&

&

353 331 Module RS/2555

..


:
)

1, 1,

References
1. , , .
1 , 2554.
2. Katzung BG, Masters SB, Trevor AJ, eds. Basic and clinical Pharmacology 11th
ed. McGraw Hill Medica, 2009.
3. Waller DG, Renwick AG and Hillier K, eds. Medical Pharmacology and
Therapeutics 2nd ed. Edinburgh, 2005.
4. Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilmans The Pharmacological
Basis of Therapeutic 12th ed. New York: McGraw Hill.

COUGH
:

- 8
- 8
)
)


)

Cough reflex :
- Cough receptors > afferent impulses
- Cough center (medulla)- integration
- Efferent impulses > motor nerves

NTS

Cortex
Cough and respiratory
pattern generator

Vagus Nerve

Respiratory
motorneurons

Airway

Cough
Reflex

CNS

Nucleus tractus solitarius

Respiratory
muscles

COUGH

Epithelium

Drugs with proven or potential antitussive effect currently available to clinicians

Agents approved as antitussives

Centrally acting
Narcotic opioids: Codeine, hydrocodone, morphine
Non-narcotic opioids: Dextromethorphan
Older-generation antihistamines
Peripherally acting
Benzonatate
Levodropropizine
Moguisteine
Guaifenesin

Drugs approved for other indication; not approved as antitussives

Centrally acting
Amitriptyline, Baclofen
Peripherally acting
Tiotropium

Non-pharmaceutical agents with possible antitussive activity

Theobromine
Dicpinigaitis PV. Pulmonary Pharmacology & Therapeutics 22 (2009) 148-151.

Management of cough

-
)
- ) )
Drugs affecting cough
Cough suppressants (Antitussives) () :
I. Narcotic antitussives

():

Opioids : Codeine, hydrocodone

II. Non-narcotic antitussives

() :

Dextromethorphan, noscapine, diphenhydramine, benzonatate

Expectorants () :
Guaifenesin, Potassium iodide, Terpin hydrate, Ammonium chloride

Mucolytics

() :

Bromhexine, Ambroxol, Acetylcysteine

I. Narcotic antitussives
Codeine, Hydrocodone
1)
)
8
) ))

Codeine : half-life 4-6 h

Hydrocodone : half-life 3-4 h

Uses: ) ))

: - CNS depression ,
- ), ,
Antidote for overdose: Opioid antagonist; naloxone

Drug interactions:

Dextromethorphan
D-isomer

II. Non-narcotic antitussives

of Levorphanol

1 threshold 8
11

8 mucociliary clearance
)
: ) ),
,
Overdose: stupor, ataxia, euphoria

Noscapine - Opium alkaloid, no other opioid effects on CNS

-
, )
()
) histamine)

II. Non-narcotic antitussives

An antihistamine
Suppresses cough center
Anticholinergic effect

** ) ) mucus
,

II. Non-narcotic antitussives

a long chain polyglycol derivative chemically related
to procaine
Peripherally acting antitussive
- Suppresses cough reflex
(inhibits voltage-gated Na+ channels

action potential

afferent nerve conduction to medulla)

: )
- nausea, vomiting, constipation, headache,
vertigo, hypersensitivity

Uses: )
( tachyphylaxis)

Expectorants ()
Mechanism of action:
1 gastropulmonary
vagal reflex )
)88
(guaifenesin, ammonium chloride, potassium iodide)

1 ) bronchial glands secretory mucosa cells

(terpin hydrate, potassium iodide)
Clinical uses :
)

Expectorants ()
Side effects:

Guaifenesin (glyceryl guaicolate)

-
) )

Ammonium chloride
- )
- metabolic acidosis, mental confusion,
hypoK+

- ) ammonium

Expectorants ()
Side effects:

Potassium iodide
), ), 8, , metallic taste,
)

Long-term high dose iodide

iodism

, , hyperthyroidism

Terpin hydrate
)
)

Mucolytics ()
Mechanism of action:

1 ) mucopolysaccharides

8
Bromhexine, Ambroxol
Acetylcysteine, Carbocysteine,
Methylcysteine
Enzymes: Deoxyribonuclease, trypsin, chymotrysin

Bromhexine
1) lysosomal activity )
)8
Side effects: ), ,

Ambroxol
Metabolite of bromhexine

1 bromhexine 1
8
) mucus

Acetylcysteine, Carbocysteine, Methylcysteine

Side effects:

sulfhydryl ) disulfide
bonds
)

)
, ) ,
, 8 , ,
, ) )

ANTIHISTAMINES
H1-antihistamines

Histamine
)) )
basophils, mast cells, platelets,
lymphocytes histaminergic neurons
Receptor subtypes

Distribution

H1

Smooth muscle,
endothelium, brain

H2

Gastric mucosa,
cardiac muscle, brain

H3

Presynaptic: brain, myenteric

plexus

H4

Bone marrow, peripheral

hematopoietic cells

( Maintz L & Novak N. Am J Clin Nutr. 2007; 5: 1185-96)

H1-antihistamines
First-generation H1-antihistamines
(Classic,
8)
Second-generation H1-antihistamines
(Newer,
)
histamine )1)
Ketotifen

Alkylamines:

Lipophilic
Cross BBB
Half-life 4-6 hr

Brompheniramine
Chlorpheniramine
Triprolidine

Common component
of cold medication

Ethanolamines:
Dimenhydrinate
Diphenhydramine
Doxylamine

Ethylenediamines:

Marked sedation

Antazoline
Tripelennamine
Pyrilamine

Phenothiazines:
Promethazine
Trimepazine

Piperazines:
Cyclizine
Meclizine
Hydroxyzine

Piperidine:
Cyproheptadine

Used to treat
motion sickness

Lipophobicity, not cross BBB

, long duration of action
Half-life 8-24 hr
Alkylamines:
Mild sedating
effects

Acrivastine

Piperazines:
Cetirizine
Levocetirizine

Piperidines:
Loratadine
Desloratadine
Terfenadine
Fexofenadine
Astemizole
Mizolastine
Rupatadine

Major
metabolized
by liver

1st generation
non-specific, non-selective

Histamine H1-receptor
blockers

Cyproheptadine

Others

Cholinergic
(muscarinic)
receptor

-Adrenergic
receptor

Postural
hypotension
Reflex
tachycardia

Serotonin
receptor

All-H1
Antihistamine

Histamine-H1
receptor
Reversible
competitive
binding

Side effects of H1-antihistamines

8
(tinnitus) , , , )
>>> )))

ethylenediamines
)
Cyproheptadine 1

8

Anticholinergic effect

(teratogenic) hydroxyzine,

fexofenadine

Clinical uses of H1-antihistamines

) )

: 1 anticholinergic
8 )

- ) dimenhydrinate

1. Antihistamine ---

2. Terfenadine
Astemizole

Transquilizers, Hypnotics,
Antidepressants, Alcohol

CYP3A4

Active metabolites

Ketoconazole, grapefruit juice,

Erythromycin, liver disease

CARDIAC TOXICITY
QT prolongation
Torsades de points

2nd gen. Desloratadine, fexofenadine, cetirizine

)8) 8 CYP3A4
P-glycoprotein

 histamine )1)
Ketotifen
antihistamine )1 mast cell basophil
stabilizing agents
Clinical uses
1. Conjunctivitis
2. Urticaria ()
3.

()

Side effects
classic H1- antihistamine 8 )

DECONGESTANTS

(Nasal)Decongestants
) (Nasal congestion,
stuffy nose) )
)
decongestants )8
) 8

Types of decongestants
Systemic decongestants
Ex. Ephedrine
Phenylephrine
Pseudoephedrine
Topical decongestants
Ex. Ephedrine
Epinephrine
Phenylephrine
Nephazoline
Tetrahydrozoline
Xylometazoline
Oxymetazoline

Mechanism of action
11 sympathomimetic
drugs

sympathetic ) -adrenergic receptors

epinephrine, phenylephrine, xylometazoline, oxymetazoline
) norepinephrine 8 ephedrine

() )8))

Clinical uses
)) 8:
Profuse discharge from nose
Allergic rhinitis
Post nasal drip
Common cold
Sinusitis
Rhinitis

Side effects
systemic decongestants )

)

)
)

)
topical decongestants
Rebound nasal congestion

)
)

(Nasal) Decongestants
) antihistamine
topical decongestants
local effect 1

8) decongestant
sympathomimetic drugs ) dopamine, terbutaline,
isoproterenol

systemic decongestant monoamine oxidase

inhibitor (MAOI)