Exclude digoxin toxicity
"-blockers
Verapamil
Often refractory to drug treatment treat with radiofrequency

ablation (RFA)
Treatment of atrial flutter:
Drugs are generally ineffective, but can try:

o
Amiodarone:
! Drug most likely to work
o
Digoxin:
! Rate control only
o
"-blockers:
! Rate control
! Chance of return to sinus rhythm (SR)
o
Verapamil:
! Rate control
! Chance of return to SR
DC cardioversion anticoagulation can work
RFA is the treatment of choice

Treatment of atrial fibrillation (AF):
Acute:
o
Treat underlying cause (e.g. pneumonia)
o
DC cardioversion (first-line choice):
75
www.garrypettet.com
! Anticoagulation is not essential if AF is of recent onset
(<48 hours) with a structurally normal heart (but most
people do)
! If required, give warfarin for at least 3 weeks before and
at least 4 weeks after
o
Control ventricular rate:
! Digoxin
! If ventricular rate still too fast:
"-blocker (can return patient to sinus rhythm)

o
Chemical cardioversion:
! Amiodarone or
! Flecainide (if haemodynamically stable) or
! "-blocker
Chronic:
o
Control ventricular rate:
! Digoxin
! If rate still too fast consider:
(Cautiously) $ digoxin dose
"-blocker
Amiodarone
o
Anticoagulation:
! > 65 years:
Warfarin (INR 2.5 3.5)

! <65 years with no risk factors or > 65 years and unable
to be warfarinised:
Aspirin
Treatment of ventricular tachycardia (VT):
Acute:
o
Haemodynamically stable:
! Amiodarone or
! Lidocaine
o
Not haemodynamically stable:
! Synchronised DC cardioversion
! Amiodarone
Recurrent / paroxysmal:
o
Drugs:
! Amiodarone
! "-blocker (works synergistically with amiodarone)
! Sotalol
o
Implantable defibrillator:
! # mortality
Drug treatment of Torsade de Pointes:
Often associated with prolongation of the QT interval
Causes of QT prolongation:
o
Electrolyte disturbances:
! Hypokalaemia
76
www.garrypettet.com
! Hypocalcaemia
o
Congenital long QT syndromes
o
Drugs:
! Class Ic and III anti-arrhythmics
! TCAs
o
Ischaemia
Treatment:
o
IV MgSO4
Treatment of bradyarrhythmias:
Haemodynamically compromised:
o
Drugs:
! Atropine
! Isoprenaline / adrenaline
o
Pacing:
! External
! Temporary transvenous
Stable:
o
Withdraw any negatively chronotropic drugs (e.g. "-blockers)
o
Exclude secondary causes:
! ACS
! Hypothyroidism
o
Assess need for permanent pacemaker
Adenosine:
Indications:
o
Paroxysmal SVT
o
To aid diagnosis of broad complex SVTs
o
Binds to adenosine (A1) receptors in the cardiac conduction
system:
! Opens ACh-sensitive K+ channels
o
Slows conduction in the heart by prolonging the refractory
period in the AVN / bundle of His
Adverse effects:
o
All are short-lived (half-life of 8 10secs)
o
Bronchospasm
o
Chest pain
o
Flushing
o
Severe bradycardia (rare)
Contraindications:
o
Asthma
o
2
nd
or 3
rd
degree heart block (unless pacemaker in-situ)
Interactions:
o
Dipyridamole:
! Prolongs / enhances action of adenosine
o
Theophylline:
! Inhibits adenosine
77
www.garrypettet.com
Amiodarone:
Indications:
o
Paroxysmal:
! SVT
! Nodal tachycardia
! VT
o
Atrial flutter
o
AF
o
VF
Amiodarone is generally used when other drugs have been

ineffective or are contraindicated
o
Not fully understood
o
Blocks several channels:
! !-adrenoceptors, "-adrenoceptors, Na
+
and Ca
2+
o
Generally slows conduction through the heart
Pharmacokinetics:
o
Very long half-life:
! 10 100 days (average 36 days)
o
Requires a loading dose in life-threatening arrhythmias:
! Central vein (causes phlebitis in peripheral veins)
o
This means that drug interactions can occur long after
amiodarone has been stopped
Adverse effects:
o
Common:
! Corneal microdeposits (reversible):
Can cause driver headlight dazzling at night

! Photosensitive rash
o
Less common:
! Thyroid dysfunction (hyper- or hypo-)
! Pulmonary fibrosis
! Grey skin colour
! Peripheral neuropathy
! Ataxia
Special notes:
o
Thyroid function must be checked before treatment and every 6
months:
! If hyperthyroidism develops, this can be very refractory
and may require cessation of amiodarone
o
Shortness of breath suggests development of pulmonary fibrosis
Contraindications:
o
Thyroid disease
o
Pregnancy
o
Iodine allergy (as amiodarone contains iodine)
Interactions:
o
"-blockers / non-dihydropyridines (e.g. diltiazem, verapamil):
! $ risk bradycardia, AV block and myocardial depression
78
www.garrypettet.com
o
Digoxin:
! Amiodarone $ plasma levels of digoxin
o
Class Ia drugs:
! $ QT interval
o
Phenytoin:
! Amiodarone $ plasma levels of phenytoin
o
Warfarin:
! Amiodarone $ plasma levels of warfarin
Lidocaine (lignocaine):
Indications:
o
Ventricular arrhythmias (especially after MI):
! Stops VT and # risk of VF
! Does not # mortality when used prophylactically
o
Local anaesthesia
o
Class Ib anti-arrhythmic agent
o
Not active orally (massive 1
st
-pass metabolism)
o
Blocks fast Na+ channels:
! Slows conduction in the heart (only ventricles)
! Inhibits AP propagation in nerve axons
Adverse effects:
o
Uncommon:
! Convulsions
! Drowsiness
! Bradycardia
! Cardiac arrest
Contraindications:
o
AV node block (all degrees)
o
Severe heart failure
o
Hypovolaemia
Interactions:
o
Cimetidine:
! $ plasma levels of lidocaine
Flecainide:
Indications:
o
AVRT
o
WPW syndrome associated arrhythmias
o
Paroxysmal AF (chemical cardioversion)
o
Class Ic anti-arrhythmic agent
o
Na
+
channel blocker
Contraindications:
79
www.garrypettet.com
o
Previous MI
o
Haemodynamically significant valvular disease
80
www.garrypettet.com
Hypertension
British hypertension society (BHS) classification of BP levels:
Optimal:
o
<120 / <80 mmHg
Normal:
o
<130 / <85 mmHg
High normal:
o
130-139 / 85-89 mmHg
Hypertension:
o
Grade 1 (mild):
! 140-159 / 90-99 mmHg
o
Grade 2 (moderate):
! >160 179 / 100-109 mmHg
o
Grade 3 (severe):
! >=180 / >=110 mmHg
o
Isolated systolic:
! Systolic BP is more important than diastolic
! Grade 1:
140-159 / <90 mmHg

! Grade 2:
>=160 / <90 mmHg

Complications of hypertension:
Cerebral:
o
Encephalopathy
o
Haemorrhage
o
Thromboembolism
o
TIA
Other:
o
MI (hypertension accounts for 25% of MIs)
o
Heart failure
o
Dissecting aneurysm
o
Renovascular disease
o
Peripheral vascular disease
When to treat patients with anti-hypertensive agents:
Definitely treat:
o
>=160 / >=100 mmHg (i.e. grade II hypertension)
Treat if
o
>=140 / >=90 mmHg and (i.e. grade I hypertension)
o
Target organ damage or
o
CVS complications or
o
Diabetes or
o
CV event risk >=2%/year (>=20% at 10 years)
Target blood pressure for patients on anti-hypertensive medication:
81
www.garrypettet.com
There is evidence for these systolic values but the diastolic is arbitrary
Patients with diabetes, renal impairment or CVS disease:

o
<=130 / <=80 mmHg
Other patients:
o
<=140 / <=85 mmHg
The BHS ABCD approach to the treatment of hypertension:
Key:
o
ACE inhibitor
o
Beta blocker
o
Calcium channel blocker
o
Diuretic (thiazide)
Step 1:
o
Young (<55 yrs) and non-black:
! A (or B*)
o
Older (>55 yrs) or black:
! C or D
Step 2:
o
A (or B*) + C or D
Step 3:
o
A (or B*) + C + D
Step 4 (resistant hypertension):

o
Add either:
! !-blocker
! Spironolactone
*"-blockers will probably be removed from this algorithm as they may

induce new onset diabetes mellitus
82
www.garrypettet.com
Antibiotic therapy
Below are empirical treatments only the correct antibiotic will depend upon
sensitivities determined by bacteriological culture
Treating pneumonia:
Community acquired:
o
Mild (streptococcus, haemophilus, mycoplasma):
! Amoxicillin po
! Erythromycin po (if penicillin sensitive or atypicals)
o
Severe (same bugs as for mild):
! Co-amoxiclav IV or
! Cefuroxime IV and
! Erythromycin IV
o
Atypical:
! Legionella:
Clarithromycin rifampicin
! Chlamydia:
Tetracycline
! Pneumocystis carinii:
Co-trimoxazole
Hospital acquired (Gram (ve), pseudomonas, anaerobes):

o
Aminoglycoside IV and
o
3
rd
generation cephalosporin IV
o
Anti-pseudomonal penicillin IV
Aspiration:
o
Cefuroxime IV and
o
Metronidazole IV
Treating meningitis:
Immediate treatment:
o
Outside hospital:
! Benzylpenicillin 1.2g IV/IM
o
Inside hospital:
! Cefotaxime 2g IV
Subsequent treatment:
o
Depends on sensitivities
o
Generally cefotaxime
o
Benzylpenicillin and rifampicin for meningococcal meningitis
Contacts eradicate carriage:

o
Rifampicin (2 days)
o
Ciprofloxacin (single dose)
Treating tuberculosis:
Initial phase (8 weeks on 34 drugs):

83
www.garrypettet.com
o
Rifampicin
o
Isoniazid
o
Pyrazinamide
o
Ethambutol (if isoniazid resistance is possible)
Continuation phase (410 months on 23 drugs, depends on site):

o
Rifampicin
o
Isoniazid
o
Ethambutol
Give pyridoxine throughout treatment (prevents isoniazid neuropathy)

Treating septicaemia source unknown:
Take blood cultures first!
Anti-pseudomonal penicillin (e.g. ticarcillin) and
Cefuroxime IV or
Gentamicin IV
Treating Neutropenic sepsis:
Take blood cultures first!
First-line:
o
Piperacillin + Gentamicin
Second-line:
o
Ceftazidime + vancomycin
Third-line:
o
Add amphotericin B
Treating a UTI:
Depends on sensitivities
Cystitis:
o
Mild:
! Trimethoprim
o
More severe:
! Co-amoxiclav
! Ciprofloxacin
Acute pyelonephritis:
o
Cefuroxime
Treating MRSA infection:
Vancomycin or
Teicoplanin
Treating clostridium difficile:
Metronidazole po or
Vancomycin po
Treating cellulitis:
Depends on the organism, but a good start would be:

o
Benzylpenicillin and
84
www.garrypettet.com
o
Flucloxacillin
Prophylactic antibiotics and surgery:
Single bolus as good as prolonged therapy:

o
Metronidazole IV and
o
Cefuroxime IV
Helicobacter pylori eradication therapy:
One PPI and two antibiotics for two weeks
Usual combination (but there are many):

o
Omeprazole
o
Clarithromycin
o
Amoxicillin (or metronidazole)
Resistance to metronidazole is common

85
www.garrypettet.com
Antibiotics
Antibiotics that inhibit cell wall synthesis:
"-lactams:
o
Penicillins
o
Cephalosporins
Glycopeptides:
o
Vancomycin
o
Teicoplanin
Carbapenems:
o
Imipenem
Monobactams:
o
Aztreonam
Antibiotics that inhibit protein synthesis:
30S ribosome:
o
Aminoglycosides:
! Gentamicin
! Amikacin
o
Tetracyclines:
! Tetracycline
! Doxycycline
50S ribosome:
o
Macrolides:
! Erythromycin
! Clarithromycin
o
Chloramphenicol
o
Fusidic acid
Antibiotics that inhibit nucleic acid synthesis:
Quinolones:
o
Ciprofloxacin
Metronidazole
Trimethoprim
Rifampicin
Sulphonamides
Antibiotics that do not accumulate in renal impairment:
Chloramphenicol
Co-trimoxazole
Doxycycline
Isoniazid
Macrolides
Quinolones
Rifampicin
Penicillins:
Are all active against Gram +ve bugs (some against Gram ve bugs)
86
www.garrypettet.com
A common mechanism of resistance is the production of an enzyme ("-

lactamase) that degrades the drug
Penicillin:
o
Benzylpenicillin (penicillin G):
! Parenteral (is destroyed by gastric acids)
o
Phenoxymethylpenicillin (penicillin V):
! Oral (but poor bioavailability)
! Used for prophylaxis in:
Splenectomy patients
Sickle cell anaemia patients

o
Indications:
! Pneumococcus
! Streptococcus
! Meningococcus
! Leptospiral infections
Broad-spectrum (activity against some Gram ve bugs as well):

o
Amoxicillin (oral or parenteral)
o
Indications:
! (As for penicillin)
! Escherichia coli
! Haemophilus influenzae (resistance is increasing ~15%)
! Salmonella
"-lactamase resistant:
o
Flucloxacillin:
! Indications:
"-lactamase-producing staphylococci
o
Co-amoxiclav (Augmentin):
! Amoxicillin +
! Clavulanic acid ("-lactamase inhibitor)
! Indications:
Amoxicillin resistant URTIs and UTIs
Anti-pseudomonal:
o
Ticarcillin
o
Pipericillin:
! Combined with Tazobactam (a "-lactamase inhibitor) as
Tazocin
Adverse effects:
o
Rash:
! Common to all penicillins
! Maculopapular rash in glandular fever if given amoxicillin
o
Nausea / vomiting
o
Uncommon:
! Anaphylactic shock
! Convulsions
Contraindications:
o
Penicillin hypersensitivity
Interactions:
87
www.garrypettet.com
o
COC pill:
! Penicillins reduce the efficacy of the pill
o
Probenicid:
! Probenicid # excretion of the penicillins
! Allows for a # dose of penicillin to be used or for
prolonged high plasma levels to be attained
Cephalosporins:
Have a similar range of activity to amoxicillin but are more "-

lactamase stable
Are 3 generations of parenteral cephalosporins:

o
As the generations progress, the cephalosporins become more
effective against Gram ve bugs
o
First generation have pretty much been superseded
o
Second:
! Cefuroxime:
Similar spectrum to amoxicillin

o
Third:
! All are a common cause of C. difficile diarrhoea
! Cefotaxime:
Important drug in the treatment of meningitis

! Ceftazidime:
Pseudomonas and others

! Ceftriaxone:
Long-half life (once daily administration)
Effective in serious infections:

o
Pneumonia
o
Septicaemia
Are 2 generations of orally active cephalosporins:

o
Both have similar spectrums of action:
! URTIs
! Refractory cystitis
! Otitis media
o
First (e.g. cefalexin)
o
Second (e.g. cefaclor)
Adverse effects:
o
Bleeding
o
Diarrhoea
o
Nausea / vomiting
o
Thrombophlebitis (parental cephalosporins)
Contraindications:
o
Hypersensitivity:
! There is also a 10% cross-reactivity with penicillins
Interactions:
o
Probenicid:
! Probenicid # excretion of the cephalosporins
! Allows for a # dose of cephalosporin to be used
88
www.garrypettet.com
Glycopeptides:
E.g. vancomycin, teicoplanin
Active against aerobic and anaerobic Gram +ve bacteria
Vancomycin (oral or IV):

o
Indications:
! IV:
Infective endocarditis
MRSA
! Oral:
Clostridium difficile (pseudomembranous colitis)
Teicoplanin:
o
Indications (IV or IM):
! Used for serious Gram +ve infections
IV Vancomycin requires therapeutic drug monitoring
Adverse effects:
o
Ototoxicity (tinnitus and deafness)
o
Nephrotoxicity (less so with teicoplanin)
o
Neutropenia
Interactions:
o
Increased risk of ototoxicity with:
! Loop diuretics
o
Increased risk of nephrotoxicity with:
! Aminoglycosides
! Cyclosporin
Carbapenems:
E.g. imipenem, meropenem
Incredibly broad spectrum:

o
Active against both Gram +ve and ve bacteria
o
"-lactamase stable
o
Is effective against MRSA and anaerobes
o
Best single agent choice for nosocomial infection
Imipenem:
o
Rapidly degraded by renal dipeptidase
o
Must be given in conjunction with cilastatin (a dipeptidase
inhibitor)
Meropenem:
o
Similar to imipenem but is stable to renal dipeptidase, does not
need to be given with cilastatin
Adverse effects:
o
Nausea / vomiting / diarrhoea (34% of patients)
o
Cross-reactivity with "-lactam antibiotics
o
Seizures (imipenem >> meropenem)
Aminoglycosides:
E.g. Gentamicin, amikacin, streptomycin
Active against many Gram ve and some Gram +ve bacteria

89
www.garrypettet.com
Indications:
o
Second line treatment for severe Gram ve infection:
! Infective endocarditis
! Septicaemia
! Acute pyelonephritis
o
Topical:
! Eye
! Ear
o
Streptomycin is reserved for resistant tuberculosis
o
Bactericidal
o
Inhibit bacterial protein synthesis by binding to the 30S
ribosome
Pharmacokinetics:
o
Inactive orally (must be given IV / topically)
o
Excreted unchanged by the kidneys:
! Use with caution in renal impairment (adjust dose)
o
Therapeutic drug monitoring is required:
! Peak plasma levels should be measured (~1 hour after
administration)
Adverse effects:
o
Nephrotoxicity (renal tubular damage)
o
Ototoxicity (damage to CN VIII):
! Deaf and dizzy
! Can be irreversible
Contraindications:
o
Myasthenia gravis:
! Aminoglycosides can impair neuromuscular transmission
by inhibiting Ca
2+
-influx into nerve terminal and
preventing release of ACh
o
Pregnancy
Interactions:
o
Drugs potentiating the nephrotoxicity of aminoglycosides:
! Cyclosporin
! Loop diuretics:
Also potentiate ototoxicity

o
Anticholinesterases (e.g. neostigmine):
! Aminoglycosides antagonise the effects of these drugs
Notes:
o
Neomycin is very poorly absorbed:
! Often used dermatologically or as part of bowel prep
o
Tobramycin:
! Can be inhaled (good in CF patients)
! Can precipitate acute airway obstruction
Tetracyclines:
E.g. tetracycline, doxycycline
Indications:
90
www.garrypettet.com
o
Good for some intracellular organisms (as they penetrate
macrophages):
! Chlamydia (STD) # doxycycline
! Rickettsia (Q-fever)
! Borrelia burgdorferi (Lyme disease)
o
Acne
o
Anthrax (doxycycline)
Pharmacokinetics:
o
Were the first orally-active broad-spectrum antibiotics (can be
given IV)
o
Bacteriostatic
o
Absorption from gut is variable - # by:
! Ca
2+
(milk)
! Mg
2+
(antacids)
! Iron preparations
o
Excreted unchanged in the urine (except doxycycline)
Adverse effects:
o
Deposited in growing bones / teeth:
! Causes staining and (occasionally) dental hypoplasia
! Do not use in children <12 years or in pregnancy
o
Renal impairment (except doxycycline)
Contraindications:
o
Renal impairment (except doxycycline)
Fusidic acid:
Potent narrow-spectrum anti-staphylococcal antibiotic
Always used in combination to prevent resistance
Indications:
o
Infections caused by penicillin-resistant staphylococci
o
Especially:
! Osteomyelitis (well concentrated in bone)
! Staphylococcal endocarditis
o
Can be used topically
Adverse effects:
o
Reversible jaundice
o
Acute renal failure (monitor renal function)
o
Liver impairment (monitor LFTs)
Macrolides:
E.g. erythromycin, clarithromycin
Indications:
o
Erythromycin:
91
www.garrypettet.com
! Active against Gram +ve bacteria (e.g. staphylococci,
streptococci) and the atypicals (e.g. mycoplasma,
chlamydia, legionella)
! A good respiratory antibiotic
! A substitute for penicillin in those with hypersensitivity
o
Clarithromycin:
! More potent than erythromycin (except H. influenzae)
! Part of helicobacter pylori eradication therapy
Do not cross the blood-brain-barrier (no good for meningitis)
Adverse effects:
o
Erythromycin causes nausea / vomiting / diarrhoea:
! Is an agonist at the motilin receptor in the gut
o
Phlebitis
Interactions:
o
Inhibit cytochrome P450:
! $ levels of warfarin, theophylline, cyclosporin A (and
many others)
o
Digoxin:
! $ plasma levels of digoxin
o
Terfenadine (non-sedating antihistamine):
! $ risk of arrhythmias
Quinolones:
E.g. ciprofloxacin, ofloxacin
Active against many Gram ve and some Gram +ve bacteria:

o
Campylobacter
o
Escherichia coli
o
Pseudomonas
o
Salmonella
Indications:
o
UTI
o
Salmonella infection
o
Cystic fibrosis lung infections
o
Gonorrhoea
o
Tuberculosis (3
rd
-line drug)
o
Anthrax
Pharmacokinetics:
o
Ciprofloxacin has a near 100% bioavailability when taken
orally
Adverse effects:
o
GI disturbance
o
Tendon damage (including rupture)
o
Seizures (lowers seizure threshold)
Cautions:
o
Epilepsy
o
Myasthenia gravis
o
History of tendon damage
Interactions:
92
www.garrypettet.com
o
Inhibits cytochrome P450 (many interactions):
! $ levels of warfarin, theophylline, cyclosporin A
Metronidazole:
Indications:
o
Anaerobes
o
Protozoal infections:
! Entamoeba histolytica
! Giardia lamblia
! Trichomonas vaginalis
o
Part of helicobacter eradication therapy
o
Pseudomembranous colitis (C. difficile)
Pharmacokinetics:
o
Oral, IV or rectal
o
Clinical / laboratory monitoring if treatment > 10 days
Adverse effects:
o
GI disturbances (uncommon and well tolerated)
Cautions:
o
Hepatic impairment
Interactions:
o
Disulfiram (Antabuse)-like reaction with alcohol:
! Flushing
! Hypotension
! Abdominal pain
o
Phenytoin:
! $ plasma levels of phenytoin
o
Warfarin:
! $ plasma levels of warfarin
Rifampicin:
Indications:
o
Tuberculosis
o
Leprosy
o
Meningitis contact prophylaxis
o
MRSA
Adverse effects:
o
Deranged LFTs (usually mild but can be serious)
o
Stains secretions pink / orange:
! Saliva
! Tears
! Urine
Contraindications:
o
Jaundice
Interactions:
o
Potent cytochrome P450 inducer (many reactions):
! # efficacy of:
Carbamazepine
COC pill
Corticosteroids
93
www.garrypettet.com
Phenytoin
Warfarin
Isoniazid:
Indications:
o
Tuberculosis
Adverse effects:
o
Peripheral neuropathy (more likely in):
! Alcoholism
! Chronic renal failure
! Diabetics
! HIV
! Malnutrition
! Can be prevented by pyridoxine (vitamin B6)
o
Hepatitis
o
Psychosis
Contraindications:
o
Hepatic impairment
Interactions:
o
Anticonvulsants (carbamazepine, phenytoin):
! Isoniazid $ plasma levels of these drugs
Pyrazinamide:
Indications:
o
Tuberculosis
Pharmacokinetics:
o
Good CSF penetration (good in TB meningitis)
Adverse effects:
o
Hepatocellular toxicity
Contraindications:
o
Gout (avoid in acute attack)
o
Hepatic impairment
o
Porphyria
Ethambutol:
Indications:
o
Tuberculosis (if isoniazid resistance is suspected)
Adverse effects:
o
Visual disturbances (reversible if drug stopped early):
! Caused by a retorbulbar neuritis
! Not too much of a problem with only 8 weeks of therapy
Contraindications:
o
Renal impairment ($ risk of visual damage)
94
www.garrypettet.com
Diabetes
Treatment of diabetes:
Both types:
o
Diet:
! # weight (as this # insulin resistance)
! # simple sugars
! $ complex carbohydrates
! $ fibre intake
o
Address associated risk factors:
! Hyperlipidaemia
! Hypertension (<=130 / <=80 mmHg)
! Smoking
Type I:
o
All require insulin
Type II:
o
BMI < 25:
! Sulphonyurea
o
BMI > 25:
! Meformin (a biguanide)
o
If not controlled on a sulphonylurea, add metformin
o
If not controlled on metformin, add a sulphonylurea
o
If not controlled on 2 drugs or intolerant consider adding:
! A glitazone
! Acarbose
o
Insulin if poor glycaemic control with oral agents:
! 50% of pts will require insulin within 6 years of diagnosis
What to check at a diabetics annual review:
Blood glucose record
BP
HbA1c
Lipids
Renal function
Urine (protein / glucose)

Treatment of diabetic ketoacidosis (DKA):
Only occurs in type I diabetes
IV fluids:
o
Patients may be 510L fluid deplete
o
Use 0.9% saline (first bag usually ran in stat)
Monitor (initially hourly):

o
Creatinine (to look for pre-renal failure)
o
Glucose
o
HCO3
-
/ pH
o
K
+
(Initially plasma levels $ - masks body wide K
+
depletion)
Insulin:
o
Aim for a glucose fall of 5mmol/h
95
www.garrypettet.com
o
Initial bolus of soluble insulin then insulin infusion
Potassium replacement (monitor plasma levels):

o
Has been lost due to the diuresis
o
Dont give more than 20mmols/L in each bag
If acidosis severe (pH <7.0) consider bicarbonate:

o
Severe acidosis can impair insulin binding to its receptor
o
Comes in 50ml bottles (8.4% = 1mg / ml)
Identify the cause of the DKA (e.g. infection)
LMWH (to prevent thrombosis) until mobile

Treatment of hyperglycaemic hyper-osmotic non-ketotic (HHONK) coma
Only occurs in type II diabetes
No acidosis (as ketosis is suppressed by endogenous insulin)
IV fluids
Insulin (small doses):

o
Wait until 1 hour after fluids (may not be needed)
Full heparin anticoagulation

Treatment of hypoglycaemia:
If able to take oral treatment:

o
Lucozade (or other high sugar drink / sweet)
Else:
o
2030mg dextrose IV (e.g. 200300mls 10% dextrose):
! high concentrations (e.g. 50%) can be irritative and can
even cause stroke!)
o
Glucagon 1mg IV/IM:
! Almost as fast as IV dextrose
! Doesnt work when given repeatedly or if given to
patients with no or poor glycogen reserves (e.g.
alcoholics)
Once conscious:
o
Give the patient a meal
When to admit:
o
If patient is hypoglycaemia following oral anti-diabetics (as
they can be very long-acting)
Sulphonylureas:
E.g. tolbutamide (very short-acting), glicazide (short-acting),

glibenclamide (once daily)
o
Are insulin secretagogues (thus require some functional "-
cells)
o
Reduce the K
+
permeability of "-cells by blocking ATP-sensitive
K
+
channels:
! Causes depolarisation and Ca
2+
entry
! Thus causing insulin secretion
Pharmacokinetics:
o
All bind strongly to albumin (several drug interactions)
Adverse effects:
96
www.garrypettet.com
o
Weight gain (largely due to $ appetite)
o
Hypoglycaemia (can be severe / fatal):
! Admit (as the hypoglycaemia can persist for up to 24 hrs)
! Much greater risk than with metformin
o
GI disturbances (~3% of patients)
o
Bone marrow suppression (rare)
Cautions:
o
Elderly renal impairment:
! $$ risk of hypoglycaemia (mainly glibenclamide)
o
Breast-feeding
Interactions:
o
Drugs potentiating the hypoglycaemic effect:
! Sulphonamides (including co-trimoxazole)
! Chloramphenicol
Metformin:
Usually given twice daily
A biguanide (the only available one!)
o
Is an insulin-sensitizer
o
# gluconeogenesis
o
$ peripheral utilization of insulin
o
# LDL / VLDL
Does not cause hypoglycaemia
Adverse effects:
o
GI disturbances:
! Start at ~1g / daily
! Nausea / anorexia / vomiting / diarrhoea
o
Lactic acidosis (uncommon):
! Caused by a build-up of pyruvate
o
# absorption of vitamin B12
Contraindications:
o
Conditions predisposing to metformin-induced lactic acidosis:
! Mild renal impairment
! Severe hepatic impairment
! Severe heart failure
o
Pregnancy / breast-feeding
Interactions:
o
Alcohol:
! $ risk of lactic acidosis
Glitazones (thiazolidinediones):
E.g. pioglitazone, rosiglitazone
Indications:
o
Type II diabetes:
97
www.garrypettet.com
! Pat i ent s who c annot t ol er at e ( or t her e ar e
contraindications to) combination therapy with metformin
and a sulphonylurea
! In such cases, the glitazone should replace whichever
drug i n the combi nati on i s poorl y tol erated /
contraindicated
o
Interact with a nuclear receptor (peroxisome proliferator-
activator receptor gamma " PPAR-')
o
PPAR-' regulates genes involved in lipid metabolism and insulin
action
o
Reduce insulin resistance
o
# circulating insulin relative to plasma glucose but do not #
glucose levels to normal
Adverse effects:
o
Hepatotoxicity:
! Monitor LFTs before and during treatment
o
Weight gain
o
Anaemia (uncommon)
Contraindications:
o
Hepatic impairment
o
Combination with insulin (risk of heart failure)
Acarbose:
o
Intestinal !-glucosidase inhibitor
o
Delays the digestion of starch and sucrose
o
Is taken with meals and lowers the post-prandial increase in
blood glucose (~1-2mmol/L)
Adverse effects:
o
Abdominal pain / bloating
o
Flatulence
Contraindications:
o
IBD
o
History of abdominal surgery
o
Pregnancy
Insulin:
N.B. normal individuals require ~60U of endogenous insulin daily
Indications:
o
All T1DM
o
T2DM where control / symptoms / complications poor
o
Hyperkalaemia (with glucose)
Pharmacokinetics:
o
Physical state:
! Short-acting soluble insulins (rapid onset):
E.g. Actrapid, insulin lispro, insulin asparte
Inject 1530 mins before meals

98
www.garrypettet.com
Onset in 3060 mins
Maximum effect 24 hours
Duration up to 8 hours
! Intermediate-acting (isophane insulins):
Are insulin with protamine preparations
E.g. insulatard
! Long-acting:
Either insulin zinc suspensions (e.g. ultratard) or

synthetics (e.g. insulin glargine)
! Mixed-insulins:
E.g. mixtard
o
Human insulin absorbed faster than porcine / bovine insulin
o
Porcine / bovine insulin may cause less hypoglycaemia
o
Factors affecting absorption:
! Temperature
! Exercise
Insulin effects:
o
Adipose tissue:
! $ lipoprotein lipase activity:
# TGs
! $ GLUT-4 activity:
$ glucose storage as fat

! # lipolysis:
o
Liver:
! # glycogenolysis
! # gluconeogenesis
! Inhibition of ketogenesis
o
Muscle:
! # proteolysis
! $ GLUT-4 activity:
# plasma glucose levels
Insulin regimes:
o
Twice daily mixed insulins:
! Possibly better for children or older T2DM
o
Basal bolus (qds) regime:
! More physiological
! Involves more injections
! Best regimen for # diabetic complications
Problems with Actrapid (short-acting human insulin):

o
Needs to be given 15 minutes before meals
o
Can cause a late post-prandial hypoglycaemia:
! Leads to post-prandial hyperglycaemia (as patients dont
give enough as they fear the hypoglycaemia)
Problems with insulin glargine (long-acting human insulin analogue):

o
Nocturnal hypoglycaemia (can be dangerous)
o
Uniform action (not physiological)
Adverse effects:
o
Hypoglycaemia:
! 30% of T1DM ever (10%/year, 3% frequent episodes)
99
www.garrypettet.com
! Sweating
! Tachycardia
! Tremor
! Aggression
! Confusion
! Coma
o
Fat hypertrophy / atrophy at injection site (rotate site to avoid
this)
o
Weight gain:
! As blood [glucose] is # you get hungry!
100
www.garrypettet.com
Epilepsy
Classification of epilepsy:
Generalised:
o
Implies bilateral abnormal electrical activity in the brain with
bilateral motor manifestations
o
Consciousness is impaired
o
Types:
! Tonic-clonic (grand-mal)
! Absence (petit-mal)
! Myoclonic
Partial:
o
A localised seizure that may be either:
! Simple (without loss of consciousness):
Jacksonian seizure
! Complex (with loss of awareness)
o
May progress to a generalised seizure
Management of status epilepticus:
Remember 25% of status turns out to be pseudostatus
ABC (need to maintain airway)
Oxygen
If alcoholism / malnutrition give thiamine
If hypoglycaemic give glucose
Stop the seizure:

o
Lorazapam (slow IV bolus) if fails
o
Phenytoin (IV infusion) if fails
o
Phenobarbital IV if fails
o
Anaesthetise with thiopentone / propofol
Drug treatment of epilepsy (NICE recommendations):
Generalised seizures:
o
First-line (all):
! Valproate
o
Second-line (tonic-clonic):
! Carbamazepine
! Phenytoin
o
Second-line (absence):
! Ethosuximide
o
Second-line (myoclonic):
! Ethosuximide
! Lamotrigine
Partial seizures:
o
First-line:
! Carbamazepine
! Valproate
o
Second-line:
! Lamotrigine
101
www.garrypettet.com
! Gabapentin
! Vigabatrin
o
Third-line:
! Phenytoin
Carbamazepine:
Indications:
o
Partial seizures (first-line)
o
Tonic-clonic seizures (second-line)
o
Trigeminal neuralgia
o
Bipolar disorder
o
Related to the tri-cyclic antidepressants
o
Induces a use-dependent block of neuronal Na
+
channels
Pharmacokinetics:
o
Has an active metabolite (produced in the liver)
o
t! of 1020 hours
o
Is an enzyme inducer (even of its own metabolism)
o
Requires therapeutic drug monitoring
Adverse effects:
o
Ataxia
o
Nausea
o
Neutropenia
o
Sedation
o
SIADH
o
Teratogenic:
! Foetal neural tube defects
Contraindications:
o
AV conduction abnormalities (unless paced)
o
History of bone marrow depression
o
Porphyria
Interactions (many as is an enzyme inducer):

o
Carbamazepine # the efficacy of:
! COC pill
! Corticosteroids
! Cyclosporin
! Phenytoin
! Warfarin
o
Drugs that $ the level of carbamazepine:
! Cimetidine
! Erythromycin
Phenytoin:
Indications:
102
www.garrypettet.com
o
All types of epilepsy (except absence seizures) but not
first-line
o
Status epilepticus
o
Trigeminal neuralgia
o
Related to the barbiturates
o
Induces a use-dependent block of neuronal Na
+
channels
Pharmacokinetics:
o
t! of 2060 hours
o
Has a saturable metabolism (zero-order kinetics):
! Thi s means that over the therapeuti c pl asma
concentration range, the rate of inactivation does not $ in
proportion to the plasma concentration
! This means that the t! $ as the dose is $
o
~90% protein bound:
! Some drugs (e.g. valproate, salicyclates) inhibit this
binding competitively
! This $ the free [phenytoin] but also $ the hepatic
clearance of phenytoin
! The net result is unpredictable
o
Is a potent enzyme inducer
o
Once daily dosage (should be nocte)
o
Requires therapeutic drug monitoring
Adverse effects:
o
Ataxia
o
Sedation
o
Acne
o
Folate deficiency
o
Gum hypertrophy
o
Hirsuitism
o
Lymphadenopathy
o
Osteomalacia (vitamin D resistance)
o
Photosensitivity
Cautions:
o
Hepatic impairment (# dose) # common
o
Pregnancy:
! Cleft palate
Interactions (many):
o
Phenytoin # the efficacy of:
! COC pill
! Rifampicin
! Warfarin
o
Drugs that $ the level of phenytoin:
! Aspirin
! Cimetidine
Sodium valproate:
Indications:
o
All types of epilepsy (first-line)
103
www.garrypettet.com
o
Not fully understood
o
Causes a significant $ in brain [GABA]
Pharmacokinetics:
o
t! of 815 hours
o
Metabolised by the liver but not an enzyme inducer (may be an
enzyme inhibitor)
Adverse effects (fewer severe effects than most anticonvulsants):

o
Hepatotoxicity:
! Need to monitor LFTs
o
Teratogenicity:
! Neural tube defects
! Probably the safest anticonvulsant to use in pregnancy
o
Thinning / curling of the hair
o
Thrombocytopenia
o
Tremor
o
Sedation
o
Weight gain
Contraindications:
o
Severe liver disease
Interactions:
o
Drugs that # the efficacy of valproate:
! Neuroleptics
! Tri-cyclic antidepressants
Phenobarbital:
Indications:
o
All types of epilepsy (except absence seizures) but not first-line
o
Status epilepticus
o
Is a barbiturate
o
Binds to the GABA receptor and enhances actions of GABA
Pharmacokinetics:
o
Well absorbed
o
50% protein bound
o
t! 36120 hours
o
Enzyme inducer
Adverse effects:
o
Sedation wi th i mpai rment of i ntel l ectual and motor
performance
o
Ataxia
o
Osteomalacia
o
Folate deficiency
Cautions:
o
Elderly
o
Respiratory depression
o
Impaired hepatic / renal function
104
www.garrypettet.com
Interactions (many more than shown below):

o
Phenobarbital # the efficacy of:
! COC pill
! Warfarin
Vigabatrin:
Indications:
o
Epilepsy (usually second- or third-line)
o
Was the first designer drug in the field of epilepsy
o
Is a irreversible GABA-transaminase inhibitor:
! $ [GABA] in the CSF
Pharmacokinetics:
o
t! 5 hours (although duration of action is long)
o
Is not an enzyme inducer
Adverse effects:
o
Depression
o
Psychotic disturbances
o
Visual field defects (~30% of patients)
Contraindications:
o
Those with visual field defects
Lamotrigine:
Indications:
o
Can be used as monotherapy of:
! Generalised seizures (especially absence seizures)
! Partial seizures
Pharmacokinetics:
o
t! 1570 hours
Adverse effects:
o
Rashes (very common):
! Can be as severe as Stevens-Johnson syndrome
o
Drowsiness
o
Tremor
Interactions:
o
Valproate:
! Valproate $ the plasma levels of lamotrigine
Primidone:
Is a pro-drug of phenobarbital
? an anticonvulsant in its own right
Adverse effects:
o
As for phenobarbital
Ethosuximide:
Indications:
o
Absence seizures (second-line)
Pharmacokinetics:
o
t! of 3070 hours
105
www.garrypettet.com
o
Is not an enzyme inducer
Adverse effects:
o
Nausea / anorexia
o
Sedation
o
Ataxia
o
Hypersensitivity (rare)
Gabapentin:
Indications:
o
Adjunctive treatment of partial seizures
o
Neuropathic pain
o
Its role is likely to increase in the future
Pharmacokinetics:
o
t! of 57 hours
o
Not metabolised
o
Few (if any) interactions
Adverse effects:
o
Ataxia
o
Drowsiness

106
www.garrypettet.com
Migraine
Prophylaxis against migraine:
Avoid precipitating factors (if possible):

o
Foods (mainly tyramine containing food)
o
Irregular meals / sleeping patterns
o
Alcohol
o
Weekend migraines are probably caused by caffeine
withdrawal
5-HT antagonists:
o
E.g. pizotifen
o
Methysergide:
! Only prescribed by those experience in its use
! Good for cluster headaches
! Fibrotic side effects:
Cardiac fibrosis
Pulmonary fibrosis
Retroperitoneal fibrosis
"-blockers:
o
E.g. propranolol, atenolol, metoprolol
o
High doses often needed
Amitriptylline:
o
Unrelated to its antidepressant effect
Sodium valproate:
o
Refractory migraines
Treatment of migraine:
Simple analgesics:
o
E.g. paracetamol / aspirin / NSAIDs
o
Give with metoclopramide:
! Anti-emetic and $ gastric emptying (thus $ absorption of
the analgesic)
o
Must be given early in an attack
5-HT1D agonists:
o
E.g. sumatriptan
o
Can be given oral / sc / intranasally
o
Is a (relatively) selective vasoconstrictor
o
~70% efficacy:
! Best if taken at onset to abort the migraine
o
Adverse effects:
! Dizziness
! Flushing
o
Avoid:
! In patients with IHD or uncontrolled hypertension:
Can cause angina-like pain (discontinue)

! With SSRIs and MAOIs
Ergotamine:
o
Rarely used now
107
www.garrypettet.com
o
Primarily a vasoconstrictor
o
Adverse effects:
! Nausea / vomiting
! Peripheral /coronary vasoconstriction
108
www.garrypettet.com
Multiple sclerosis
Drug treatment of an acute relapse of MS:
IV methylprednisolone:
o
High dose
o
Short course (35 days)
o
Does not alter the long-term prognosis
No other approaches have shown any benefit

Prevention of relapse in MS:
Interferon-"1 (IFN-"1a and IFN-"1b):

o
Given SC / IM
o
Trials have shown a 30%# in relapses (only in relapsing /
remitting disease)
o
Probably does not alter the natural history
o
Expensive:
! ~10,000/person/year
o
Adverse effects:
! Flu-like symptoms
! Depression
Glatiramer:
o
May prevent relapsing as for IFN-" but does not alter the long-
term prognosis
Symptomatic treatment of MS:
Spasticity / painful spasms:

o
Baclofen:
! Inhibits nerve transmission at the spinal level
! Adverse effects:
Sedation
Hypotonia
Urinary disturbance
! Serious side effects can occur on abrupt withdrawal:
Convulsions
Hyperthermia
Psychiatric reactions
o
Dantrolene:
! Inhibits muscle contraction:
Prevents Ca
2+
release from sarcoplasmic reticulum
! Adverse effects:
Aggravates weakness
Hepatotoxic
Detrusor instability:
o
Anticholinergics (e.g. oxybutynin, TCAs)
Paroxysmal pain:
o
Anticonvulsants / TCAs
109
www.garrypettet.com
Parkinsons disease
Features of Parkinsons disease:
Bradykinesia
Rigidity (lead-pipe)
Tremor (47 Hz, pill-rolling)
Festinant gait
Loss of arm swinging
Monotonous speech
Loss of facial expression
Micrographia
Drug treatment of Parkinsons disease (PD):
Treatment should not be started before it is necessary because of

delayed unwanted effects
Levodopa (L-dopa):
o
First-line therapy
Direct dopamine agonists:

o
E.g. apomorphine, bromocriptine, lisuride, pergolide
o
Used as an alternative or adjunct to L-dopa
Amantadine:
o
Useful in mild / moderate PD
o
May have a use in late disease with marked dyskinesia
Anticholinergics:
o
E.g. benzhexol
o
Most useful in mild PD with tremor in younger patients
o
Also good for controlling dribbling
Monoamine oxidase B inhibitors (MAO-BIs):

o
E.g. selegiline
o
Used as an adjunct to L-dopa to allow a # in dose:
! Can also # dose-related response fluctuations
Catechol O methyl transferase (COMT) inhibitors:

o
E.g. entacapone
o
May be useful in # end-of-dose fluctuations with L-dopa
Levodopa:
An example of a prodrug
Must be combined with a peripheral dopa-decarboxylase inhibitor:

o
E.g. carbidopa, benserazide
o
Prevents L-dopa metabolism in the periphery
o
Do not cross the blood-brain barrier (BBB)
o
Thus # dose (by about 10 fold)
o
# adverse effects
Pharmacokinetics:
o
t! of 2 hours
o
There is a large individual variation in kinetics, thus slow
titration is essential
110
www.garrypettet.com
o
Is a pro-drug of dopamine
o
(Dopamine is not used as it cannot cross the BBB)
o
L-dopa crosses the BBB and is rapidly converted to dopamine
by dopa-decarboxylase in the brain
o
This dopamine replaces the deficiency in the basal ganglia
With L-dopa, ~80% show improvement in rigidity and hypokinesia and

~20% are restored to near-normal function (for a period)
Adverse effects:
o
Short-term:
! Nausea / vomiting:
Treat with domperidone (dopamine antagonist)

! GI disturbances
! Postural hypotension
! Cardiac dysrhythmias
! Haemolytic anaemia (rarely)
o
Long-term:
! Neuropsychiatric syndromes:
Delirium
Hallucinations (patient maintains insight)
Psychosis
Treatment:
o
Dose #
o
Atypical neuroleptics (e.g. clozapine)
! Response fluctuations:
Akinesia:
o
End-of-dose
Dyskinesia:
o
Peak dose
o
Onset / end-of-dose
Unpredictable on-off responses (yo-yo-ing)
Treatment:
o
Careful regulation of plasma L-dopa levels
o
Use modified-release preparations
o
Try:
! COMT inhibitor
! MAO-BI
! Dopamine agonist
! Loss of response:
Usually within 25 years
~50% are back to pre-treatment status after 5 yrs
Treatment:
o
Try dopamine agonist
Contraindications:
o
Closed angle glaucoma
Interactions:
o
Non-selective MAOIs:
111
www.garrypettet.com
! Risk of hyperthermia syndrome with concomitant use
! Withdraw MAOIs 2 weeks before starting L-dopa
o
Anti-hypertensives:
! Enhanced hypotensive effect
o
Neuroleptics:
! Neuroleptics antagonise the action of L-dopa (and vice-
versa)
Apomorphine:
PD indications:
o
Advanced disease with on-off periods with L-dopa
Pharmacokinetics:
o
Must be given parenterally (SC)
o
Very potent dopamine D1 and D2 agonist
Adverse effects:
o
Profound nausea / vomiting
o
As for L-dopa
Contraindications:
o
Respiratory / CNS depression
o
Neuropsychiatric problems / dementia
Dopamine agonists:
Older compounds (ergot derivatives):

o
Bromocriptine, cabergoline, lisuride, pergolide
Recent compounds (synthetic):

o
Pramipexole, ropinirole
o
Side-effects are less than the older agents
Indications:
o
Can be used as an alternative to L-dopa but are usually used as
adjuncts
Pharmacology:
o
Duration of action:
! Pergolide = cabergoline > bromocriptine > lisuride
o
Potency:
! Pergolide = lisuride > cabergoline > bromocriptine
Are less effective than L-dopa but are associated with fewer late
unwanted dyskinetic effects
Adverse effects:
o
Nausea / vomiting
o
Hypotension
Amantadine:
o
Unknown
112
www.garrypettet.com
o
May cause release of dopamine
o
May be a weak anticholinergic
Is less effective than L-dopa or even bromocriptine but its use may be
revived for late onset dyskinesia
Adverse effects:
o
Dizziness
o
Insomnia
o
Livedo reticularis
o
Peripheral oedema
Anticholinergics:
E.g. benzhexol, procyclidine
Until L-dopa was discovered, anti-muscarinic agents were the only

available treatment for PD
o
As the nigrostriatal neurones progressively degenerate in PD,
the release of (inhibitory) dopamine # and the excitatory
cholinergic interneurones in the striatum become relatively
overactive
o
Blocking these mACh receptors resets this balance
o
Only really reduce the tremor of PD (little effect on rigidity
and Bradykinesia)
Use is declining rapidly (especially in the elderly) largely due to

their unwanted effects on memory
Adverse effects:
o
CNS:
! Confusion
! Hallucinations
! Memory impairment
o
Other:
! Blurred vision
! Dry mouth
! Constipation
Monoamine oxidase B inhibitors (MAO-BIs):
E.g. selegiline
Indications:
o
May allow L-dopa dose #
o
# end-of-dose deteriorations in advanced PD
o
Can be used alone to delay need for L-dopa for a few months
Adverse effects (reasonably well tolerated):

o
No cheese reaction (does not affect MAO-A)
o
Potentiates L-dopa related symptoms
o
Insomnia
Catechol-O-methyl transferase (COMT) inhibitors:
E.g. entacapone
o
Prolongs the action of a single dose of L-dopa
113
www.garrypettet.com
o
Has no anti-PD activity when used alone but # the off time in
late disease when used with L-dopa
Adverse effects:
o
GI disturbances
o
Dyskinesias
o
Urine may be coloured reddish-brown
114
www.garrypettet.com
Drug-induced movement disorders
The most commonly implicated drugs in this section are the antipsychotics
(but also more common drugs such as metoclopramide)
To be covered:
Acute dystonias
Akathisia
Parkinsonism
Tardive dyskinesia
Neuroleptic malignant syndrome

Acute dystonias:
Dystonia is a syndrome of sustained muscle contractions that produce

twisting and repetitive movements or abnormal postures
Presentation:
o
Most common in young males
o
Occurs within hours / days of starting the implicated drug
o
Usually oculogyric:
! Spasm of the extra-ocular muscles, forcing the eyes into
upward or lateral gaze
Treatment:
o
IV anticholinergics (e.g. procyclidine)
o
? continue oral anticholinergics for ~48 hours
Akathisia:
This is a restless, repetitive and irresistible need to move
Can culminate in suicide
Occurs within days or months of starting the implicated drug
Equal sex incidence
May persist even after drug is stopped
Treatment:
o
Often ineffective
o
May respond to:
! Amantadine
! Anticholinergics
! "-blockers
Parkinsonism:
Bradykinesia and rigidity but little tremor

115
www.garrypettet.com
Affects up to 20% of patients on antipsychotics
Presentation:
o
Usually in first few months of starting the drug
o
More common in the elderly
Treatment:
o
Withdraw / # dose of drug if possible
o
Anticholinergics / Amantadine may be effective:
! Do not use L-dopa
o
May persist even after drug is stopped
Tardive dyskinesia (TD):
Are involuntary movements of the tongue, lips, face, trunk and

extremities
Presentation:
o
Occurs after many months / years of using the drug
o
Affects up to ~20% of patients
o
More common in women and the elderly
Treatment:
o
Some neuroleptics are less likely to cause TD:
! Clozapine, risperidone, sulpiride
o
A change of neuroleptic may help
Malignant hyperthermia syndrome:
Is a rare idiosyncratic drug reaction that is unpredictable
Commonly implicated drugs:

o
Antipsychotics
o
Suxamethonium
Presentation:
o
Often a young male
o
Extreme rigidity
o
Hyperthermia
o
Fluctuating conscious level
There is a very high mortality if the syndrome goes unrecognised
Treatment:
o
Stop the causative drug
o
Dantrolene:
! Stops Ca
2+
release in muscle
! Thus stopping the excessive muscle contractions
116
www.garrypettet.com
Myasthenia gravis
The Tensilon (edrophonium) test:
Give edrophonium IV as a bolus dose
Positive test:
o
Improvement of weakness occurs within seconds and the
response lasts for 23 minutes
To be certain, the test should be preceded by a bolus of saline to act

as a control
Drug treatment of myasthenia gravis (MG):
Oral anticholinesterases:
o
Provide symptomatic improvement (complete relief is rare)
Corticosteroids:
o
Lead to a rapid improvement in most patients
o
Can produce total remission
o
High doses are usually needed (60mg on alternate days)
Immunosuppressants:
o
E.g. azathioprine, cyclophosphamide, cyclosporin
o
Lead to an improvement in most patients
o
Are steroid-sparing agents
o
More effective in older patients
Thymectomy:
o
Improves prognosis (especially in women <40 years with
positive AChR antibodies and a history of <10 years)
o
Must always remove a thymoma if present
o
Complete remission is rare
Plasmapheresis:
o
Useful during exacerbations
o
Effects may last up to 3 months
Anticholinesterases:
E.g. neostigmine, pyridostigmine
Indications:
o
Myasthenia gravis (oral)
o
Reversal of non-depolarising muscle relaxants (IV)
o
Inhibit acetylcholinesterase, thus $ the concentration of ACh
in the synaptic cleft
o
Myasthenia gravis:
! The $ concentration of ACh has an $ probability of binding
to a receptor at the neuromuscular junction
o
Reversal of muscle relaxants:
! The $ concentration of ACh overcomes the competitive
blockade of the muscle relaxant
Adverse effects:
o
Abdominal cramps
117
www.garrypettet.com
o
Bradycardia
o
Hypersalivation
o
Nausea / vomiting
o
Sweating
Interactions:
o
Aminoglycosides:
! # the action of anticholinesterases
118
www.garrypettet.com
Diuretics
Loop diuretics:
E.g. furosemide
Indications:
o
Acute pulmonary oedema
o
Chronic heart failure
o
Oliguria secondary to acute renal failure
o
Inhibit NaCl reabsorption in the thick segment of the
ascending loop of Henle:
! Inhibit the Na
+
/K
+
/2Cl
-
pump
o
This section has a high capacity for absorbing NaCl and so loop
diuretics produce the most profound diuresis
o
The $ Na+ that reaches the distal tubule also leads to an
osmotic effect, drawing yet more water into the lumen
o
Also possess venodilator properties that are independent of
their diuretic effect
Adverse effects:
o
Hypokalaemia
o
Hypocalcaemia
o
Hypomagnesaemia
o
Hyperuricaemia (can cause gout)
o
Deafness (high doses effects on the endolymph)
o
Contraindications:
o
Renal failure with anuria
Interactions:
o
Aminoglycosides:
! $ risk of ototoxicity and nephrotoxicity
o
Digoxin:
! Hypokalaemia caused by furosemide $ risk of digoxin
toxicity
o
Lithium:
! # excretion of lithium - $ plasma levels
Thiazide diuretics:
E.g. bendrofluazide, metolazone
Indications:
o
Hypertension
o
Heart failure
o
Moderately powerful diuretics (metolazone > bendrofluazide)
o
# reabsorption of Na
+
in the distal tubule
o
The $ Na+ load in the distal tubule stimulates Na+ exchange
with K+ and H+ ions thus $ their excretion and tending towards
hypokalaemia and a metabolic alkalosis
Adverse effects:
119
www.garrypettet.com
o
Hypokalaemia
o
Hyponatraemia
o
Hyperglycaemia
o
Hypercalcaemia
o
Hyperlipidaemia
o
Hyperuricaemia
o
o
Impotence
Contraindications:
o
Severe hepatic / renal impairment
o
Gout
Interactions:
o
Digoxin:
! Hypokalaemia caused by thiazides $ risk of digoxin
toxicity
o
Lithium:
Spironolactone (a potassium-sparing diuretic):
Indications:
o
Chronic heart failure (shown to # mortality)
o
Refractory hypertension (BHS step 4)
o
Ascites / oedema caused by cirrhosis
o
Conns syndrome (primary hyperaldosteronism)
o
Potassium conservation with thiazide and loop diuretics
o
Is a competitive aldosterone antagonist
o
Aldosterone causes Na
+
reabsorption and K
+
excretion in the
distal tubule
o
Inhibition of this action leads to a mild diuresis and retention of
K
+
o
It is a weak diuretic because only 2% of the total Na
+

reabsorption is under aldosterone control
Adverse effects:
o
Hyperkalaemia
o
Gynaecomastia
o
Impotence
Contraindications:
o
Hyperkalaemia
o
Addisons disease
Interactions:
o
$ risk of hyperkalaemia:
! ACE inhibitors / AII receptor antagonists
! NSAIDs
o
Lithium:
o
Potassium salts ($ risk of hyperkalaemia)
Other potassium-sparing diuretics:
120
www.garrypettet.com
E.g. amiloride, triamterene
Indications:
o
Potassium conservation with thiazide and loop diuretics
o
Block Na
+
channels in the distal tubule
o
$ Na
+
excretion (thus causing a diuresis) and # K
+
excretion
Adverse effects:
o
Hyperkalaemia
Contraindications:
o
Renal impairment
Interactions:
o
$ risk of hyperkalaemia:
! ACE inhibitors / AII receptor antagonists
! NSAIDs
o
Lithium:
o
Potassium salts ($ risk of hyperkalaemia)
Osmotic diuretics:
E.g. mannitol
Indications:
o
Cerebral oedema
o
Mannitol is a compound that is filtered by the kidneys but is not
reabsorbed
o
Is given in amount such that it significantly contributes to
plasma osmolarity
o
The $ plasma osmolarity (by compounds which cannot cross
the blood-brain barrier) leads to extraction of water from
the brain
Adverse effects:
o
Chills
o
Fever
Contraindications:
o
Congestive cardiac failure
o
Pulmonary oedema
121
www.garrypettet.com
Muscle relaxants
Types of muscle relaxants:
Depolarizing:
o
Suxamethonium
Non-depolarizing (competitive):
o
Can be reversed wi th an anti chol i nesterase (unl i ke
suxamethonium)
o
Pancuronium:
! Long-duration of action
! Atropine-like effects
o
Vecuronium:
! No cardiovascular effects
! Short duration of action
o
Atracurium:
! Decomposes spontaneously in plasma:
! Does not depend on liver / kidneys for excretion
o
Rocuronium:
! Rapid onset (almost as fast as Suxamethonium)
Suxamethonium:
Pharmacokinetics:
o
Is 2 ACh molecules linked by their acetyl groups
o
Rapid onset (11.5 minutes)
o
Very short duration of action (37 minutes):
! Metabolised by plasma pseudocholinesterase
o
Suxamethonium diffuses slowly to the motor endplate and
persist for long enough to cause loss of electrical excitability
o
Before paralysis occurs, the muscle fibres are activated causing
twitching (fasciculation)
Adverse effects:
o
Muscle aches (caused by the fasciculation)
o
Prolonged block:
! ~1 in 2000 people have a deficiency of plasma
pseudocholinesterase and paralysis may last several
hours
o
Bradycardia
o
K
+
release (from muscle)
o
Malignant hyperthermia:
! Very high mortality (~65%)
! Treated with dantrolene
Contraindications:
o
Family history of malignant hyperthermia
o
Hyperkalaemia
Interactions:
o
Drugs $ action of Suxamethonium (many):
122
www.garrypettet.com
! Aminoglycosides
! Metoclopramide
! Verapamil
Non-depolarizing muscle relaxants:
E.g. pancuronium, vecuronium, atracurium, rocuronium
o
Do not cross the BBB or the placenta
o
Block the nicotinic ACh receptor at the motor endplate,
thus inhibiting muscle contraction
Adverse effects:
o
These vary between the various drugs (see above)
o
Hypotension
o
Anaphylactoid reactions
123
www.garrypettet.com
Anti-emetics
Causes of nausea and vomiting:
Drugs:
o
Antibiotics (e.g. erythromycin)
o
Cytotoxic agents
o
Digoxin
o
Opioids
Vestibular disease (e.g. labyrinthitis)
Provocative movement (e.g. seasickness)
Migraine
Abdominal disease
Pregnancy
Physiology of nausea:
Emesis is coordinated by the vomiting centre (medulla oblongata)
An important input to the vomiting centre is the chemoreceptor

trigger zone (CTZ) in the area postrema:
o
The CTZ is not protected by the BBB, therefore circulating
toxins/drugs can stimulate it
o
Possesses the following receptors:
! Dopamine (D2)
! Serotonin (5HT3)
The vomiting centre also receives cholinergic (muscarinic) and

histamine input
Thus the following drug classes are helpful anti-emetics:

o
D2 receptor antagonists
o
5-HT3 receptor antagonists
o
Anti-muscarinic agents
o
Antihistamines (H1)
Dexamethasone i s a useful anti -emeti c fol l owi ng cancer

chemotherapy
Vomiting is easier to prevent than it is to stop

D2 receptor antagonist anti-emetics:
E.g. metoclopramide, domperidone
Indications:
o
Nausea and vomiting due to:
! Abdominal disease
! Drugs (especially opioids)
! Migraine
! Post-operative nausea / vomiting
o
Blocks D2 receptors in the CTZ
o
Prokinetic actions on the gut ($ absorption of many drugs):
! Can be an advantage (e.g. analgesics in migraine with
vomiting)
Adverse effects:
124
www.garrypettet.com
o
Acute dystonia (especially if age <20 years and female)
o
Hyperprolactinaemia
Domperidone does not readily cross the BBB and is much less
likely to cause central reactions (e.g. dystonic reactions)
Contraindications:
o
GI obstruction / perforation / haemorrhage
o
Recent (34 days) GI surgery
Interactions:
o
NSAIDs:
! $ absorption of NSAIDs $ their beneficial (and toxic)
effects
5-HT3 antagonist anti-emetics:
E.g. ondansetron, granisetron
Indications:
o
! Cytotoxic agents
! Radiotherapy
! Post-operative nausea / vomiting
Adverse effects:
o
Headache
o
Constipation
Anti-muscarinic anti-emetics:
E.g. hyoscine
Indications:
o
Prophylaxis against motion sickness
Adverse effects:
o
Blurred vision
o
Dry mouth
o
Drowsiness
Contraindications:
o
Prostatic enlargement
o
Glaucoma
o
Myasthenia gravis
o
Paralytic ileus
Interactions:
o
Alcohol:
! Sedative effects of hyoscine are enhanced by alcohol
Antihistamine anti-emetics:
E.g. cinnarizine, cyclizine
Indications:
o
125
www.garrypettet.com
! Vestibular disease
! Drugs
Adverse effects:
o
Drowsiness
o
Anti-muscarinic effects, e.g.:
! Blurred vision
! Dry mouth
Contraindications:
o
Prostatic enlargement
o
Glaucoma
o
Urinary retention
126
www.garrypettet.com
The eye
Maintenance of intraocular pressure (IOP):
The IOP is determined by aqueous humour volume
Production:
o
Aqueous humour is produced by the highly vascularised
processes of the ciliary body
o
The ciliary epithelial cells (which contain ATPase and carbonic
anhydrase) absorb Na
+
from the stroma and transport it to the
intercellular clefts (which open on the aqueous humour side)
o
The hyperosmolality in the clefts leads to water flow from the
stroma, producing a continuous flow of aqueous
o
The ciliary epithelium is also leaky and ~30% of aqueous is
formed by ultrafiltration
Drainage:
o
Pupil " trabecular meshwork " canal of Schlemm " episcleral
veins
Treatment of acute narrow-angle glaucoma:
This must be treated quickly to prevent permanent retinal damage
# aqueous production:
o
Acetazolamide IV stat
$ aqueous outflow:
o
Pilocarpine eye drops stats
o
Mannitol IV stat:
! To draw water out of the eye
Prevent recurrence:
o
Surgery (Peripheral iridotomy)
Drug treatment of chronic open-angle glaucoma:
All of the following treatments are given topically (eye drops)
# aqueous production:
o
"-blockers
o
!-agonists
o
Carbonic anhydrase inhibitors
$ aqueous outflow:
o
Muscarinic agonists
Age-related macular degeneration (AMD):
Most common cause of blindness in the UK
New blood vessels form under the retina and leakage of fluid and blood
from the vascular complexes causes severe loss of vision within a few
years
Treatment (relatively new):

o
Verteporfin (photodynamic therapy):
127
www.garrypettet.com
! Is a light-sensitive dye that is given IV and is taken up by
vascular endothelium
! A laser is then applied to the eye and this activates the
dye, which releases free radicals that destroy the new
vessels
Mydriatic drugs:
Muscarinic antagonists:
o
Also cause cycloplegia (paralysis of the ciliary muscle)
o
Tropicamide
o
Cyclopentolate
!-agonists:
o
Do not affect the pupillary light reflex or accommodation
o
Phenylephrine
"-blockers and glaucoma:
E.g. timolol
Drugs of choice in chronic open-angle glaucoma
o
Block "2 receptors on the ciliary processes and # aqueous
secretion
o
May also block "-receptors on afferent blood vessels to the
ciliary processes (this vasoconstriction # ultrafiltration)
Adverse effects (may be absorbed systemically):

o
Bradycardia
o
Bronchospasm
Contraindications:
o
Asthma
o
Heart block
o
Heart failure
!-agonists in glaucoma:
E.g. adrenaline, phenylephrine
# IOP by vasoconstriction of the ciliary body afferent blood vessels
Interestingly, !-antagonists and "-agonists also # IOP:

o
$ aqueous outflow rather than #production
o
Dilatation of the aqueous / episcleral veins
Carbonic anhydrase inhibitors:
E.g. Acetazolamide (IV / IM / oral), dorzolamide (topical)
Inhibition of carbonic anhydrase prevents HCO3

-
formation
Since HCO3
-
and Na
+
transport are linked, this leads to a # in aqueous
formation
Dorzolamide can be used alone in those in whom "-blockers are

contraindicated
Dorzolamide is a sulphonamide and systemic side effects can occur:

o
Rashes
o
Bronchospasm
128
www.garrypettet.com
Muscarinic agonists:
E.g. pilocarpine
# IOP by contracting the ciliary muscle
This pulls the scleral spur and results in the trabecular meshwork
being stretched and separated
The fluid pathways are opened up and aqueous outflow is increased
Adverse effects:
o
Miosis:
! Causes near-sightedness (blurred distance vision)
! Brow ache
! Headache
! Poor night vision
129
www.garrypettet.com
Antipsychotics (neuroleptics)
The dopamine hypothesis of psychosis:
Psychotic symptoms result from $ dopamine neurotransmission
Dopamine receptors:
o
D1-like:
!
D1 and D5
! Are post-synaptic
! Stimulate adenylate cyclase and $ cAMP
o
D2-like:
!
D2, D3 and D4
! Are both pre- and post-synaptic
! Inhibit adenylate cyclase and # cAMP
Dopaminergic pathways:
o
Mesolimbic / mesocortical:
! Concerned with mood and emotional stability
! Ventral tegmental area:
Ventral striatum and the frontal cortex

o
Nigrostriatal:
! Concerned with movement
! Substantia nigra and the dorsal striatum
Neuroleptics block D2 receptors:

o
Explains why they cause movement disorders as a side effect
Clinical classification of neuroleptics:
Typical:
o
Produce extrapyramidal symptoms (EPS)
Atypical:
o
So-called because they have a low incidence of EPS
o
However, all apart from clozapine can cause EPS at high doses
Chemical classification of neuroleptics:
Typical:
o
Phenothiazines:
! Propylamines (chlorpromazine):
Sedation ++
Anticholinergic ++
EPS ++
! Piperidines (thioridazine):
Sedation ++
Anticholinergic ++
EPS +
Can cause torsade de pointes

! Piperazines (fluphenazine):
Sedation +
Anticholinergic +
EPS +++
o
Thioxanthines (flupenthixole):
! Sedation +
130
www.garrypettet.com
! Anticholinergic +
! EPS ++
o
Butyrophenones (haloperidol):
! Sedation -
! Anticholinergic -
! EPS +++
Atypical:
o
True:
! Clozapine:
Sedation ++
Anticholinergic +
EPS -
o
Apparent:
! Sulpiride:
Sedation +
Anticholinergic
EPS +
! Risperidone:
Sedation ++
Anticholinergic +
EPS +
General effects of the neuroleptics:
Early (hours):
o
Desired:
! Sedation (histamine / !-receptor blockade)
! Tranquilisation (dopamine blockade)
o
Unwanted:
! Acute dystonic reactions
Medium (daysweeks):
o
Desired:
! Suppression of:
Delusions
Disordered thinking
Hallucinations
o
Unwanted:
! Akathisia
! Parkinsonism
Late (monthsyears):
o
Desired:
! Prevention of relapse
o
Unwanted:
! Tardive dyskinesia
Any time:
o
Neuroleptic malignant syndrome
Chlorpromazine:
Indications:
o
Psychotic disorders (e.g. schizophrenia / mania)
o
Labyrinthine disorders / vertigo
131
www.garrypettet.com
o
Nausea / vomiting
o
Chronic hiccups
Adverse effects:
o
Common:
! Sedation
! Anticholinergic effects:
Blurred vision
Dry mouth
Constipation
Urinary retention
! Extrapyramidal effects:
Acute dystonia
Akathisia
Parkinsonism
Tardive dyskinesia
! Hyperprolactinaemia:
Amenorrhoea
Galactorrhoea
Impotence
o
Uncommon:
! Neuroleptic malignant syndrome
! Agranulocytosis
! Cholestatic jaundice
Interactions:
o
ACE inhibitors:
! Can cause severe hypotension
Haloperidol:
Indications:
o
Psychosis
o
Motor tics
Adverse effects:
o
Common:
! Extrapyramidal effects:
Acute dystonia
Akathisia
Parkinsonism
o
Uncommon:
! Convulsions
! Neuroleptic malignant syndrome
! Tardive dyskinesia
! Weight loss
Interactions:
o
Amiodarone:
! $ risk of ventricular arrhythmias
o
Carbamazepine:
! # plasma levels of haloperidol (metabolism accelerated)
132
www.garrypettet.com
o
Fluoxetine:
! $ plasma levels of haloperidol
Clozapine:
Regarded by many as the only true atypical neuroleptic:

o
EPS is not evident even at high doses
o
Effective in patients refractory to other neuroleptics
o
Can treat the negative symptoms of schizophrenia
o
Blocks D4 and 5-HT2 receptors
o
Weak blockade of striatal D2 receptors
Adverse effects:
o
Agranulocytosis (requires regular blood monitoring)
o
Myocarditis / cardiomyopathy
o
Ileus
Contraindications:
o
Severe cardiac disorders
o
History of neutropenia / agranulocytosis
Interactions:
o
Avoid concomitant use with drugs that have a high risk of
causing agranulocytosis (e.g. carbimazole)
133
www.garrypettet.com
Drugs in the elderly, young or pregnant
Pharmacokinetics in the elderly:
Distribution:
o
# body water:
! Thus water soluble drugs have a # volume of distribution
(Vd)
! Thus $ [water soluble drugs]
o
$ body fat:
! Lipid soluble drugs have an $ Vd
! Thus # [fat soluble drugs]
o
# plasma albumin:
! # drug protein binding
! Thus $ levels of drugs that usually bind to protein
o
# weight (no longer a 70kg man!):
! Thus standard dose will lead to $ [drug]
Metabolism:
o
# oxidation
o
# first-pass metabolism
o
# induction of liver enzymes
o
Warfarin is more effective
Excretion:
o
# GFR
o
# tubular secretion
Altered end-organ sensitivity in the elderly:
Autonomic nervous system:

o
Defective compensatory mechanisms:
! E.g. antihypertensives " postural hypotension
o
"-receptors (# density)
Brain:
o
$ sensitivity to anxiolytics and hypnotics (may lead to confusion)
Heart (failing):
o
# perfusion of liver / kidneys " # function of these organs
Two groups of drugs in the elderly cause 2/3 of all adverse drug reactions:
Drugs acting on the:
Brain:
o
Antidepressants
o
Anti-Parkinsons drugs
o
Hypnotics
Circulation:
o
Antihypertensives
o
Digoxin
o
Diuretics
Compliance issues in the elderly:
Living alone / unsupervised

134
www.garrypettet.com
Confusion because of change in tablet shape / colour
Impaired vision
Arthritic hands
Pharmacokinetics in neonates:
Absorption:
o
# gastric motility
o
Variable peripheral perfusion (care with IM injections)
Distribution:
o
Blood brain barrier is immature
o
$ body water:
! Thus # [water soluble drugs]
o
# body fat:
! Thus $ [fat soluble drugs]
o
Protein binding low (adult levels at 1 year of age)
Metabolism:
o
# P450 activity
o
# conjugation:
! E.g. chloramphenicol " grey baby syndrome
Excretion:
o
# GFR:
! The neonate has 30% of adult GFR and 20% of adult
tubular secretion
! This $ to 50% at 1 week of age
! $ to 100% at 6 months of age
Drugs with adverse effects on foetal development:
ACE inhibitors
Alcohol
Androgens
Anticonvulsants
Folate antagonists (e.g. methotrexate)
Tetracyclines
Thalidomide
Warfarin
Drugs to avoid in later pregnancy:
Aspirin:
o
Haemorrhage
o
Kernicterus
Aminoglycosides:
o
CN VIII damage
Anti-thyroid drugs (e.g. carbimazole):

o
Goitre
o
Hypothyroidism
Benzodiazepines:
o
Floppy baby syndrome
Chloramphenicol:
o
Grey baby syndrome
135
www.garrypettet.com
Warfarin:
o
Haemorrhage
Sulphonylureas:
o
Kernicterus
136
www.garrypettet.com
Cytotoxic chemotherapy
Classification of anti-cancer drugs:
Alkylating agents:
o
Cyclophosphamide
o
Chlorambucil
o
Cisplatin
o
Dacarbazine
o
Ifosfamide
o
Mitomycin C
Anti-metabolites:
o
Folate antagonists:
! Methotrexate
o
Pyrimidine analogues:
! 5-Fluorouracil (5-FU)
! Cytarabine (cytosine arabinoside)
! Gemcitabine
o
Purine analogues:
! Azathioprine
Cytotoxic antibiotics:
o
Anthracyclines:
! Doxorubicin (adriamycin)
o
Bleomycin
Plant derivatives:
o
Taxanes:
! Paclitaxel
o
Vinca alkaloids:
! Vincristine
! Vinblastine
Epipodophyllotoxins:
o
Etoposide
Hormonal:
o
Antagonists:
! Anti-androgens:
Cyproterone
! Anti-oestrogens:
Tamoxifen
o
Corticosteroids
o
GnRH analogues:
! Goserelin
o
Somatostatin analogues:
! Octreotide
Miscellaneous compounds:
o
Hydroxyurea
Some example chemotherapy regimens:
BEP:
o
Bleomycin
137
www.garrypettet.com
o
Etoposide
o
Cisplatinum
o
Testicular teratoma
CHOP:
o
Cyclophosphamide
o
Hydroxydaunomycin (doxorubicin)
o
Oncovin (vincristine)
o
Prednisolone
o
Radical treatment of non-Hodgkins lymphoma (NHL)
ABVD:
o
Adriamycin (doxorubicin)
o
Bleomycin
o
Vinblastine
o
Dacarbazine
o
Hodgkins lymphoma
FEC:
o
5-Fluorouracil
o
Etoposide
o
Cyclophosphamide
o
Breast cancer
General adverse effects of cytotoxic agents:
Nausea / vomiting
Alopecia
Oral / intestinal ulceration
Diarrhoea
Bone marrow suppression:

o
Anaemia
o
Leucopenia
o
Thrombocytopenia
Teratogenicity
Carcinogenesis
Emesis-risk:
High risk:
o
Treat with granisetron + dexamethasone + domperidone)
o
Cisplatinum (high dose)
o
Etoposide (high dose)
o
Dacarbazine
o
Ifosfamide
Moderate risk:
o
Cisplatinum (low dose)
o
Cyclophosphamide
o
Doxorubicin
o
Methotrexate (high dose)
Low risk:
o
Treat with domperidone dexamethasone
o
Bleomycin
o
Methotrexate (low dose)
138
www.garrypettet.com
patients biggest concern
physicians biggest concern
o
Mitomycin
o
Vincristine
Prevention of nausea / vomiting:
Acute:
o
5-HT3 antagonist (e.g. granisetron) +
o
Dexamethasone
Delayed:
o
Domperidone / metoclopramide
o
Dexamethasone
Alkylating agents:
E.g. cyclophosphamide, chlorambucil, cisplatin, dacarbazine,

ifosfamide, mitomycin
o
Readily form covalent bonds with the bases in DNA
o
Prevent cell division by cross-linking the two strands of the
double helix
o
Their main action occurs during replication (i.e. during S phase
with a block at G2)
o
Results in apoptotic cell death
Cyclophosphamide:
o
Indications:
! Malignancy
! Autoimmune disease (e.g. SLE, rheumatoid arthritis)
! Nephritic syndrome
! Vasculitis
o
Adverse effects (in addition to the general ones above):
! Haemorrhagic cystitis:
Due to the metabolite acrolein
Can be ameliorated by:

o
$ fluid intake
o
Mesna (a sulphydryl donor)
! Infertility in men:
Long-term use
May be irreversible
Cisplatin:
o
A platinum containing alkylating agent
o
Revolutionised the treatment of tumours of the testes / ovary
o
Adverse effects:
! Nephrotoxicity
! Very severe nausea / vomiting
! Peripheral neuropathy
! Ototoxicity
! Anaphylactoid reactions
Pyrimidine analogues:
E.g. 5-FU, cytarabine, gemcitabine
5-FU:
139
www.garrypettet.com
o
! Interferes with thymidylate synthetase (essential for
the production of thymidylic acid)
! Impairs DNA synthesis (but not RNA or protein
synthesis)
Cytarabine:
o
! Incorporated into DNA and RNA
! Inhibits DNA replication and (to a lesser extent) DNA
repair
Gemcitabine:
o
An analogue of cytarabine
o
Has fewer unwanted effects:
! Flu-like symptoms
! Mild myelotoxicity
Purine analogues:
E.g. 6-mercaptopurine (6-MP), azathioprine (a pro-drug of 6-MP)
Indications:
o
Autoimmune diseases (e.g. rheumatoid arthritis, SLE)
o
Prevention of transplant rejection
o
Steroid-sparing agent
o
6-MP is converted to a fraudulent nucleotide
o
Is incorporated into and interferes with replicating DNA
o
Also impairs the de novo pathway of purine synthesis
Adverse effects:
o
Nausea / vomiting
o
Bone marrow suppression
o
Alopecia
o
Jaundice
Interactions:
o
Allopurinol:
! Allopurinol inhibits the metabolism of azathioprine, thus $
its toxicity
Cytotoxic antibiotics:
E.g. doxorubicin
o
Inserts itself between base pairs (intercalation):
! Alters the topography of DNA
! Causes unwinding of DNA
o
Causes topoisomerase II-associated DNA strand breaks
o
Causes free-radical formation:
! Responsible for cardiac toxicity (as the heart cannot
inactivate them due to a lack of catalase activity)
Adverse effects:
o
Cardiac toxicity:
! Acute Myocarditis / pericarditis
140
www.garrypettet.com
! Late onset cardiac failure:
5% of patients after high dose therapy

Taxanes:
E.g. paclitaxel (taxol)
Derived from Yew tree bark
o
Stabilise cell microtubules (in effect freezing them)
o
Prevents spindle formation in mitotic cells and causing cell cycle
arrest in metaphase
Adverse effects:
o
Bone marrow suppression
o
Hypersensitivity:
! Must pre-treat the patient with:
Antihistamines
Corticosteroids
o
Neurotoxicity
Vinca alkaloids:
E.g. vincristine, vinblastine
Extracts of the periwinkle plant
o
Bind to tubulin and inhibit its polymerisation into
microtubules
o
This prevents spindle formation
o
Leads to cell cycle arrest in metaphase
Adverse effects:
o
Relatively non-toxic
o
Neurotoxicity:
! Paraesthesia
! Neuromuscular abnormalities
o
Fatal if given intrathecally
Hydroxyurea:
Indications:
o
Malignancy
o
Sickle cell anaemia ($ production of fetal Hb)
o
A urea analogue
o
Inhibits ribonucleotide reductase
o
Interferes wi th the conversi on of ri bonucl eoti des to
deoxyribonucleotides
Anti-malarials
Main signs / symptoms of malaria:
Flu-like symptoms:
o
Headache
o
Malaise
o
Myalgia
141
www.garrypettet.com
Fever chills
Anaemia
Jaundice
Hepatosplenomegaly
No lymphadenopathy / rash
Poor prognostic signs:
Young (< 3 years)
Pregnant
Hyperparisitaemia (> 5% of RBCs)
CNS:
o
Fits
o
Coma
Renal:
o
Blackwater fever (haemoglobinuria)
o
Oliguria
o
Acure renal failure
Hypoglycaemia (< 2.2 mmol/L)
Acidosis ($ [lactate])
Treatment of malaria:
If species unknown or mixed infection then treat as for falciparum
P. Falciparum:
o
Quinine and
o
Tetracycline or doxycycline or clindamycin
o
Alternatives:
! Malarone or
! Fansidar
Non-falciparum:
o
Chloroquine
o
Primaquine (if P.ovale / P.vivax):
! Improves liver clearance of the parasite
Prophylaxis against malaria:
Avoid getting bitten if possible
High risk of P.falciparum:

o
Mefloquine
o
Malarone
o
Doxycycline
No / low risk of P.falciparum:

o
Chloroquine and proguanil
Quinine:
Adverse effects:
o
Tinnitus
o
Nausea
Chloroquine:
Adverse effects:
o
Retinopathy
142
www.garrypettet.com
o
Psychosis
Fansidar:
Adverse effects:
o
Stevens-Johnson syndrome
o
Blood dyscrasias
o
Deranged LFTs
Primaquine:
Adverse effects:
o
Haemolytic anaemia (G6PD-deficiency)
o
Methaemoglobinaemia
Mefloquine:
Adverse effects:
o
Severe psychiatric reactions:
! More common in young women with a previous history of
psychiatric illness
Has a long t! (needs to be started 23 weeks before travelling)

143
www.garrypettet.com

Pharmacology Notes

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Pharmacology Notes

Uploaded by

Copyright:

Available Formats

Clinical Pharmacology and

Therapeutics (CPT) Revision

A biological measurement which substitutes for the therapeutic end-

Characteristics of a good surrogate:

Changes in the patients disease over time

Is the study large enough to answer the studys question?

Type 1 error (!):

Type 2 error ("):

Power = 1 - " (i.e. 80 90% usually)

3 40% of inpatient admissions

Affects 10 20% of hospital patients

Up to 30 60% are preventable

Augmented pharmacological effect

Combined oral contraceptive (COC) pill

Drugs increasing the effect of warfarin:

Drugs decreasing the effect of warfarin:

Drugs with a short t1/2 may have a long duration of action:

This is the apparent volume into which the drug is distributed

Is used to calculate the clearance of a drug

Is high for lipid-soluble drugs

Is low for water-soluble drugs

Depends on drug lipid solubility

The proportion of administered drug reaching the systemic circulation

IV drugs have 100% bioavailability

Drugs with high bioavailability:

Drugs with low bioavailability:

Also known as pre-systemic metabolism

Occurs in the liver and gut wall

Some drugs undergo extensive first-pass metabolism:

Is generally a nuisance for two reasons:

The main purpose is to increase water-solubility of the drug

Most important are the P450 enzymes

Xanthine oxidase metabolises 6-mercaptopurine

Monoamine oxidase inactivates 5-HT, NA, tyramine

In practice, a steady state concentration is effectively achieved after

Faster attainment of the steady state is achieved by starting with a

Half-lives are approximate ranges when renal impairment present

Amoxicillin (t1/2 2 14 hours):

Atenolol (t1/2 6 100 hours):

Captopril (t1/2 2 14 hours):

Probably due to a direct effect on sensory afferents

Digoxin (t1/2 36 90 hours):

Gentamicin (t1/2 2! - >50 hours):

Vitamin D has to undergo two hydroxylation reactions within the body

Kidney forms the 1-hydroxy form of vitamin D and requires the

In renal impairment, the above step may not happen

Bone di sease caused by renal di sease i s t ermed renal

A1-acidic glycoprotein deficiency:

Reduced synthesis of clotting factors:

These drugs will not be metabolised as much in liver impairment (if

Also causes a SLE-like syndrome (ssDNA Abs)

Gastroprotection (if on NSAID / long-term steroids):

Disease modifying anti-rheumatic drug (DMARD):

Steroids are controversial but useful in acute flares

Calcitonin (may be considered)

HRT no longer has role

Unclear mechanism of action

Probably similar efficacy to simple NSAIDs

Better tolerated than NSAIDs but not free of side-effects:

(Non- selectively) inhibit cyclo-oxygenase (COX)

COX converts arachidonic acid (derived from membrane phospholipids)

The endoperoxides are further converted into:

There are 2 isoforms of COX - COX-I and COX-II: