Wording
Sympathomimetic drugs Adrenomimetic drugs Adrenergic agonists Adrenoceptor agonists
Outline
A. Review of sympathetic activation B. Introduction C. Types and subtypes of adrenoceptors D. Mechanism of action E. Classification of sympathomimetic drugs F. Mode of action
Outline
G. Chemistry, SAR and Pharmacokinetics H. Organ system effects I. Clinical application of sympathomimetics J. Adverse effects of sympathomimetics K. Drug interactions
Objectives
1. List tissues that contain sig. No. of alpha receptors of the a 1 or a 2 type and b 1 or b 2 receptors. 2. Describe the major organ system effects of a pure alpha agonist, a pure beta agonist, and a mixed alpha and beta agonist. Give examples of each type of drug.
Objectives
3. Describe a clinical situation in which the effects of an indirect sympathomimetic would differ from those of a direct agonist. 4. List the major clinical applications of the adrenoceptor agonists.
Suggested Reading
Katzung BG. Basic & clinical pharmacology. 8th ed., 2001. Katzung BG, Trevor AJ. Examination &board review pharmacology. 5th ed. 1998. Goodman&Gilman. Basic pharmacology. 9th ed., 1996. Pharmacology, Lippincotts Illustrated Reviews 1992.
Vessels (arterioles)
Skin, cutaneous, visceral : constrict Skeletal muscle, coronary: dilate
Lung
Tracheal and bronchial muscle: relax
Urinary bladder
Detrusor or bladder wall: relax Trigone, sphincter: constrict
Skeletal muscle
contractility, glycogenolysis, K+ uptake
B. Introduction
The effects of adrenomimetic drugs are similar to sympathetic activation. But why each adrenomimetic drug can produce different responses? The differences in affinity to adrenoceptor subtypes are responsible for different responses.
Type of adrenoceptor
a 1,a 2
b1,b2 , b3
DA1, DA2
a2
type
:Clonidine, BHT920
:Oxymetazoline
Ca 2+ Cell Membrane
a1
Gq
IP
3
Phospholipase C
SR
Ca 2+
DAG
Protein kinase C
a2 - Agonist
a2
Cell Membrane
AC
ATP cAMP
Gi
Enzyme-PO4
AC= Adenylyl cyclase
No biological effect
b -Agonist
b - receptor
Gs
AC
ATP cAMP
Cell Membrane
Enzyme-PO4
AC= Adenylyl cyclase
Biological effect
DA2 type
cAMP
D1A, D1B, D5 D2, D3, D4
Ca2+ channels
ATP
b 2 agonists
cAMP
Proteinkinase A MLCK-(PO4)2
Myosin-LC- PO4
Myosin-LC Relaxation
Actin Contraction
b1-Agonist
Ca Vagus 2+
M Gs
Heart
b1-receptor
AC
Gi
kinase cAMP
ATP Ca
2+ Heart rate
Contraction Conduction
E. Classification of Sympathomimetics
By chemistry
Catecholamines Non-catecholamines
By mode of action
direct acting indirect acting
E. Classification of Sympathomimetics
I. Catecholamines (CAs) II. Non-catecholamines A. Direct acting
classified by alpha, beta receptor subtypes
a 1 -selective, a 2 -selective, nonselective b 1 -selective, b 2 -selective , nonselective
B. Indirect acting
-Releasers - Reuptake inhibitors
F. Mode of action
I. Direct acting
bind to receptor directly
a 1 , a 2 , b 1 : Norepinephrine*
a 1 > a 2 : a 2 > a 1
:Clonidine*, methylnorepinephrine,
apraclonidine, brimonidine
b 1 = b 2 : Isoproterenol*
C C N
b
a
Ethylamine
different duration
Catecholamines
cannot be given orally short half-life, short duration not cross blood-brain barrier (BBB)
Pharmacokinetics of sympathomimetics
Drug
Catecholamines
Oral activity
No
Duration
minutes
Epinephrine
Norepinephrine
Isoproterenol
No
Poor
minutes
minutes
Dopamine
Dobutamine
No
No
minutes
minutes
Pharmacokinetics of sympathomimetics
Other sympathomimetics
Drug Amphetamine,
Duration Hours
Ephedrine
Phenylephrine
Yes
Poor
Hours
Hours
Albuterol,
Yes
Hours
metaproterenol, terbutaline
Pharmacokinetics of sympathomimetics
Other sympathomimetics
Drug Oxymetazoline,
xylometazoline
Cocaine
2. Heart
3. Net cardiovascular actions 4. Bronchi 5. Eye 6. Gastrointestinal tract (GI tract)
Dopamine
Low dose (0.5-2 mcg/kg/min): activate Dopamine receptors
Intermediate dose(2-10): activate Beta receptors High dose(>10): activate Alpha receptor Very useful in treatment of renal failure associated with shock (low to moderate dose)
endings, sympathetic ganglia --inh NE release : adrenal cortex ---inh AII-mediated aldosterone secretion : pituitary gland---inh prolactin release : emetic center of medulla---emesis
2. Cardiac effects
b agonists
eg, isoproterenol predominantly b 1 receptor(also b 2 ) activation of which produces an increase in
the rate of cardiac pacemakers (normal and abnormal) force of contractions AV node conduction velocity
a 1 ,a 2 ,b 1
a 1 ,a 2 ,b 1,b
2
b 1,b 2
4. Respiratory System
b 2 agonists
eg, terbutaline
produce relaxation of tracheal and bronchial muscle
5. Eye
Radial muscle, iris (pupillary dilator)
6. Gastrointestinal tract
alpha and beta receptors locate on smooth muscle and on neurons of enteric nervous system
Stomach and intestine Motility and tone: (a 2 ,b 2) Sphincters : contraction (a 1) Secretion (intestine): inhibition (a 2)
: inhibit salt and water secretion
7. Genitourinary tract
Urinary bladder Detrusor or bladder wall: relax (b 2) Trigone, sphincter, prostate gland: constrict (a 1 ) Uterus non-pregnant: relax (b 2) pregnant: 2) contract(a 1 ), relax (b
Pancreatic
b cells
(b 1)
(b 2)
9. CNS effects
Catecholamines do not produce CNS effects eg, Amphetamine have stimulant effects on CNS Beginning with mild alerting or reduction of fatigue Progressing to anorexia, euphoria, and insomnia CNS effects probably represent the release of dopamine in certain dopaminergic tracts Very high doses lead to marked anxiety or aggressiveness, paranoid, and sometimes convulsions
1. Cardiovascular application
A. Increase blood flow acute heart failure (b 1), decrease PVR through partial b 2 effect: Dobutamine
cardiogenic shock from MI, CHF or septic shock : Dopamine
C. Cardiac application
2. Respiratory application
Especially selective b 2 agonists are drug of choice in treatment of acute asthmatic bronchoconstriction (Epi and Iso also) Emphysema, bronchitis
3. Anaphylaxis
Epinephrine is drug of choice for immediate treatment of anaphylactic shock (a 1 ,b 1, b 2) sometimes supplemented with antihistamines and corticosteroids
4. Ophthalmic Application
Alpha agonists, especially phenylephrine, often used topically to produce mydriasis, eg, ophthalmologic exam reduce the conjunctival itching and congestion caused by irritation or allergy do not cause cycloplegia (paralysis of accommodation)
Epi and prodrug, dipivefrin, sometimes used for glaucoma. Phenylephrine also
6. CNS Application
Amphetamine: widely used and abused Legitimate indication: narcolepsy, attention deficit hyperkinetic syndrome, weight reduction Metabolism effect (b 2, b 3 ) and anorexant effect Misuse or abuse for deferring sleep, for mood-elevating, euphoria-producing action
7. Additional uses
Central a 2 agonists
hypertension
J. ADRs of Sympathomimetics
Catecholamines little CNS toxicity high dose: excessive vasoconstriction, cardiac arrhythmias, MI, pulmonary edema or hemorrhage, tissue necrosis. Other sympathomimetics Phenylisopropylamines mild to severe CNS toxicity depending on dosage small dose: nervousness, anorexia, insomnia
J. ADRs of Sympathomimetics
Phenylpropylamines (PPA) higher dose: anxiety, aggressiveness, paranoid, convulsion Peripherally acting agents: predictable toxicity
J. ADRs of Sympathomimetics
No drug are perfectly selective; at high dose, selectivity will decrease.
Cocaine:
K. Drug interaction
Tyramine --MAO inhibitors
tyramine not a drug, found in many foods
K. Drug interaction
Reuptake inhibitors -- Direct acting sympathomimetics eg, Cocaine vs NE when cocaine is given before NE -- intensify the effects of NE Epinephrine reversal Beta blockers -- Sympathomimetics