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Adrenergic Antagonists OBJECTIVES Adrenergic Antagonists •Red : important •Black : in male / female slides •Pink : in female’s slides only •Blue : in male’s slides only •Green : Dr’s notes •Grey: Extra information, explanation OBJECTIVES: By the end of this lecture, students should be able to: Chapter 1 ✓ Outline the mechanisms of action of adrenergic neuron blockers. ✓ Classify a-receptor blockers into selective & non-selective. ✓ Know the pharmacokinetic aspects & pharmacodynamic effects of adrenergic blockers. ✓ Identify the specific uses of non selective and selective a-adrenergic blockers. Chapter 2 ✓Outline the mechanisms of action of B-blockers. ✓Classify B-receptor blockers into selective & non-selective. ✓Know the pharmacokinetic aspects & pharmacodynamic effects of B-adrenergic blockers. ✓Identify the specific uses of non selective and selective B -adrenergic blockers. Editing File Review “just for better understanding “ α1 β2 β1 β3 Post-synaptic located in tissue (meaning it is mediated by a neuron which received a signal from a preganglionic neuron by synapsis) excitatory in function inhibitory in function excitatory in function, present In (cause contraction) except (cause relaxation) mainly in heart, adipose in GIT juxtaglomerular cells of the tissue kidney Present mainly in smooth muscles Contraction of pregnant Relaxation of the uterus uterus (Delay premature labor) also called tocolytic effect ↑ heart rate: chronotropic effect Vasoconstriction of skin & Relaxation of skeletal & (Tachycardia) peripheral blood vessels → coronary blood vessels increased peripheral resistance ↑ force of contraction : (vasodilatation) (resistance to blood flow due to + inotropic effect constriction of blood vessels)→ ↑ Increase cardiac output hypertension. Agonists used as lipolysis nasal decongestants. ↑ conduction velocity: + dromotropic effect (via A.V. node)(dromotropic effect means an effect in ↑ free Relaxation of GIT muscles & urinary bladder’s muscles. the speed of conduction of electrical fatty impulses) Contraction of GIT sphincter (constipation) & urinary acids bladder’s sphincter urinary retention ↑ blood pressure Contraction of radial .Relaxation of bronchial muscle of eye causes smooth muscles ↑ renin release (this is an enzyme produced by the kidney in active mydriasis, (bronchodilation) response to stretch receptors found on (dilation of pupil, cholinergic agents .Tremor of skeletal muscles blood vessels, its function is to increase have no effect on this muscle) blood pressure) Increase blood glucose level (hyperglycemia), by: .↑ glycogenolysis .↑ glucagon release from pancreas .↑ liver & muscle glycogenolysis α2 β2 Pre-synaptic Inhibition of norepinephrine release Increase release of norepinephrine (negative feedback mechanism) (Positive feedback mechanism) How? this mainly happen by an autoreceptor ‘presynaptic receptor’ which is present on the neuron releasing the neurotransmitter itself, the neurotransmitter bind to the receptor of the same neuron it was released by and inhibiting further release of the neurotransmitter, producing a negative feedback mechanism α1 β2 β1 α1 α1 &β2 α1 &β2 β2 overview Act on: α1 e.g. Phenylephrine Selective Review to refresh Act on: β1 your mind e.g. Dobutamine Adrenergic Stimulants (Sympathomimetics) Act on: α1, α2 , β1 , β2, β3 e.g. Adrenaline Non-Selective Act on: β1 , β2, β3 e.g. Isoprenaline Non-selective α1+ α2 e.g phentolamine selective α1 α-Adrenergic e.g Prazosin Receptor Blockers selective α2 e.g yohimbine Adrenergic Drugs Non-selective β1 + β2  β- Adrenergic e.g Propranolol Receptor Blockers selective β1 Adrenergic e.g Esmolol Receptor Blockers α & β -Adrenergic e.g Labetalol Receptor Blockers Adrenergic Depressants (Sympatholytics) Formation of False e.g α-Methyl dopa Transmitters Depletion of Adrenergic Neuron e.g Reserpine Blockers storage sites Inhibition of release & e.g Guanethidine enhance uptake Stimulation of e.g Clonidine AND presynaptic α2 α-Methyl dopa receptors Chapter 1 : α Adrenergic Antagonists Adrenergic Neuron Blockers Drugs α-Methyl Dopa Clonidine Apraclonidine -Forms false transmitter -Central a2 receptor that is released instead of agonist to inhibit NE NE release “α-methylnoradrenaline replaces NE -Suppresses Acts by decreasing in vesicles” sympathetic outflow aqueous humor -Centrally acting a2 Action activity from the brain formation. adrenergic agonist that inhibits NE release “Can cross BBB” - Little use as - Drug of choice in antihypertensive agent treatment of hypertension due to rebound in pregnancy hypertension upon Open angle (gestational hypertension, abrupt withdrawal. glaucoma as eye Uses pre- eclampsia “disorder of “side effect” drops (topical) pregnancy characterized by “Extra: Clonidine causes downregulation of a2 receptors, but proteinuria and rise in BP” ) its efficacy as an a2 agonist compensates for the decreased “NO teratogenic effect “ receptors. Therefore in withdrawal physiological neurotransmitters fail to produce the same effect, and due to poor stimulation of a2 receptors rebound hypertension occurs” α-Methyl Dopa MeNE Adrenergic Receptors Blockers Classification of α-receptor Antagonists selective Selective α1- antagonists Non-selective α antagonists α2-adrenoceptor e.g. e.g. e.g. ● prazosin ● phenoxybenzamine ● yohimbine ● doxazosin ● phentolamine ● terazosin Non-Selective α-Receptor Blockers Phentolamine Phenoxybenzamine MOA Non-selective antagonists of both α1 & α2 receptors. ● Reversible block of both α1 & α2 ● Irreversible blocking of α1 receptors.”non-covalent bond so less & α2 receptors.”by covalent P.K duration of action” bond” ● Short acting (4 hrs) ● Long-acting (24 hrs) ● Increase cardiac output (α2 block) ● Decrease peripheral vascular resistance. Pharmacological ● Postural (orthostatic) hypotension. “due to baroreceptor reflex, pull of gravity and reduced BP contribute to low venous return actions which causes hypotension when standing” ● Reflex tachycardia due to fall in B.P, mediated by baroreceptor reflex and due to block α2 in heart. In Pheochromocytoma : Should be given before surgical removal to protect against hypertensive crisis. Indication (pheochromocytoma is a tumor of the adrenal medulla that causes an excessive release of NA “synthesized in the medulla”, resulting in an overstimulation of a1 receptors, resulting in hypertension ) ● Headache ● Nasal stuffiness or congestion ● Vertigo & drowsiness “ caused by the hypotension” ADRs ● Male sexual dysfunction (Inhibits ejaculation) ● Tachycardia . ● Postural hypotension. Patients with decreased coronary perfusion, because both drugs can precipitate Contradiction arrhythmias and angina. Selective α1 - adrenoceptor Antagonists ● Prazosin ● Doxazosin● Terazosin MOA Selective α1 -adrenoceptor Antagonists ● Prazosin has short half-life. P.K ● Doxazosin, terazosin have long half lives. ● Vasodilation due to relaxation of arterial and venous smooth muscles. ● Pharmacological Fall in arterial pressure with less reflex tachycardia than with non-selective α- blockers. actions ● First dose may produce an orthostatic hypotensive response that can result in syncope and fainting. ● Treatment of essential hypertension WITH prostate enlargement.(Hypertrophy) ● Urinary obstruction associated with benign prostatic hyperplasia (BPH). Indication ● Raynaud's disease causes some areas of your body such as your fingers and toes to feel numb and cold in response to cold temperatures or stress. Selective α1A & Selective α2 Antagonists Selective α1A Selective α2 Drugs Tamsulosin Yohimbine Increase nitric oxide “NO” released in the corpus cavernosum thus producing ● Relaxation of smooth muscles vasodilator action and contributing to of bladder neck & prostate the erectile process. MOA →improve urine flow. ● Has minimal effect on blood pressure. Treatment of benign prostatic Used as aphrodisiac in the treatment Indication hypertrophy (BPH). of erectile dysfunction. As before with non selective but to a ——————- ADRs lesser degree. Chapter 2 : β- Adrenergic Antagonists β - Adrenoceptors Blockers Pharmacodynamic Classifications: According to selectivity Non-selective Selective Mixed “β1 & β2” “β1” “β & α” “Mnemonic=POST” act on α1 and classes of β :β1,β2,β3” Propranolol Atenolol Bisoprolol Pindolol Labetalol Metoprolol Sotalol Esmolol Acebutolol Timolol Betaxolol Carvedilol Oxprenolol Celiprolol According to presence of agonistic/antagonistic action Intrinsic Sympathomimetic Activity (ISA) Without ISA With ISA “adrenergic partial agonists” Atenolol Labetalol Bisoprolol Metoprolol Acebutolol Propranolol Sotalol Pindolol Timolol Carvedilol Oxprenolol According to presence of membrane stabilizing effects Drugs Effects Propranolol -Block Na Channels -Quinidine-like action labetalol -Antiarrhythmic action “Local anesthetic” Pharmacokinetic Classification: According to lipid solubility Lipophilic Hydrophilic Oral absorption Complete Irregular Liver Yes No metabolism Long T 1/2 Short Except Esmolol → 10 min & given “Most of them 3-10 Hrs” intravenously. Cross BBB, High depressant actions Low CNS side effects Sedative effect →↓ anxiety Metoprolol / Propranolol Atenolol / Bisoprolol Drugs Timolol / Labetalol Esmolol / Sotalol Carvedilol Pharmacological actions: CVS - Negative (inotropic, chronotropic, dromotropic) → ↓ Cardiac Output Antianginal effects (ischemic heart disease): Antiarrhythmic effects: (class II) - ↓ Heart rate (Bradycardia) → ↓ Oxygen - ↓ Excitability, ↓ automaticity & consumption ↓conductivity - ↓ Force of contraction → ↓ Cardiac work Due to its sympathetic blocking. Blood pressure: Blood vessels
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