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Home , Adrenergic antagonist

antagonist

OBJECTIVES:

• Describe the different classifications for that can block sympathetic nervous system. •Describe the kinetics, dynamics, uses and side effects of alpha adrenergic drugs. • Identify Difference between selective and non selective alpha blockers. • Know the difference between and other selective alpha blockers. •Identify the different classifications for beta receptors blockers. •Describe the kinetics, dynamics, uses and side effects of beta adrenergic drugs. •Know the preferable for diseases as , glaucoma, arrythmia, , anxiety, migraine and ect….

• Important. • Extra notes Adrenergic receptors It’s a recall, if you know it you can skip it!

Adrenergic receptors

Dopaminergic adrenoceptors adrenoceptors α− β− receptors

β3 α1 α2 β1 β2 e.g. D1

α1 β2 β1 β3 Post-synaptic excitatory in function (cause inhibitory in function excitatory in In adipose contraction) except in GIT. (cause relaxation) function, present tissue mainly in Present mainly in smooth muscles. Contraction of pregnant Relaxation of the uterus ↑ heart rate: ↑ lipolysis uterus. (Delay premature labor) + chronotropic ↑ free fatty effect, of skin & Relaxation of skeletal & acids. Tachycardia peripheral blood vessels coronary blood vessels →increased peripheral (vasodilatation) ↑ force of → resistance hypertension. contraction : Relaxation of GIT muscles & urinary bladder’s muscles. + inotropic effect Contraction of GIT sphincter (constipation) & urinary bladder’s sphincter (urinary retention). ↑ conduction velocity: Contraction of radial muscle • Relaxation of bronchial + dromotropic of eye causes active smooth muscles effect mydriasis • Tremor of skeletal muscles • ↑ lipolysis ↑ Increase blood glucose level () , by: ↑ renin release • !insulin •↑ glucagon release from Renin is an • ↑ glycogenolysis pancreas involved in the •↑ liver & muscle glycogenolysis production of angiotensin II, a potent α2 vasoconstrictor.β2

Pre-synaptic Inhibition of release Increase release of NE (negative feed back mechanism). (Positive feed back mechanism). Classification of adrenergic drugs

Adrenergic drugs

Adrenergic Adrenergic Depressants stimulants (ADRENOLYTIC) sympathomimetic s

Adrenergic Neuron Adrenoceptor Blockers Blockers () (Adrenolytic)

Alpha & beta- Alpha-adrenergic Beta-adrenergic blockers receptor blockers receptor blockers

1. Formation of False transmitters (alpha-2 ): α- (a-methyl tyrosine( -False: Means released instead of NE (norepinephrine). -Acts centrally as α2 receptor agonist to inhibit NE release. -DRUG OF CHOICE in pregnancy hypertension (pre-eclampsia - gestational hypertension). 2. Deplete storage: - (not used anymore(. 3. Inhibition of release & enhance uptake: -Gaunethidine (not used anymore). 4. Stimulation of presynaptic α2 receptors: - & α- Methyldopa Note that Clonidine acts like α- Methyldopa as in pregnancy, but it has a limited use due to it’s rebound hypertension (withdrawal symptoms after you stop or decrease the drug dose)

Apraclonidine (A derivative that doesn't affect blood pressure – used topically as eye drops in treating open angle glaucoma by decreasing aqueous humor formation (. α -receptor Antagonists

1. Non- selective antagonists (a1 & a2):

Pharmacokineti Therapeutic ADRs cs use - Postural • before removal of (form • Irreversible Pheochromocytom of low blood pressure Phenoxybenzami • Long-acting a to prevent that happens when Hypertensive you stand up from ne (24 hours) sitting or lying down). crisis . - Reflex Tachycardia (due to the fall in BP, mediated by baroreceptor* reflex and due to α2 block in heart).

Before removal of - Headache - Pheochromocytoma Nasal stiffness or (tumor in the congestion • Reversible - adrenal medulla that Vertigo & • Short-acting cause increase drowsiness - (4 hours) secretion of Male sexual norepinephrine and dysfunction inhibits ejaculation epinephrine). - - Increase cardiac output (α2 block - Decrease peripheral .

Note : Both drugs can precipice(cause) arrhythmias and angina. Contra-indicated in: patients with decreased coronary perfusion*.

*baroreceptor reflex is one of the body's homeostatic mechanisms that helps to maintain blood pressure at nearly constant levels. *Coronary perfusion pressure (CPP): pressure gradient that drives coronary blood pressure, meaning the difference between the diastolic aortic pressure and the right atrial diastolic pressure. α -receptor Antagonists

2. α1- selective antagonists: Pharmacokinetic Therapeutic use ADRs s & Mechanism • • Fall in arterial (Short half-life) pressure with -Used in Raynaud’s less tachycardia disease*: induce than with non- peripheral selective vasodilatation. - Hypertension , especially with prostate enlargement (Long half-life) Like Non- Uroselective: As α1 selective but receptors present in with a lesser prostate so when Selectively used degree tamsulosin binds to the in Benign receptor, it produce Tamsulosin relaxation of bladder prostatic (Uroselective( neck and prostate hyperplasia with resulting in increasing urine flow minimal effect on blood pressure

*Raynaud’s phenomenon is excessively reduced blood flow in response to cold or emotional stress, causing discoloration of the fingers, toes, and occasionally other areas (vasospasm) 3. α2- selective antagonists:

Pharmacokinetics Therapeutic use • Increase NO &ADH Used as aphrodisiac* (the released in the treatment of erectile corpus cavernosum dysfunction) • Vasodilatation • Contributing to the erectile process

*Aphrodisiac: a food, drink, or other thing that stimulates sexual desire. β -Adrenoceptors blockers

Classification of β- Adrenoceptors Blockers:

1. According to selectivity: Suffix: olol (except the mixed)

Selective β1 Non selective β- Mixed α,b antagonists Antagonists receptors • • • blockers • • • • • (PST) •

CAT BITES ME.

2. According to presence of agonistic/antagonistic action; Intrinsic Sympathomimetic Activity ((ISA(

With ISA Without ISA )may activate beta receptors( , initially act as agonist but permanently act as Atenolol, Bisoprolol, labetalol antagonist. Metoprolol Propranolol, Sotalol, Timolol, carvedilol β -Adrenoceptors blockers

3. According to presence of membrane stabilizing effects: Eg: Propranolol, labetalol - Block Na Channels Local anesthetic action. - -like action Quinidine is antiarrhythmic drug , the action is decreasing propagation action potential. - Antiarrhythmic action. 4 . According to lipid solubility:

Lipophilic Hydrophilic

Oral Complete Irregular

absorption

Liver Yes No

metabolism

Short [(mostly Long, except Esmolol t 1/2 3-10h)] (10min given IV)

low CNS side High (↓ Anxiety) effects

Metoprolol Atenolol, Bisprolol,

Propranolol, Esmolol , Sotalol E.g. Timolol ( BASE ) Labetalol , The BASE is hydrophilic Carvedilol

-Most of them are lipid soluble. -Most of the lipid soluble metabolized in liver & excreted in urine. β Adrenoceptors blockers

Pharmacological actions

Antianginal* effects (ischemic heart disease): Anti-arrhythmic Negative inotropic, 1-Decrease heart rate effects: chronotropic, = () Decrease excitability dromotropic . 2-Decrease force of Decrease automaticity CVS contraction =! cardiac Decrease conductivity *important* = Decrease work cardiac output 3-decrease oxygen )due to its sympathetic consumption due to blocking). bradycardia Increase peripheral Decrease blood flow to In Reynaud's disease , BLOOD resistance (PR) by organs = cold extremities. better use selective contraindicated in peripheral beta 1 blockers , beta 2 VESSELS blocking vasodilatory effect diseases like Reynaud's blockers Exacerbating disease the disease. of β2 Antihypertensive: decrease blood pressure in hypertensive patients due to effects on: Decrease renin, angiotensin BLOOD Presynaptic 2 (vasoconstrictor( and PRESSURE Decrease cardiac output inhibition of NE aldosterone secretion β1 β1 release from Beta receptors control renin adrenergic nerves system. RESPIRATORY TRACT β2 " Bronchoconstriction + contraindicated in asthmatic patients. In glaucoma, reduce intraocular pressure (IOP) + decrease aqueous EYE humor production from ciliary body e.g. Timolol as eye drops INTESTINE Increase intestinal motility Hypoglycemia: ↓ glycogenolysis in liver , ↓ glucagon secretion in pancreas , ↓ lipolysis in adipocytes Na+ retention** 2ndry to decrease blood pressure + decrease renal perfusion METABOLIC All β–Adrenergic blockers mask hypoglycemic manifestations in diabetic EFFECT patients type 1 ( taking insulin) The patient cant feel the reflex caused by hypoglycemia ( tachycardia + sweating) # cause COMA All beta blockers are contraindicated for diabetic patient type 1 ( taking insulin) *Angina = the amount of oxygen reaching the heart by coronary artery not enough , treatment either increase blood flow or decrease heart work load . ** This Na retention is due to the stimulation of aldosterone, but this stimulation is not strong enough to increase the hypertension (still b-blockers control the situation) Beta-Adrenoceptors blockers

Clinical Uses of β receptor blockers:

DISEASE DRUG

Labetalol INJECTION Labetalol (α, β blockers ) Hypertension - Propranolol, non selective used in treatment of atenolol, bisoprolol hypertensive pregnant & hypertensive crisis.

Used In supraventricular & ventricular arrhythmias. Cardiac Bisopoprolol and Carvedilol Beta blockers are preferred in ventricular arrhythmia Arrhythmias (antioxidant action(* more than atrial.

↓ heart rate, cardiac work & oxygen demand. CVS Angina pectoris ↓ the frequency of angina episodes.

Carvedilol is non selective Congestive Heart Carvedilol Decrease myocardial remodeling & decrease risk of sudden Failure )antioxidant action(* death.

Have cardio-protective effect, decrease infarct size, decrease Myocardial morbidity & mortality, decrease myocardial O2 demand. Infarction Beta blocker Anti-arrhythmic action. Decrease the incidence of sudden death.

Glaucoma Timolol Used as eye drop

Protect the heart against sympathetic over stimulation Hyperthyroidism Beta blocker Controls symptoms; tachycardia, tremors, sweating.

Anxiety Controls symptoms; tachycardia, tremors, sweating. (Social and performance type)

Propranolol USED ONLY AS PROPHELACTIC NOT EFFECTIVE IN ACUTE CONDITIONS !reduce episodes of chronic migraine Migraine !-induced vasodilatation in the brain vasculature Treatment : antagonize the sympathetic effect.

Combination α-blockers lower the elevated blood pressure. Pheochromocytoma Alpha & Beta blockers β -blockers protect the heart from NE.

Antioxidant: A substance that reduces damage due to oxygen free radicals. Beta-Adrenoceptors blockers

Drug Pharmacological action Admin Indication • Lipid soluble (CNS effect ! sedative action + protection against anxiety( • Metabolized in liver, and excreted in urine • NO ISA • Membrane stabilization (block Na channel !local anesthetic effect (antiarrhythmic effect( • Heart: (β1) • ↓ cardiac output • Anti-ischemic: ↓ cardiac work +↓ O2 consumption • Hypertension • Anti-arrhythmic (by membrane • Arrhythmias stabilization):↓excitability + • Angina ↓automaticity + ↓ conductivity • Myocardial • Blood Pressure: )β1, β2) infarction • • ↓ cardiac output Migraine [Prophylaxis] • ↓ renin and RASS system • Pheochromocytom • Inhibition of presynaptic NE Orally Non- Propranolol a; used with α- release or IV selective • Inhibition of sympathetic blockers )never outflow in CNS alone( β- • • Blood Vessels: (β2) Chronic glaucoma blockers • Tremors • Vasoconstriction ! ↓ blood • Anxiety; (specially flow to organs except brain ! social & cold extremities performance type( • Bronchi: (β2) • Hyperthyroidism • Bronchospasm • Intestine: (β2) • ↑ intestinal motility • Metabolism: (β2) • Liver: ↓Glycogenolysis ! Hypoglycemia • Pancreas: ↓Glucagon secretion • Adipocytes: ↓Lipolysis • Skeletal muscles: ↓glycolysis • PNS and CNS: • Local anesthetic effect:↓tremors, ↓anxiety • ↓ aqueous humor production Eye BetaTimolol Blockers from ciliary body Chronic glaucoma • ↓intraocular pressure (IOP) drops Beta-Adrenoceptors blockers

Drug Pharmacological action Admin Indication Adverse Effects

• Severe hypertension • Rapid acting with ISA in and local anesthetic pheochromocy effect toma • Orthostatic • Does not alter serum Orally • Hypertensive hypotension Labetalol lipids or blood or IV crisis (abrupt • Sedation and glucose withdrawal of dizziness Mixed • Membrane clonidine) α/β- stabilization • Pregnancy- block induced hypertension ers

• NO ISA • Congestive • NO local anesthetic heart failure Carvedilol effect (by reversing Edema • Has antioxidant pathophysiolo action gical changes)

• Asthma/COPD Bisoprolol • Raynaud’s phenomenon and PVD • Selectively present recurrent Select Esmolol vasospasm of the Mne in low doses fingers and toes ive mo • Lost in high doses and usually β1- nic: • NO change in lipid or occurs in BEA Atenolol glucose response to block stress or cold M • NO exposure er bronchoconstriction • Diabetics/ Dyslipidemias Metroprolo • Variant Angina l (coronary spasm) β-blocker Contraindications:

2) Bronchial 3) Peripheral 6) Alone in 4) Diabetes 1) Heart Block Asthma vascular disease pheochromocyto (Masking of (can precipitate (safer with (safer with 5) Hypotension ma selective β- hypoglycemia( (must be give heart block) selective β- Given Cautiously blockers)) blockers) with α-blockers) Beta-Adrenoceptors blockers

β-blockers Adverse Effects: ••Bradycardia β1 blockage ••Hypotension ••Heart Failure

••Hypoglycemia ••Bronchoconstriction ••Vasoconstriction ! cold extremities ••Erectile dysfunction ••↑TG (hyperglyceridemia) elevated levels of triglyceride β2 ••Coronary spasm (angina patient) blockage ••Masked hypoglycemic manifestations !Coma (when hypoglycemic manifestations are masked, the patient could fall into a hypoglycemic coma without any prior warning) ••Depression + Hallucinations ••GI disturbances ••Sodium retention

Precaution: Sudden stoppage will give rise to a withdrawal syndrome: Rebound angina, arrhythmia, myocardial infarction & Hypertension WHY ? # Up-regulation of β-receptors. To prevent withdrawal manifestations#drug withdrawn gradually.

Disease Drug of choice

Hypertension Atenolol, Bisoprolol > Metoprolol, Propranolol

Cardiac Arrhythmia Esmolol (ultra-short acting), Atenolol, Propranolol

Congestive Heart Failure Carvedilol, Bisoprolol, Metoprolol

Myocardial Infarction Atenolol, Metoprolol, Propranolol

Glaucoma Timolol

Migraine Prophylaxis Propranolol

Relief of Anxiety (Social and Propranolol performance)

Thyrotoxicosis Propranolol THANK YOU FOR CHECKING OUR WORK THE PHARMACOLOGY TEAM عبدالرحمن السياري شماء السعد ﻟوﻟوه اﻟﺻﻐﯾر أحمد اليحيى رهف بن عباد شادن العمران ّ خالد الزهراني سارة الخليفة عبدال الجنيدل لى الزامل

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