AUTONOMIC DRUGS: ADRENOCEPTOR AGONISTS AND SYMPATHOMIMETICS Lecture 4
Introduction (review) 5 key features of neurotransmitter function, which can be targets for pharmacotherapy Synthesis Storage Release Termination of action Receptor effects
Sympathetic agents MOA Direct acting Directly stimulate the receptor Indirect acting Displace/release stored catecholamines from the nerve (ex. tyramine) Decrease clearance of NE by Inhibiting reuptake of catecholamines (ex. cocaine and TCAs) By inhibiting NET (norepinephrine transporter) By altering NET to become a reverse transporter Preventing the metabolism of NE (ex. MAO inhibitors)
Normal activity of NET
Blockage of NET by cocaine
Blockage of and reverse transport of NET by amphetamine
MAO inhibitors
Sympathetic agents NET EFFECT = increase NE activation or supply to the receptors Binding of agonist or drug to receptors
Sympathetic agents MOA to the adrenoceptors Act on G-protein coupled receptors, which then activates the 2 nd messenger system Receptor subtypes Alpha Beta Dopamine
Adrenoceptors Receptor Alpha 1 Alpha 2 Beta 1 Beta 2 D1 D2 Location Postsynaptic effector cells, especially smooth muscle Presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscle Postsynaptic effector cells (heart, lipocytes, brain) Presynaptic adrenergic and cholinergic nerve terminals Juxtaglumerular (JG) apparatus Postsynaptic effector cells (smooth and cardiac muscles) Brain, effector tissues, kidney vascular bed Brain, effector tissues, smooth muscles
Sympathetic agents Alpha receptors alpha1 (α 1 ) alpha2 (α 2 ) Beta receptors Beta1 (β 1 ) Beta2 (β 2 ) Beta3 (β 3 ) Dopamine receptors D 1 D 2
Sympathetic agents Selective Majority of the drugs are selective (will preferentially bind to a specific receptor). But as concentration increases, the other receptors will also be stimulated. Ex. Phenylephrine is a selective α 1 agonist. If given at higher doses, it may eventually stimulate α 2 and even β receptors at toxic doses.
Alpha agonists Phenylephrine, methoxamine Clonidine Mixed alpha and beta agonists Norepinephrine Epinephrine Beta agonists Dobutamine Isoproterenol Albuterol, terbutaline Dopamine agonist (Dopamine) Relative receptor affinities α1 > α2 >>>>> β α2 > α1 >>>>> β α1 = α2; β1 >> β2 α1 = α2; β1 = β2 β1 > β2 >>>> α β1 = β2 >>>> α β2 >> β1 >>>> α D1 = D2 >> β >> α
Sympathetic agents Receptor regulation More for adrenoceptors than cholinoceptors Down regulation or desensitization There will be less response to the agonist 2 mechanisms Slow desensitization (hours to days) Decrease in receptor production (down regulation) Rapid desensitization (minutes) Decrease in function of a receptor thru phosphorylation (rapid negative-feedback effect)
Sympathetic agents Chemistry of catecholamines Basic chemistry is that of phenylethylamine
Sympathetic agents Substitution of H by OH at the 3 and 4 carbon atoms in the benzene ring will produce the group Catecholamines Epinephrine, Norepinephrine, Isoproterenol, Dopamine Further substitutions or removal of OH among the different carbon atoms will alter the characteristics of the succeeding drugs. Non-catecholamines: phenylephrine, methoxamine, ephedrine, amphetamine
Catecholamines
Non-catecholamines
Catecholamines Maximal alpha and beta activity Inactivated by COMT (catechol-omethyltransferase) Found in the gut and liver = does not allow oral administration of epi and norepi Absence of one or both OH groups on the phenyl ring susceptibility to COMT bioavailability after oral adminstration duration of action entry of drug to the CNS Ex. non-catecholamines = phenylephrine and amphetamine
Catecholamines Alterations in the amine side-chain Increasing the size of the amino group tends to increase βreceptor activity, with corresponding decreased α receptor activity (ex. NE Epi Isoproterenol)
Alpha agonists Phenylephrine, methoxamine Clonidine Mixed alpha and beta agonists NE Epi Beta agonists Dobutamine Isoproterenol Albuterol, terbutaline Dopamine agonist (Dopamine) Relative receptor affinities α1 > α2 >>>>> β α2 > α1 >>>>> β α1 = α2; β1 >> β2 α1 = α2; β1 = β2 β1 > β2 >>>> α β1 = β2 >>>> α β2 >> β1 >>>> α D1 = D2 >> β >> α
Catecholamines and noncatecholamines Alterations in the amine side-chain Substitution at the αcarbon blocks metabolism by monoamine oxidase (MAO) = duration of action Ex. Ephedrine and amphetamine
Sympathomimetic agents General Effects Cardiovascular system Compensatory reaction by the parasympathetic system Alpha1 Arterial and venous vasoconstriction Reflex response of HR Skin, nasal mucosa and GIT vessels constrict Alpha2 Mild vasoconstriction More prominent CNS effect = vasodilation and chronotropy = BP
Sympathomimetic agents General Effects Cardiovascular system Beta receptors Heart = inotropy, chronotropy, dromotropy Beta2 = vasodilation Net effect = systolic but diastolic pressure Dopamine receptors D1 = Vasodilation of renal, splanchnic (GIT), coronary, cerebral Improve perfusion to kidneys = urine output Dopamine activates beta receptors in the heart
Sympathomimetic agents Noncardiac effects Lungs = beta2 = bronchodilation Eye alpha pupillary dilation and increase outflow of aqueous humor Beta antagonism Decrease aqueous humor production Genito-urinary Alpha Increase urinary sphincter tone (improve continence) Ejaculation and detumescence
Sympathomimetic agents Noncardiac effects Fat cells Beta2 = glycogenolysis and increase insulin secretion Beta3 = lipolysis Diabetogenic Potassium Beta2 = promote uptake of potassium into cells Treatment for hyperk (salb, insulin, calcium) Renin Beta1 = increase secretion blood volume BP
Sympathomimetic agents Noncardiac effects CNS Most seen among non-catecholamines Increased alertness, attentiveness Elevation of mood, insomnia, euphoria and anorexia
Adrenoceptors - Functions Type Tissue location Action α1 Most vascular smooth muscle Contraction Pupillary dilator muscle Pilomotor smooth muscle Prostate Heart Contraction (dilates pupil) Erects hair Contraction inotropy α2 Post synaptic CNS neurons Probably multiple ( BP) Platelets Adrenergic and cholinergic nerve terminals Some vascular smooth muscle Fat cells Aggregation Inhibits transmitter release Contraction Inhibits lipolysis
Type Tissue location Action β1 Heart, juxtaglomerular cells chronotropy and inotropy renin release β2 Respiratory, uterine and vascular smooth muscle Skeletal muscle Human liver Smooth muscle relaxation β3 Fat cells lipolysis Potassium uptake Activates glycogenolysis D1 Smooth muscle Dilates renal blood vessels D2 Nerve endings Modulates transmitter release
Sympathomimetic drugs Endogenous catecholamines Epinephrine Norepinephrine Receptor activity α1 = α2; β1 = β2 α1 = α2; β1 >> β2 Dopamine D1 = D2 >> β >> α Effect Vasoconstrictor (except in muscles = vasodilation) inotropy, chronotropy in heart BP + Inotropy, chronotropy + inotropy, chronotropy Reward stimulus renal perfusion
Sympathomimetic drugs Direct Acting Phenylephrine Methoxamine Alpha2 agonists Clonidine, methyldopa Receptor activity α1 > α2 >>>>> β α1 > α2 >>>>> β α2 > α1 >>>>> β Oxymetazoline α2 >>> α1 Isoproterenol β1 = β2 >>>> α Effect Mydriasis, decongestant, slight inc in BP Vasoconstriction and vagally mediated bradycardia BP. Mild sedative Topical decongestant (constrict nasal mucosa) Vasodilator, with increase in cardiac output with a fall in diastolic pressure
Direct Acting Beta agonists Receptor activity Isoproterenol β1 = β2 >>>> α Dobutamine β1 > β2 >>>> α Effect Vasodilator, with increase in cardiac output with a fall in diastolic pressure CO with less reflex tachycardia
Sympathomimetic drugs Mixed acting Receptor activity Ephedrine β1 > β2 >>>> α Phenylpropanolam ine Cocaine α1 > α2 >>>>> β Effect Mild stimulant Appetite suppressant Affects pleasure centers
Uses Treatment of acute hypotension Fluids first before sympathomimetic agents Temporary emergency management of complete heart block Drug induced cardiac stress test (dobutamine injection) Local vasoconstriction Mucous membrane decongestants rebound hyperemia may follow.
Uses Asthma Anaphylaxis Mydriatic agent
BREAK
Adrenoceptor Antagonists Selectivity to a receptor depends on chemical structure and dose MOA Alpha blockers Reversible: ex. phentolamine, prazosin, labetalol Irreversible: covalent bond with receptor Phenoxybenzamine Beta blockers Competitive antagonists Well absorbed orally, but generally of low bioavailability Extensive 1 st pass effect in the liver Affected by Cytochrome P450 inducers and inhibitors
Adrenoceptor Antagonists Beta blockers Average half life of 3-10 hours Except esmolol = rapid effect and rapidly inactivated (10min) = good for hypertensive crisis
Adrenoceptor Antagonists Alpha antagonists Receptor Affinity Prazosin, terazosin, doxazosin α 1 >>>>α 2 Phenoxybenzamine α 1 > α 2 Phentolamine α 1 = α 2 Yohimbine, tolazoline α 2 >> α 1 Mixed antagonists Labetalol, carvedilol β 1 = β 2 α 1 > α 2 Beta antagonists Metoprolol, acebutolol, alprenolol atenolol, esmolol, nevibolol, etc. β 1 >>> β 2 Propanolol, carteolol, pindolol, timolol β 1 = β 2 Butoxamine β 2 >>> β 1
Adrenoceptor Antagonists = Opposite effect Type Tissue location Action α1 Most vascular smooth muscle Contraction Pupillary dilator muscle Pilomotor smooth muscle Prostate Heart Contraction (dilates pupil) Erects hair Contraction inotropy α2 Post synaptic CNS neurons Probably multiple ( BP) Platelets Adrenergic and cholinergic nerve terminals Some vascular smooth muscle Fat cells Aggregation Inhibits transmitter release Contraction Inhibits lipolysis
Adrenoceptor Antagonists = Opposite effect Type Tissue location Action β1 Heart, juxtaglomerular cells chronotropy and inotropy renin release β2 Respiratory, uterine and vascular smooth muscle Skeletal muscle Human liver Smooth muscle relaxation β3 Fat cells lipolysis Potassium uptake Activates glycogenolysis D1 Smooth muscle Dilates renal blood vessels D2 Nerve endings Modulates transmitter release
Alpha Antagonists Phenoxybenzamine Irreversible alpha blocker Also blocks histamine, Ach, and 5HT receptors Reduces blood pressure when sympathetic tone is high useful for pheochromocytoma ADR orthostatic hypotension and tachycardia Nasal congestion and inhibition of ejaculation
Alpha Antagonists Phentolamine Competitive blocker of α1 and α2 Vasodilation with direct and reflex tachycardia (due to antagonism to α2 receptors) ADR: tachycardia, arrythmia Used for tx of pheochromocytoma
Alpha Antagonists Prazosin, Terazosin and Doxazosin α1 blocker Vasodilation with minimal effect on the heart Relaxes prostate muscle (useful for BPH) Half life Half life (hours) Prazosin 3 Terazosin 9-12 Doxazosin 22
Beta Antagonists Propanolol Non-selective beta blocker Decreased chronotropy and inotropy Mild bronchoconstriction Metoprolol, atenolol Selective beta1 blocker Decreased chronotropy and inotropy Mild hypoglycemia and vasodilation
Beta Antagonist Nebivolol Most selective beta1 inhibitor Esmolol Ultra short acting beta1 selective antagonist Treatment for arrythmias, perioperative hypertension and myocardial ischemia
Mixed Antagonists Labetalol and carvedilol β 1 = β 2 α 1 > α 2 Decreased blood pressure, but with less reflex tachycardia due to low alpha antagonism
Uses Alpha blockers Treatment for Pheochromocytoma Urinary obstruction and BPH Other uses (not drug of choice) Hypertensive emergencies Chronic hypertension Peripheral vascular disease Erectile dysfunction
Uses Beta blockers Treatment for Angina and following myocardial infarction Decrease work load and oxygen demand of heart Heart arrythmias Regulate heart rate and heart conduction speed Chronic heart failure Decrease cardiac remodeling Glaucoma Hypertension Especially for patient with uncontrolled diabetes In combination with a diuretic and a peripheral vasodilator
Uses Beta blockers Treatment for Hyperthyroidism (for Propanolol) Sympathetic antagonism and decreased peripheral conversion of T4 to T3 (more active to less active)
Precautions Beta blockers Hypercholesterolemia May increase LDL and decrease HDL Congestive heart failure? Beta2 blockers Patients with asthma Use another anti-hypertensive drug Patients with diabetes and inadequate glucose reserves Inhibits lipolysis and glycogenolysis = available blood glucose = may promote hypoglycemia