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 Indirect 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) MAO – mono-amine oxidase

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 2nd messenger system Receptor subtypes Alpha Beta Dopamine

Adrenoceptors Receptor Location Alpha 1 Postsynaptic effector cells, especially smooth muscle Alpha 2 Presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscle Beta 1 Postsynaptic effector cells (heart, lipocytes, brain) Presynaptic adrenergic and cholinergic nerve terminals Juxtaglumerular (JG) apparatus Beta 2 Postsynaptic effector cells (smooth and cardiac muscles) D1 Brain, effector tissues, kidney vascular bed D2 Brain, effector tissues, smooth muscles

Sympathetic agents Alpha receptors Beta receptors Dopamine receptors

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 α1 agonist. If given at higher doses, it may eventually stimulate α2 and even β receptors at toxic doses.

Relative receptor affinities Alpha agonists Phenylephrine, methoxamine α1 > α2 >>>>> β Clonidine α2 > α1 >>>>> β Mixed alpha and beta agonists Norepinephrine α1 = α2; β1 >> β2 Epinephrine α1 = α2; β1 = β2 Beta agonists Dobutamine β1 > β2 >>>> α Isoproterenol β1 = β2 >>>> α Albuterol, terbutaline β2 >> β1 >>>> α Dopamine agonist (Dopamine) 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 Benzene ring + ethylamine side chain

Sympathetic agents Substitution of H by OH at the 3 and 4 carbon atoms in the benzene ring will produce the group Catechol- amines 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-O- methyltransferase) 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)

Relative receptor affinities Alpha agonists Phenylephrine, methoxamine α1 > α2 >>>>> β Clonidine α2 > α1 >>>>> β Mixed alpha and beta agonists NE α1 = α2; β1 >> β2 Epi α1 = α2; β1 = β2 Beta agonists Dobutamine β1 > β2 >>>> α Isoproterenol β1 = β2 >>>> α Albuterol, terbutaline β2 >> β1 >>>> α Dopamine agonist (Dopamine) D1 = D2 >> β >> α

Catecholamines and non-catecholamines Alterations in the amine side-chain Substitution at the αcarbon  blocks metabolism by monoamine oxidase (MAO) =  duration of action Ex. Ephedrine and amphetamine

MAO metabolizes 5HT and NE into inactive metabolites. MAOI = inhibits destruction of serotonin and NE  increasing 5HT and NE stores.

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 Dromotropy = AV conduction speed is increased

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 Contraction (dilates pupil) Pilomotor smooth muscle Erects hair Prostate Heart inotropy α2 Post synaptic CNS neurons Probably multiple (BP) Platelets Aggregation Adrenergic and cholinergic nerve terminals Inhibits transmitter release Some vascular smooth muscle Fat cells Inhibits lipolysis Dromotropy = passing thru AV node. Faster or shorter duration.

Type Tissue location Action β1 Heart, juxtaglomerular cells chronotropy and inotropy renin release β2 Respiratory, uterine and vascular smooth muscle Smooth muscle relaxation Skeletal muscle Potassium uptake Human liver Activates glycogenolysis β3 Fat cells lipolysis D1 Smooth muscle Dilates renal blood vessels D2 Nerve endings Modulates transmitter release

Sympathomimetic drugs Endogenous catecholamines Receptor activity Effect Epinephrine α1 = α2; β1 = β2 Vasoconstrictor (except in muscles = vasodilation) inotropy, chronotropy in heart Norepinephrine α1 = α2; β1 >> β2 BP + Inotropy, chronotropy Dopamine D1 = D2 >> β >> α + inotropy, chronotropy Reward stimulus renal perfusion

Sympathomimetic drugs Direct Acting Receptor activity Effect Phenylephrine α1 > α2 >>>>> β Mydriasis, decongestant, slight inc in BP Methoxamine Vasoconstriction and vagally mediated bradycardia Alpha2 agonists Clonidine, methyldopa α2 > α1 >>>>> β BP. Mild sedative Oxymetazoline α2 >>> α1 Topical decongestant (constrict nasal mucosa) Isoproterenol β1 = β2 >>>> α Vasodilator, with increase in cardiac output with a fall in diastolic pressure

Direct Acting Receptor activity Effect Beta agonists Isoproterenol β1 = β2 >>>> α Vasodilator, with increase in cardiac output with a fall in diastolic pressure Dobutamine β1 > β2 >>>> α CO with less reflex tachycardia

Sympathomimetic drugs Mixed acting Receptor activity Effect Ephedrine β1 > β2 >>>> α Mild stimulant Phenylpropanolamine α1 > α2 >>>>> β Appetite suppressant Cocaine 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 1st 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 Receptor Affinity Alpha antagonists Prazosin, terazosin, doxazosin α1 >>>>α2 Phenoxybenzamine α1 > α2 Phentolamine α1 = α2 Yohimbine, tolazoline α2 >> α1 Mixed antagonists Labetalol, carvedilol β1 = β2 ≥ α1 > α2 Beta antagonists Metoprolol, acebutolol, alprenolol atenolol, esmolol, nevibolol, etc. β1 >>> β2 Propanolol, carteolol, pindolol, timolol β1 = β2 Butoxamine β2 >>> β1

Adrenoceptor Antagonists = Opposite effect Type Tissue location Action α1 Most vascular smooth muscle Contraction Pupillary dilator muscle Contraction (dilates pupil) Pilomotor smooth muscle Erects hair Prostate Heart inotropy α2 Post synaptic CNS neurons Probably multiple (BP) Platelets Aggregation Adrenergic and cholinergic nerve terminals Inhibits transmitter release Some vascular smooth muscle Fat cells Inhibits lipolysis Dromotropy = passing thru AV node. Faster or shorter duration.

Adrenoceptor Antagonists = Opposite effect Type Tissue location Action β1 Heart, juxtaglomerular cells chronotropy and inotropy renin release β2 Respiratory, uterine and vascular smooth muscle Smooth muscle relaxation Skeletal muscle Potassium uptake Human liver Activates glycogenolysis β3 Fat cells lipolysis 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 Metoprolol, atenolol Non-selective beta blocker Decreased chronotropy and inotropy Mild bronchoconstriction Metoprolol, atenolol Selective beta1 blocker Mild hypoglycemia and vasodilation

Beta Antagonist Nebivolol Esmolol Most selective beta1 inhibitor Ultra short acting beta1 selective antagonist Treatment for arrythmias, perioperative hypertension and myocardial ischemia

Mixed Antagonists Labetalol and carvedilol β1 = β2 ≥ α1 > α2 Decreased blood pressure, but with less reflex tachycardia due to low alpha antagonism

Uses – Alpha blockers Treatment for Other uses (not drug of choice) 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 Beta2 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