Sympathomimetic Drugs Dumrongsak Pekthong M.Sc.(Pharmacology)

Wording Adrenergic agonists Adrenomimetic drugs Adrenoceptor agonists Sympathomimetic drugs

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 a1 or a2 type and b1 or b2 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, Lippincott’s 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 b 1 , b 2 , b 3 DA1, DA2

C. Types and subtypes of adrenoceptors a1 type :Phenylephrine, methoxamine a1A, a1B a1D a2 type :Clonidine, BHT920 a2A :Oxymetazoline a2B , a2C

C. Types and subtypes of adrenoceptors b type :Isoproterenol b1 :Dobutamine b2 :Procaterol, terbutaline b3 :BRL37344 Peripheral Dopamine (DA) type :Dopamine DA1 :Fenoldopam DA2 :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+ -dependent protein kinase Phosphatidylinositol 4, 5-diphosphate a1 -Agonist Ca 2+ a1 Cell Membrane Gq Phospholipase C IP3 SR DAG Ca 2+ Ca 2+ -dependent protein kinase Protein kinase C

AC Gi ATP cAMP a2 - Agonist a2 Cell Membrane Enzyme-PO4 No biological effect Enzyme-PO4 AC= Adenylyl cyclase

AC Gs ATP cAMP Cell Membrane Enzyme-PO4 Biological effect b -Agonist b - receptor Gs AC ATP cAMP Enzyme-PO4 AC= Adenylyl cyclase Biological effect

Mech. of action of Dopamine DA1 type cAMP DA2 type Central Dopamine Receptor -different effect D1-like: D1A, D1B, D5 D2-like: D2, D3, D4

Vascular smooth muscle Myosin-LC kinase (MLCK) Ca2+ channels Ca2+ (intracellular) ATP Calmodulin b 2 agonists Ca2+ -calmodulin complex cAMP Proteinkinase A MLCK* Myosin-LC kinase (MLCK) MLCK-(PO4)2 Myosin light chain (Myosin-LC) Myosin-LC- PO4 Myosin-LC Actin Contraction Relaxation

Heart Ca 2+ AC Gi M Gs ATP Ca 2+ Vagus kinase cAMP b1-Agonist b1-receptor M Gs AC Gi kinase ATP cAMP 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 II. Indirect 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 : Phenylephrine*, methoxamine, metaraminol, midodrine a 2 > a 1 :Clonidine*, methylnorepinephrine, 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 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 Oral activity Duration Catecholamines Epinephrine No minutes Norepinephrine No minutes Isoproterenol Poor minutes Dopamine No minutes Dobutamine No minutes

Pharmacokinetics of sympathomimetics Other sympathomimetics Drug Oral activity Duration Amphetamine, Yes Hours Ephedrine Yes Hours Phenylephrine Poor Hours Albuterol, Yes Hours metaproterenol, terbutaline

Pharmacokinetics of sympathomimetics Other sympathomimetics Drug Oral activity Duration Oxymetazoline, Yes Hours xylometazoline Cocaine No Minutes to Hours

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 (cont’d) 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 (cont’d) 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: contract(a 1 ), relax (b 2)

8. Metabolic and hormonal effects Kidney renin release (b 1) Pancreatic b cells inhibit insulin release (a 2 ) stimulate insuline release (b 2) 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 1) hypotension, during spinal anesthesia (a 1) : NE congestion (a 2) : oxymetazoline

1. Cardiovascular application (cont’d) Shock due to septicemia or myocardial infarction is usually made worse by vasoconstrictors chronic orthostatic hypotension due to inadequate sympathetic tone: midodrine (a 1) C. Cardiac application paroxysmal atrial tachycardia (a 1) complete heart block or cardiac arrest (b 1) : Epi or Iso

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 ?

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