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Adrenoceptor Antagonists: Actions, Clinical Uses & Adverse Effects

Explore the impact, classification, and clinical applications of adrenoceptor antagonists in drug therapy, focusing on peripheral nervous system disorders and hypertension. Understand the pharmacological effects, mechanisms, and potential side effects of these medications.

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Adrenoceptor Antagonists: Actions, Clinical Uses & Adverse Effects

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  1. Drugs affecting peripheralnervous systemSan-HuaFang, PhD方三华Dept. of Pharmacology, School of Medicine, Zhejiang Universityfshfbzxhq@zju.edu.cn

  2. Drug actions and classification Adrenoceptor antagonists （1） receptor antagonists • 12 receptor antagonists: short-acting: phentolamine(酚妥拉明) long-acting: phenoxybenzamine (酚苄明) • 1 receptor antagonists:prazosin(哌唑嗪） • 2 receptor antagonists:yohimbine（育亨宾）

  3. Drug actions and classification Adrenoceptor antagonists （2） receptor antagonists • 12 receptor antagonists:propranolol（普萘洛尔） • 1 receptor antagonists:atenolol（阿替洛尔） • 2 receptor antagonists:butoxamine（丁氧胺） （3）,  receptor antagonists • labetalol（拉贝洛尔）

  4. epinephrine  antagonist epinephrine BP Epinephrine reversal （adrenaline reversal）

  5. Phentolamine • competitive, nonselective(1, 2 receptor antagonists) Pharmacological effects (1) Vasodilatation Blocking 1 receptor: vasodilation in both arteriolar resistance vessels and veins (2) Cardiac Stimulation Reflex；blocking 2 receptor ～NE release  (3) Cholinergic and histamine-like effects Contraction of GI smooth muscles, Gastric acid secretion 

  6. Phentolamine Clinical uses (1) • Hypertension from pheochromocytoma (short term use). • pre- and post-operation of pheochromocytoma • Diagnostic test for pheochromocytoma (2) Peripheral vascular diseases • Acrocyanosis, Raynaud’s disease (3) Local vasoconstrictor extravasation Major Adverse effects– postural hypotension, reflex tachycardia, arrhythmia, angina pectoris, GI reactions

  7. Pheochromocytoma is a rare catecholamine-secreting tumor derived from chromaffin cells of the adrenal medulla that produces excess epinephrine. • Hypertension & Crises • Elevated Metabolic Rate -heat intolerance -excessive sweating -weight loss • Temporarily manage with -adrenergic antagonists (a1 & ±b)

  8. Pheochromocytoma

  9. Phenoxybenzamine(酚苄明） • Irreversible, nonselective ( 1 and 2 antagonists ) • Long-acting • Similar to phentolamine in actions and clinical uses

  10. 1 receptor antagonists • prazosin（哌唑嗪） treatment for hypertension 2 receptor antagonists • yohimbine（育亨宾） for research use only

  11.  receptor antagonists ADME • First-pass elimination, • lower bioavailability: propranolol • Hepatic metabolism and renal excretion, hepatic and renal functions alter the effects of the drugs and result in large individual variation • So, dose individualization is necessary.

  12. Effects of an b AR Antagonist

  13.  receptor antagonists Pharmacological effects (1)  receptor blockade A. Cardiovascular effects： • Depressing heart: reduction in HR, A-V conduction, automaticity, cardiac output, oxygen consumption • Hypotension: peripheral blood flow , hypotensive effects in hypertensive patients

  14.  receptor antagonists (1)  receptor blockade B. Bronchial smooth muscles • induces bronchial smooth muscle contraction in asthmatic patients C. Metabolism • lipolysis  , glycogenolysis  , potentiating insulin effects ~ hypoglycemia D. Renin secretion • decreasing secretion of renin

  15.  receptor antagonists (2) Intrinsic sympathomimetic effects • Partial agonists: e.g. pindolol（吲哚洛尔）,acebutolol (醋丁洛尔) (3) Membrane-stabilizing effects • Larger doses of some drugs: quinidine-like effects, Na+ channel block (4) Others • Lowering intraocular pressure; • Inhibiting platelet aggregation

  16. Circulation of Aqueous humor

  17.  receptor antagonists Clinical uses (1) Arrhythmia：supraventricular, sympathetic activity  (2) Hypertension (3) Angina pectoris and myocardial infarction (4) Chronic heart failure (5) Others: hyperthyroidism, migraine headache, glaucoma（timolol）...

  18.  receptor antagonists Adverse effects (1) Heart depression: contraindicated in heart failure, severe A-V block, sinus bradycardia (2) Worsening of asthma: contraindicated in bronchial asthmatic patients (3) Withdrawal syndrome：up-regulation of the receptors (4) Worsening of peripheral vascular constriction (5) Others：central depression, hypoglycemia,etc.

  19. Propranolol • 1, 2 receptor blocking • no intrinsic activity • first-elimination after oral administration, individual variation of bioavailability Timolol (噻吗洛尔) • For treatment of glaucoma (wide-angle)

  20. Atenolol, Metoprolol • 1receptor antagonists, no intrinsic activity • atenolol : longer t1/2, once daily • usually used for treatment of hypertension

  21. α,  receptor antagonists Labetalol (拉贝洛尔) • α, β receptor blocking, β> α • usually used for treatment of hypertension

  22. summary

  23. summary

  24. summary

  25. Local Anesthetics

  26. 可卡因 普鲁卡因 丁卡因 苯佐卡因

  27. 利多卡因 甲哌卡因 布比卡因 布比卡因 依替卡因 丙胺卡因

  28. Local Anesthetics (LAs) • Reversibly block nerve conduction • Act on every type of nerve fiber non/thin myelinated sensory fibers myelinated sensory fibers autonomic fibers motor fibers • Also act on cardiac muscle, skeletal muscle and the brain • No structural damage to the nerve cell

  29. Action site: voltage-gated Na+ channels

  30. Actions of LAs • Ionic gradient and resting membrane potential are unchanged • LAs only bind in the inactive state • Decrease the amplitude of the action potential • Slow the rate of depolarization • Increase the firing threshold • Slow impulse conduction • Prolong the refractory period

  31. Use-dependent Blockade

  32. Types of local anesthesia Topical local (surface) anesthesia: for eye, ear, nose, and throat procedures and for cosmetic surgery Infiltration anesthesia: local injection around the region to be operated. Conduction anesthesia: local injection around the peripheral nerve trunk Epidural ansthesia: local injection into the epidural space Subarachnoid anesthesia or Spinal anesthesia: local injection into the cerebrospinal fluid in subarachnoid cavity

  33. Pharmacokinetics • LAs bind in the blood to a1-glycoprotein and albumin • There is considerable first-pass uptake of LAs by the liver • LAs enter the blood stream by: • Direct injection • Absorption • Epinephrine decreases this via vasoconstriction • Peak concentrations vary by site of injection

  34. Distribution of LAs • Alpha phase – rapidly redistributed to well-perfused tissues • Beta phase – distribution to less perfused or slowly equilibrating tissues • Gamma phase – clearance representing metabolism and excretion

  35. Metabolism of LAs • Esters (rapid) • Hydrolyzed in the plasma by pseudocholinesterase • Break down product – para-aminobenzoic acid • Amides (slower) • Occurs in the endoplasmic reticulum of hepatocytes • Tertiary amines are metabolized into secondary amines that are then hydrolyzed by amidases

  36. Allergic Reactions • Metabolite of “ester” LAs • Para-aminobenzoic acid • Allergen • Allergy to “amide” LAs is extremely rare

  37. CNS Toxicity • Correlation between potency and seizure threshold • Bupivacaine • 2 ug/ml • Lidocaine • 10 ug/ml

  38. Cardiovascular Toxicity • Attributable to their direct effect on cardiac muscle • Contractility • Negative inotropic effect that is dose-related and correlates with potency • Interference with calcium signaling mechanisms • Automaticity • Negative chronotropic effect • Rhythmicity and Conductivity • Ventricular arrhythmias

  39. Lidocaine • One of the most widely used local anesthetics • Rapid onset, medium duration • Also available in ointment, jelly, and aerosol • Other uses: anti-arrhythmic

  40. Eutectic Mixture of Local Anesthetic (EMLA) • Contains lidocaine, prilocaine, emulsifier, thickener, distilled water • Must be applied one hour prior to procedure

  41. Pharmacology of General Anesthetics

  42. WHAT IS ANESTHESIA ? • Definition – “induced, reversible insensibility to surgical stimulation” • Anesthesia is necessary for some diagnostic, therapeutic, and surgical intervention • Anesthetics are a class of drugs that produce anesthesia, not all induce unconsciousness • Some administered as gases or “vapors”, others can be given intravenously

  43. Inhaled anesthetics: mechanism of action • Many different, apparently unrelated molecules produce general anesthesia – inert gases, simple inorganic & organic compounds, more complex organic compounds • Characteristics – rapid onset, rapid reversibility, relationship between lipid solubility & potency

  44. Site of action • Probably on synaptic transmission • Do they act at one site (unitary hypothesis) or at multiple sites ? • Do they act via the biochemical milieu or, like many other drugs, at protein receptors ?

  45. This anesthetic is a gas at room temperature

  46. Volatile liquids at room temperature Diethyl Ether

  47. Inhaled anesthetic delivery system

  48. Vaporizing the anesthetic liquid

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