[PHARMA] Adrenergic Antagonists.pdf

PHARMACOLOGY 08/21/2024. MOD 1: ADRENERGIC ANTAGONISTS Dr. Micah Muri...

PHARMACOLOGY 08/21/2024. MOD 1: ADRENERGIC ANTAGONISTS Dr. Micah Muriel E. Oliver VOLUNTEERS I. ADRENERGIC RECEPTOR ANTAGONISTS ○ Metoprolol has greater affinity for beta 1 receptors. ○ Propranolol has equal affinities for beta 1 and beta 2 receptors. ○ Butoxamine has greater affinity for beta 2 receptors. A. NON-SELECTIVE α-ADRENERGIC ANTAGONIST Adrenergic Receptor Antagonists. Adrenergic receptor antagonists are drugs that inhibit the interaction of norepinephrine, epinephrine, and other sympathomimetic drugs with α and β adrenergic receptors throughout peripheral tissues. Most of these agents are competitive antagonists. ○ An important exemption is phenoxybenzamine – an irreversible antagonist that binds covalently to Non-Selective Alpha-Adrenergic Antagonists. the α adrenergic receptor Examples: COMPETITIVE NON-COMPETITIVE ○ Phenoxybenzamine: a haloalkylamine which ANTAGONISM ANTAGONISM produces an irreversible antagonism ○ Phentolamine: an imidazoline which produces a competitive antagonism Binds to the same site as Binds to an allosteric or Both drugs lead to a progressive reduction in the agonist but it does not non-agonist site on the peripheral resistance due to their antagonism of activate it, thus blocking receptor to prevent alpha-adrenergic receptors in the vasculature, while also agonist action receptor activation. increasing cardiac output, partially attributed to reflex sympathetic nerve stimulation. ○ Cardiac stimulation is accentuated by enhanced release of norepinephrine (NE) from cardiac sympathetic nerves due to antagonism of presynaptic α2 adrenergic receptors by these nonselective alpha blockers. Postural hypotension → reflex tachycardia ○ Postural hypotension is a prominent feature with these drugs and accompanied by reflex tachycardia that can precipitate cardiac arrhythmias. ○ Severely limits this drug to treat essential hypertension. 1. THERAPEUTIC USES THERAPEUTIC USES OF NON-SELECTIVE ALPHA Receptor Affinities of Adrenergic Antagonists. ADRENERGIC ANTAGONIST Alpha antagonists mainly affect alpha receptors except Treatment of: for phentolamine wherein it both has an equal affinity Pheochromocytomas with alpha 1 and alpha 2 receptors. Tumors of the adrenal Yohimbine and tolazoline affect the alpha 2 receptor medulla more than alpha 1 receptor. Phenoxybenzamine Sympathetic neurons that Mixed antagonists such labetalol and carvedilol have secrete enormous affinities to both alpha and beta receptor but it mainly quantities of affects beta receptors with an equal affinity for beta catecholamines into the receptor compared to alpha receptor. circulation Beta antagonists affect beta receptors. Pharmacology- Mod # Topic Title 1 of 9 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Controls episodes of severe Fall in blood pressure is opposed hypertension and minimizes by baroreceptor reflexes that the other adverse effects of cause increases in heart rate and catecholamines such as cardiac output, as well as fluid contraction of plasma retention volume and injury of the myocardium Blockade of α1 adrenergic receptors can alleviate some of the Short-term control of symptoms of BPH including: hypertension in patients ○ Resistance of urine output with pheochromocytoma resulting in mechanical Relieving pressure on urethra due to pseudo-obstruction of the increase in smooth muscle bowel in patients with Genito-urinary mass and an α-adrenergic pheochromocytoma Tract (GUT) receptor mediated increase Phentolamine is used locally in smooth muscle tone in the to prevent dermal necrosis prostate and neck of urinary following the inadvertent bladder extravasation of an alpha Antagonism of α1 receptors permits receptor agonist relaxation of the smooth muscle Hypertensive crises that and decreases the resistance to follow the abrupt withdrawal urine outflow Phentolamine of clonidine or that may result from the ingestion of tyramine-containing food during the use of non-selective monoamine oxidase inhibitor (MAOI) Buccally or orally administered phentolamine may have efficacy in some men with sexual dysfunction Phentolamine is FDA approved for reversing or limiting the duration of soft tissue local anesthesia 2. TOXICITY AND ADVERSE EFFECT Hypotension Reflex cardiac stimulation: tachycardia, cardiac arrhythmias, and ischemic cardiac events, including myocardial infarction (MI) Reversible inhibition of ejaculation may occur during impaired smooth muscle contraction in the vas deferens and ejaculatory ducts Phentolamine stimulates GI smooth muscle – an effect α1-selective Antagonist. antagonized by atropine– and enhances gastric acid secretion through histamine release 1. PRAZOSIN ○ Thus, phentolamine should be used with caution in patients with history of peptic ulcer Phenoxybenzamine is a mutagenic agent – repeated 1.1 Pharmacological Effects administration of this drug to experimental animal Its major effects result from antagonism of causes peritoneal sarcomas and lung tumors alpha-adrenergic receptors in arterioles and veins Fall in peripheral vascular resistance and in venous B. α1-SELECTIVE ADRENERGIC ANTAGONISTS return to the heart The action of alpha-selective adrenergic receptor Does not increase heart rate → little or no α2 antagonists is more on the cardiovascular and receptor-blocking effect because it does not promote genito-urinary tract, specifically in the bladder. the release of norepinephrine (NE) from sympathetic It inhibits vasoconstriction induced by the nerve endings in the heart endogenous catecholamines Decrease cardiac preload and has little effect on Vasodilation may occur in both arteriolar resistance cardiac output and rate vessels and veins. ○ Combination of reduced preload and selective Prazosin is the prototype drug under this drug category. alpha-adrenergic receptor blockade might be sufficient to account for the relative absence of EFFECTS OF α1-SELECTIVE ADRENERGIC reflex tachycardia ANTAGONISTS CNS: may suppress sympathetic outflow It may depress baroreflex function in hypertensive Cardiovascular Fall in blood pressure due to patients System decreased peripheral resistance Pharmacology - Mod 1 Adrenergic Antagonists 2 of 9 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Prazosin and related drugs in this class decrease LDLs Competitive antagonist that is selective for α2 and triglycerides and increase concentrations of adrenergic receptors HDLs Indolealkylamine alkaloid and its structure resembles that of reserpine 1.2 Pharmacokinetics Yohimbine readily enters the CNS, where it acts to increase blood pressure and heart rate and it also Oral administration and enhances motor activity and produces tremors bioavailability is about 50-70% These actions are opposite to those of clonidine, a Administration selective α2 adrenergic receptor agonist Peak concentrations in plasma are reached 1-3 hours after oral dose D. β ADRENERGIC RECEPTOR ANTAGONISTS Tightly bound to plasma proteins (primarily α1-glycoprotein) Only 5% of the drug is free in the Distribution circulation Diseases that modify the concentration of this protein may change the free fraction (e.g., inflammatory processes) Extensively metabolized in the Metabolism liver β Receptor Antagonists. Little unchanged drug is excreted Also known as BETA BLOCKERS Elimination by the kidneys Major therapeutic effects are on the cardiovascular system such as hypertension, ischemic heart disease, congestive heart failure, and certain arrhythmias 1.3 Adverse Effects Generally classified as non-subtype selective (first Marked postural hypotension and syncope are generation), beta-selective (second generation), sometimes seen 30-90 minutes after initial dose → non-subtype or subtype selective with additional Prazosin and Doxazosin cardiovascular action (third generation) Last drug has additional cardiovascular properties which 1.4 Therapeutic Uses is vasodilation which seems unrelated to β receptor blockade Hypertension Therefore, β adrenergic receptor antagonist have ○ Improved lipid profiles and glucose-insulin converse action including slower heart rate and metabolism in patients with hypertension who are decreasing myocardial contractility but ONLY if there risk for atherosclerotic disease is a sympathetic tone which is normally present CHF When tonic stimulation of β adrenergic receptors is ○ Can be used but NOT the drug of choice slow, effects of beta blockage are correspondingly ○ Increases cardiac output and induces modest. pulmonary congestion However, when the sympathetic nervous system is ○ Reduces resistance in some patients with activated during exercise, stress, or in disease-state, impaired bladder emptying caused by prostatic β receptor antagonists produce more robust cardiac obstruction or parasympathetic decentralization depressant effects. from the spinal injury The myriad β antagonists can be distinguished by the BPH following properties: ○ Drugs that are α1-selective antagonist have efficacy ○ Relative affinity for β1 and β2 receptors (and to in BPH owing to relaxation of smooth muscle in some extent β3 receptors) the bladder neck, prostate capsule, and prostatic ○ Intrinsic sympathomimetic activity urethra ○ Blockade of α receptors ○ These agents rapidly improve urinary flow ○ Differences in lipid solubility (CNS penetration) whereas the actions of finasteride are typically ○ Capacity to induce vasodilation delayed for months ○ Pharmacokinetic parameters ○ Combination therapy with doxazosin and finasteride reduces the risk of overall clinical progression of BPH significantly more than treatment with either drug alone C. α2-SELECTIVE ADRENERGIC RECEPTOR ANTAGONIST EFFECTS: blockade of α2 adrenergic receptors with selective antagonists → increased sympathetic outflow and potentiate the release of NE from nerve endings → activation of α1 and β1 adrenergic receptors in the heart and peripheral vasculature → rise in blood pressure 1. YOHIMBINE Prodrug Pharmacology - Mod 1 Adrenergic Antagonists 3 of 9 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  contractility, and systolic pressure Catecholamines increase myocardial O2 demand ○ However, in patients with coronary artery disease, fixed narrowing of these vessels attenuates expected increase in flow leading to myocardial ischemia Decreases the effects of catecholamines on the determinants of myocardial O2 consumption Antihypertensive Activity ○ Generally, beta-adrenergic antagonists do not decrease Summary of Pharmacological Properties of β Adrenergic the blood pressure in Antagonists or Beta Blockers. non-hypertensive patients. However, these drugs lower blood pressure in patients with hypertension but the mechanism for this effect is not fully understood ○ This effect is marked in patients with elevated levels of plasma renin compared to patients with normal or low concentrations of renin ○ However, beta adrenergic receptor antagonists are Pharmacological Properties of β Adrenergic Antagonists or effective even in patients Beta Blockers. with normal or low plasma renin 1. GENERAL EFFECTS OF β-ADRENERGIC ○ Presynaptic beta ANTAGONISTS adrenergic receptor ○ Long-term administration of GENERAL EFFECTS OF β-ADRENERGIC these drugs to hypertensive ANTAGONISTS patients ultimately leads to a fall in peripheral vascular Cardiovascular Cardiac rhythm and resistance System automaticity ○ Delayed fall in peripheral Reduces the sinus rate vascular resistance in the Decreases the rate of face of a persistent spontaneous depolarization of reduction of cardiac output ectopic pacemakers appears to account for much Slows conduction in the atria of the antihypertensive effect and in the AV node of these drugs Increases the functional refractory period of the AV Pulmonary Non-selective β-receptor node System antagonist (i.e. Propranolol) Most evident during dynamic block β2 receptors in the exercise when there is more bronchial smooth muscle sympathetic tone and higher This usually has little effect on levels of catecholamines pulmonary function in normal In the presence of a beta individuals blocking, exercise induce an COPD → blockade can lead to increase in heart rate and life-threatening myocardial contractility, and are bronchoconstriction attenuated These drugs should be used only ○ However, the with great caution, if at all, in exercise-induced increase patients with bronchospastic in cardiac output is less diseases affected because of an increase in stroke volume Metabolic Modify the metabolism of ○ Coronary artery blood flow Effects carbohydrates and lipids increases during exercise or ○ Catecholamines promote stress to meet the metabolic glycogenolysis and mobilize demands of the heart by glucose in response to increasing the heart rate, hypoglycemia Pharmacology - Mod 1 Adrenergic Antagonists 4 of 9 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Blocking glycogenolysis → Bradycardia blunting the perception of ○ In patients with partial or symptoms such as tremors, complete AV conduction tachycardia, and nervousness defects, beta antagonists ○ β-receptor antagonist can may cause life-threatening interfere with bradyarrhythmias. counter-regulatory effects of ○ Particular caution in patients catecholamine secreted who are taking other drugs, during hypoglycemia such as, Verapamil or other ○ Therefore, use with caution antiarrhythmic agents on patients with diabetes which may impair sinus node and frequent hypoglycemic function or AV conduction. reactions Abrupt discontinuation of Mediate activation of β-receptor antagonists after hormone-sensitive lipase in fat long-term treatment can CVS cells, leading to release of free exacerbate angina and may fatty acids into the circulation increase the risk of sudden leading to reduce HDL, increase death. This is due to enhanced DL, and increase TGA sensitivity towards β-receptor Decrease or increase insulin agonists. sensitivity ○ This increased sensitivity is ○ Decreased insulin sensitivity evident several days after during use of vasodilating stopping a β-receptor beta receptor antagonists antagonist and may persist (i.e. Carvedilol) for at least 1 week Decrease plasma concentration ○ Such enhanced sensitivity of K+ by promoting its uptake, can be attenuated by predominantly into skeletal tapering the dose of the muscle β-blocker for several weeks ○ Exercise causes an BEFORE discontinuation increase in efflux of K+ from the skeletal muscle Blockade of β2 receptors in ○ Catecholamines tend to bronchial smooth muscle → buffer the rise in K+ by may cause a life-threatening increasing the influx into the increase in airway resistance in skeletal muscle such patients ○ Beta blockers negate the ○ β2 receptors are important buffering effect of for bronchodilation for catecholamines patients with bronchospastic disease Drugs with selectivity for β1 adrenergic receptors or those with intrinsic sympathomimetic Pulmonary activity at β2 adrenergic function receptors are less likely to induce bronchospasm β blockers should be avoided, if at all possible, in patients with asthma ○ In selected patients with COPD and cardiovascular Pharmacological Action of Nonselective β-Adrenergic disease, the advantages of Receptor Antagonists and their Therapeutic Indications and using β1 receptor Adverse Effects. antagonists may outweigh the risk of worsening β1 – heart, β2 – lungs (“One heart, two lungs”) pulmonary function ○ When the heart is affected, kidneys are also usually affected. Fatigue, sleep disturbances CNS (including insomnia and 2. ADVERSE EFFECTS OF β-ADRENERGIC nightmares), and depression ANTAGONISTS Although, initially, contraindicated in chronic heart Blunt recognition of failure, is now the standard of care. hypoglycemia by patients → β1 selective antagonist (metoprolol) and may delay recovery from non-selective β blocker (carvedilol) have been shown insulin-induced hypoglycemia to improve the mortality and morbidity of heart failure Metabolism β receptor antagonists should be patients used with great caution in patients with diabetes or prone to hypoglycemic episodes. ADVERSE EFFECTS OF β-ADRENERGIC Can cause hypoglycemia ANTAGONISTS Pharmacology - Mod 1 Adrenergic Antagonists 5 of 9 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ β1-selective agents may be ○ Completely absorbed after preferable for these patients oral administration ○ Intravenously Sexual Distribution function and ○ Tightly bound in proteins reproduction ○ Readily enters the CNS ○ Approximately 90% of the Drug overdose drug in the circulation is bound to plasma proteins Metabolism 3. DRUG INTERACTIONS ○ Metabolized by the liver Aluminum salts, cholestyramine, colestipol → during its first passage decrease the absorption of β-blockers through the portal circulation Phenytoin, Rifampin, Phenobarbital, smoking → ○ Only about 25% reaches the induce hepatic biotransformation of enzyme systemic circulation Cimetidine, hydralazine → may increase the ○ Most metabolites appearing bioavailability of agents such as propranolol and in the urine metoprolol by affecting hepatic blood flow Elimination is via kidneys Lidocaine → β-receptor antagonists can impair clearance of lidocaine Nadolol Indomethacin and other NSAIDs → oppose the anti hypertensive effects of β-adrenergic receptor Timolol antagonists Pindolol 4. THERAPEUTIC USES Cardiovascular diseases ○ Treatment of hypertension, angina, and acute coronary syndromes and CHF ○ Treatment of supraventricular and ventricular arrhythmias ○ Hypertrophic obstructive cardiomyopathy, relieving angina, palpitations, and syncope in patients with this disorder ○ β-blockers may also attenuate catecholamine-induced cardiomyopathy in pheochromocytoma Glaucoma Hyperthyroidism Migraine Propranolol as Prodrug with Equal Affinity to Both β1 and β2 Panic attacks Receptors. Variceal bleeding 5. CLASSIFICATION OF β-BLOCKERS 5.1 Nonselective NONSELECTIVE β-BLOCKERS Prodrug Has equal affinities for β1 and β2 receptors. Lacks intrinsic sympathomimetic activity Does not block alpha receptors Has lower affinity for β3-adrenergic receptors Pharmacological/pharmacokinetic Pharmacological or Pharmacokinetic Properties of properties: Propranolol. Propranolol* ○ Significant membrane stabilizing activity ○ NO intrinsic agonist activity ○ High lipid solubility ○ Extent of absorption: 90% formulation of metoprolol tartrate (antagonism) is available. Oral availability: It is contraindicated for the ~30% treatment of acute MI in patients Half life: 7-10 with HR of >45 bpm, or in hours patients with heart block 0.24 98% secs., or systolic BP