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Sympathomimetic Drugs

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

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Sympathomimetic Drugs

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  1. Sympathomimetic Drugs Dumrongsak Pekthong M.Sc.(Pharmacology)

  2. Wording • Adrenergic agonists • Adrenomimetic drugs • Adrenoceptor agonists • Sympathomimetic drugs

  3. 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

  4. Outline G. Chemistry, SAR and Pharmacokinetics H. Organ system effects I. Clinical application of sympathomimetics J. Adverse effects of sympathomimetics K. Drug interactions

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 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

  11. A. Review of Sympathetic Activation • Posterior pituitary: ADH secretion • Liver: glycogenolysis, gluconeogenesis • Pancreatic b cells ---stimulate insulin release • Skeletal muscle • contractility, glycogenolysis, K+ uptake

  12. A. Review of Sympathetic Activation • Fat cells: lipolysis • Uterus • non-pregnant: relax • Sweat gland : secretion • Hair : piloerection

  13. 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.

  14. 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

  15. 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)

  16. 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

  17. C. Types and subtypes of adrenoceptors • a1type :Phenylephrine, methoxamine • a1A, a1B a1D • a2type :Clonidine, BHT920 • a2A :Oxymetazoline • a2B , a2C

  18. 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

  19. 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

  20. 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

  21. a1-Agonist a1 Phosphatidylinositol 4, 5-diphosphate Ca 2+ Cell Membrane Gq Phospholipase C IP3 SR DAG Ca 2+ Ca 2+ -dependent protein kinase Protein kinase C

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

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

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

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

  26. Heart b1-Agonist Ca 2+ Vagus b1-receptor M Gs AC Gi kinase ATP cAMP Ca 2+ Heart rate Contraction Conduction

  27. E. Classification of Sympathomimetics • By chemistry • Catecholamines • Non-catecholamines • By mode of action • direct acting • indirect acting • By selectivity (to types of receptor)

  28. 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

  29. 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

  30. 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)

  31. 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*

  32. List of Adrenomimetic Drugs B. Selective agonists • b 1 > b 2 : Dobutamine* • b 2 > b 1 : Terbutaline*, albuterol, metaproterenol, ritodrine • Dopamine agonist: Dopamine*, bromocriptine

  33. G. Chemistry, SAR and Pharmacokinetics Chemical structure of parent compound of Catecholamines

  34. Structure-Activity Relationship (SAR) of Adrenomimetics • Responsible for • different receptor selecitvity of sympathomimetics • different distribution of drugs --> different actions • different duration

  35. 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

  36. Pharmacokinetics of sympathomimetics Drug Oral activity Duration Catecholamines Epinephrine No minutes Norepinephrine No minutes Isoproterenol Poor minutes Dopamine No minutes Dobutamine No minutes

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

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

  39. 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)

  40. 1. Vascular system effects A. a 1agonists • 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 reflexbradycardia

  41. 1. Vascular system effects B. b 2agonists • 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.

  42. 1. Vascular system effects C. a 2agonists • 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)

  43. 1. Vascular system effects D. Dopamineagonists (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

  44. 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)

  45. 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

  46. 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

  47. 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.

  48. 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

  49. 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

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