Drug actions and classification

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）

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

6. 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 

7. 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

8. 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)

9. Pheochromocytoma

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

11. 1 receptor antagonists • prazosin（哌唑嗪） treatment for hypertension 2 receptor antagonists • yohimbine（育亨宾） for research use only

12.  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.

13. Effects of an b AR Antagonist

14.  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

15.  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

16.  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

17. Circulation of Aqueous humor

18.  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）...

19.  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.

20. 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)

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

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

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26. Local Anesthetics

27. 可卡因 普鲁卡因 丁卡因 苯佐卡因

28. 利多卡因 甲哌卡因 布比卡因 布比卡因 依替卡因 丙胺卡因

29. 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

30. Action site: voltage-gated Na+ channels

31. 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

32. Use-dependent Blockade

33. 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

34. 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

35. 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

37. 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

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

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

40. 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

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

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

43. Pharmacology of General Anesthetics

44. 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

45. 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

46. 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 ?

47. This anesthetic is a gas at room temperature

48. Volatile liquids at room temperature Diethyl Ether

49. Inhaled anesthetic delivery system

50. Vaporizing the anesthetic liquid