Sympathomimetic Drugs

Dumrongsak Pekthong M.Sc.(Pharmacology)

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.

A. Review of Sympathetic Activation

Fight or Flight on Stress Heart
HR, contractility, conduction velocity

Vessels (arterioles)
Skin, cutaneous, visceral : constrict Skeletal muscle, coronary: dilate

A. Review of Sympathetic Activation

Vessels (Vein): constrict Eye
Radial muscle, iris: contract Ciliary muscle: relax for far vision

Lung
Tracheal and bronchial muscle: relax

A. Review of Sympathetic Activation

Stomach and intestine
Motility and tone Sphincters : contraction Secretion (intestine): inhibition

Urinary bladder
Detrusor or bladder wall: relax Trigone, sphincter: constrict

A. Review of Sympathetic Activation

Posterior pituitary: ADH secretion Liver: glycogenolysis, gluconeogenesis Pancreatic b cells
---stimulate insulin release

Skeletal muscle
contractility, glycogenolysis, K+ uptake

A. Review of Sympathetic Activation

Fat cells: lipolysis Uterus
non-pregnant: relax

Sweat gland : secretion Hair : piloerection

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.

C. Types and subtypes of adrenoceptors

Adrenergic receptors locate on smooth muscle, cardiac muscle, exocrine glands, endocrine glands and on nerve terminals. the transmitter in all adrenergic neurons was NE When NE and Epi interacted with an adrenoceptor, in some tissues the response was excitatory while in other tissues it was inhibitory

C. Types and subtypes of adrenoceptors

Two subtypes of adrenoceptors (a and b)
a - excitatory in most tissues (except - intestinal smooth muscle) b - inhibitory in most tissues (except - heart)

C. Types and subtypes of adrenoceptors

Rank Order of Potency
1. a receptors Epi > NE >> Iso
2. b receptors Iso > Epi > NE

Type of adrenoceptor

a 1,a 2

b1,b2 , b3
DA1, DA2

C. Types and subtypes of adrenoceptors

a1
type :Phenylephrine, methoxamine

a1A, a1B a1D

a2

type

:Clonidine, BHT920

a2A a2B , a2C

:Oxymetazoline

C. Types and subtypes of adrenoceptors

b type :Isoproterenol
b1 b2 b3 :Dobutamine :Procaterol, terbutaline :BRL37344
:Dopamine

Peripheral Dopamine (DA) type

DA1 DA2 :Fenoldopam :Bromocriptine

C. Types and subtypes of adrenoceptors

Generally
a 1 ---Contraction of smooth muscle b 2 ---Relaxation of smooth muscle b 1 ---Stimulation in heart a 2 ---Inhibition, for GI tract ---Relaxation

D. Mech. of action of Adrenomimetic drugs

a 1 via coupling protein Gq

a 2 via coupling protein Gi b 1, b 2 , b 3 via coupling protein Gs

Ca 2+ Cell Membrane

Phosphatidylinositol a1 -Agonist 4, 5-diphosphate

a1

Gq
IP
3

Phospholipase C

SR
Ca 2+

DAG

Ca 2+ -dependent protein kinase

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

Mech. of action of Dopamine

DA1 type
cAMP

DA2 type
cAMP
D1A, D1B, D5 D2, D3, D4

Central Dopamine Receptor -different effect

D1-like: D2-like:

Ca2+ channels

Vascular smooth muscle

Ca2+ (intracellular) Calmodulin Ca2+ -calmodulin complex

MLCK*
Myosin light chain (Myosin-LC) Myosin-LC kinase (MLCK)

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

By selectivity (to types of receptor)

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

II. Indirect acting

cause the release of stored catecholamines inhibit reuptake of catecholamines by nerve terminals (uptake 1) increase transmitter in synapse

List of Adrenomimetic Drugs

A. General agonists
Direct (a 1 , a 2 , b 1 , b 2 ) : Epinephrine*, Ephedrine Indirect, releasers: : Tyramine*, Amphetamine, Ephedrine Indirect, uptake inhibitors : Cocaine*, Tricyclic antidepressants (TCAs)

List of Adrenomimetic Drugs

B. Selective agonists

a 1 , a 2 , b 1 : Norepinephrine*
a 1 > a 2 : a 2 > a 1
:Clonidine*, methylnorepinephrine,

Phenylephrine*, methoxamine, metaraminol, midodrine

apraclonidine, brimonidine

b 1 = b 2 : Isoproterenol*

List of Adrenomimetic Drugs

B. Selective agonists
b 1 > b 2 : Dobutamine*

b 2 > b 1 : Terbutaline*, albuterol,

metaproterenol, ritodrine

Dopamine agonist: Dopamine*, bromocriptine

G. Chemistry, SAR and Pharmacokinetics

OH (para) OH (meta) Catechol

C C N

b
a

Ethylamine

Chemical structure of parent compound of Catecholamines

Structure-Activity Relationship (SAR) of Adrenomimetics Responsible for

different receptor selecitvity of sympathomimetics different distribution of drugs --> different actions

different duration

Pharmacokinetic differences between CAs and NonCAs

Catecholamines
cannot be given orally short half-life, short duration not cross blood-brain barrier (BBB)

reasons: due to having catechol group

Rapid destruction by MAO and COMT
MAO, COMT locate at gut wall, liver High polarity

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,

Oral activity Yes

Duration Hours

Ephedrine
Phenylephrine

Yes
Poor

Hours
Hours

Albuterol,

Yes

Hours

metaproterenol, terbutaline

Pharmacokinetics of sympathomimetics
Other sympathomimetics

Drug Oxymetazoline,

Oral activity Yes No

Duration Hours Minutes to Hours

xylometazoline
Cocaine

H. Organ System Effects

1. Vascular system

2. Heart
3. Net cardiovascular actions 4. Bronchi 5. Eye 6. Gastrointestinal tract (GI tract)

7. Genitourinary tract (GTU tract)

8. Metabolic and hormonal effects 9. Central nervous system (CNS)

1. Vascular system effects

A. a 1 agonists
eg, phenylephrine (pure alpha agonist)
constrict skin, cutaneous, visceral(splanchnic), pulmonary, renal blood vessels constrict veins consequently a rise in BP and an increase in peripheral vascular resistance (PVR or TPR) Often evoke a compensatory reflex bradycardia

1. Vascular system effects

B. b 2 agonists
eg, terbutaline (pure beta agonist) dilate arterioles in skeletal muscle, coronary arteries consequently reduce PVR and BP.

[Voluntary muscle ----> tremor (b 2)]

Low dose of Epi: Beta2 activation is dominant.

1. Vascular system effects

C. a 2 agonists
eg, clonidine (antihypertensive drugs) when given orally, reduce sympathetic outflow from CNS and consequently decrease BP cause vasocontriction when given IV or topically (nasal spray)

1. Vascular system effects

D. Dopamine agonists (eg, dopamine)
DA1 receptor locate at smooth muscle of renal,
coronary, cerebral, mesenteric arteries
relaxation tubule of kidney inhibit Na+/K+ ATPase pump --> natriuresis, diuresis

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)

Distribution and Effect of Peripheral Dopamine DA2 Receptor

DA2 group
: locate at presynaptic adrenergic nerve

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

3. Net cardiovascular actions

a and b 1 agonists
eg, norepinephrine may cause a reflex increase in vagal outflow (due to BP increase) --> reflex bradycardia This reflex often dominates any direct beta effects on the heart rate.

3. Net cardiovascular actions

a and b 1 agonists (contd)
If reflex is blocked (eg, by ganglion blockers), NE can cause tachycardia (b 1 ) Pure alpha agonists eg, phenylephrine

will routinely slow heart rate via the baroreceptor reflex

3. Net cardiovascular actions

Pure beta agonists eg, isoproterenol almost always increases the heart rate Net effect on Blood Pressure Diastolic blood pressure (DBP) is affected mainly by PVR and HR

Alpha and b 1 receptors have the greatest effects on PVR

3. Net cardiovascular actions

Net effect on Blood Pressure (contd)

Systolic blood pressure (SBP) = DBP + pulse pressure (PP)

Pulse pressure is determined mainly by stroke volume (SV), which is influenced by b 1 receptors (and venous return) Cardiac output (CO) = HR x SV So, alpha and beta selectivity determine SBP, DBP and PP

Effect of NE to intact CVS

Mean arterial pressure (MAP) = DBP + 1/3 of (SBP-DBP)

a 1 ,a 2 ,b 1

Effect of Epi to intact CVS

a 1 ,a 2 ,b 1,b
2

Effect of Iso to intact CVS

b 1,b 2

Effect of DA to intact CVS

DA1, Beta1 Moderate Dose

Effect of Catecholamines to intact CVS

4. Respiratory System
b 2 agonists
eg, terbutaline
produce relaxation of tracheal and bronchial muscle

5. Eye
Radial muscle, iris (pupillary dilator)

contraction (a 1) --> mydriasis

topical phenylephrine and similar alpha agonists accommodation is not significantly affected outflow of aqueous humor may be facilitated

--> reduce intraocular pressure (IOP)

Ciliary muscle: relaxation for far vision (b 2)

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

8. Metabolic and hormonal effects

Kidney
renin release

Pancreatic

b cells

(b 1)

(a 2 ) stimulate insuline release (b 2)

inhibit insulin release Glycogenolysis in liver and skeletal
muscle

(b 2)

8. Metabolic and hormonal effects

Glucose out of liver associated with initially hyperkalemia, then transport into skeletal muscle resulting in a later hyperkalemia. Lipolysis (b 3) : break down of triglycerides (TGs) into free fatty acids(FFAs) --> increase lactate from lipid metabolism

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

I. Clinical Application of Sympathomimetics

1. Cardiovascular system 2. Respiratory system 3. Anaphylaxis 4. Eye 5. Genitourinary tract 6. CNS 7. Additional uses

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

B. Reduce blood flow and increase BP

Surgery : prolong action of local anesthetics (a hypotension, during spinal anesthesia (a 1) : NE congestion (a 2) : oxymetazoline
1)

1. Cardiovascular application (contd)

Shock due to septicemia or myocardial infarction is usually made worse by vasoconstrictors chronic orthostatic hypotension due to

inadequate sympathetic tone: midodrine (a 1)

paroxysmal atrial tachycardia (a 1) complete heart block or cardiac arrest (b 1) : Epi or Iso

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

5. Genitourinary Tract Application

Beta2 agonists (ritodrine, terbutaline) used in premature labor, but cardiac stimulant effect may be hazardous to both mother and fetus. Ephedrine (long-acting) : sometimes used to improve urinary continence in children with enuresis and in the elderly (contract trigone, prostate of bladder)

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

menopausal hot flushes

narcotics, alcohol, smoking withdrawal

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

a 1 agonists: hypertension, bradycardia (reflex)

b 1 agonists: palpitation, sinus tachycardia, serious arrhythmias b 2 agonists: skeletal muscle tremor

J. ADRs of Sympathomimetics
No drug are perfectly selective; at high dose, selectivity will decrease.
Cocaine:

special importance: drug of abuse

cardiac arrhythmias or infarction and convulsions

K. Drug interaction
Tyramine --MAO inhibitors
tyramine not a drug, found in many foods

tyramine is rapidly metabolized by MAO.

MAO inhibitors increase the stores of catecholamines in vesicles.

Tyramine is a releaser of catecholamines may occur hypertensive crisis due to massive levels of NE

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

Can you predict the resulting effects ?

Thank you for your attention