![B. Indirect-Acting Cholinergic Agonists
• Inhibit acetylcholinesterase (ACHE)
• some also have direct actions at nicotinic at receptors
at NMJ (Physostigmine).
• AChE inhibitors are divided into two main types,
1) Reversible:
Non covalent/short-acting inhibtors ; edrophonium,
tacrine, and donepezil and
Covalent /Intermediate-acting / carbamate inhibitors;
physostigmine, neostigmine, and pyridostigmine
2) Irreversible: organophosphorus or organophosphate
[ sarin, soman, and tabun, parathion and malathion;
echothiophate and isoflurophate. ]
12/14/2023 9](https://image.slidesharecdn.com/anspharmacology-231214192702-c3cdf743/85/ANS-pharmacology-pptxhealth-doc-about-autonomic-nerve-system-of-pharmacology-power-point-which-is-very-useful-for-health-students-in-univer-9-320.jpg)
ANS pharmacology.pptxhealth doc about autonomic nerve system of pharmacology power point which is very useful for health students in univer
- 3. Receptors in the ANS 12/14/2023 3
- 6. A. Direct-acting cholinomimetic drugs • Mimic the effects of ACh by binding directly to cholinoceptors (muscarinic or nicotinic). • These agents may be broadly classified into two groups: 1) Choline esters, which include endogenous ACh and synthetic esters of choline, such as methacholine carbachol , and bethanechol, and 2) Naturally occurring alkaloids, such as nicotine , lobeline, muscarine, and pilocarpine 12/14/2023 6
- 7. 1. Choline esters • They are hydrophilic. • Poorly absorbed and • poorly distributed into the central nervous system 12/14/2023 7
- 8. 2.Natural cholinomimetic alkaloids • Pilocarpine, nicotine, and lobeline are well absorbed from most sites of administration. • Muscarine, a quaternary amine, is less completely absorbed from the gastrointestinal tract than the tertiary amines • These amines are excreted chiefly by the kidneys. • Acidification of the urine accelerates clearance of the tertiary amines 12/14/2023 8
- 9. B. Indirect-Acting Cholinergic Agonists • Inhibit acetylcholinesterase (ACHE) • some also have direct actions at nicotinic at receptors at NMJ (Physostigmine). • AChE inhibitors are divided into two main types, 1) Reversible: Non covalent/short-acting inhibtors ; edrophonium, tacrine, and donepezil and Covalent /Intermediate-acting / carbamate inhibitors; physostigmine, neostigmine, and pyridostigmine 2) Irreversible: organophosphorus or organophosphate [ sarin, soman, and tabun, parathion and malathion; echothiophate and isoflurophate. ] 12/14/2023 9
- 10. 1.Reversible ACHE inhibitors • Edrophonium, neostigmine, and pyridostigmine are synthetic quaternary ammonium Poorly absorbed from the conjunctiva, skin, gut, and lungs Distribution into the central nervous system is negligible. • Physostigmine (eserine) is a naturally occurring tertiary amine It is highly lipid soluble is well absorbed from all sites and can be used topically in the eye It is distributed into the central nervous system and is more toxic 12/14/2023 10
- 11. 2. Irreversible inhibitors • Many of the organophosphates (echothiophate is an exception) are highly lipid-soluble liquids. • Echothiophate, a thiocholine derivative, is of clinical value because is more stable in aqueous solution. • Sarin is an extremely potent “nerve gas.” • Parathion and malathion are thiophosphate prodrugs they are converted to the phosphate derivatives in animals and plants and are used as insecticides paraoxon and malaoxon, respectively.. 12/14/2023 11
- 12. Effects of Cholinergic Agonists 12/14/2023 12
- 14. Therapeutic uses of cholinergic agonists • ACH lacks therapeutic importance because of its multiplicity of actions (leading to diffuse effects) and its rapid inactivation by the cholinesterases. • Other cholinergic drugs used for several indications A. Glucoma : Pilocarpine, physostigmine, carbachoal,Echothiophate,Isoflurophate B. Postoperative ileus, congenital megacolon, urinary retention (non-obstructive), constipation Bethanechol, Neostigmine 12/14/2023 14
- 15. Cont’d C. Reversal of neuromuscular blockade Neostigmine, edrophonium, Pyridostigmine D. Diagnosis of myasthenia gravis and cholinergic crisis Edrophonium E. Treatment of myasthenia gravis Pyridostigmine, neostigmine F. Sjögren syndrome/dry eyes and mouth/ Pilocarpine, Cevimeline 12/14/2023 15
- 16. Cont’d G. Anticholinergic poisoning Physostigmine H. Treat patients with Alzheimer’s disease tacrine, donepezil , galantamine, and rivastigmine I. Preventive therapy for organophosphate poising pyridostigmine, 12/14/2023 16
- 17. Adverse effects of cholinergic drugs • The side effects of muscarinic receptor agonists are an extension of their parasympathomimetic actions and include : miosis, blurred vision, lacrimation, excessive salivation and bronchial secretions, sweating, bronchoconstriction, bradycardia, abdominal cramping, increased gastric acid secretion, diarrhea, decreased blood pressure (with reflex tachycardia) and polyuria. • Muscarinic receptor agonists that can penetrate into the brain also cause tremor, hypothermia, and convulsions. 12/14/2023 17
- 18. Cont’d • The toxic effects of a large dose of nicotine are central stimulant actions, which cause convulsions and may progress to coma and respiratory arrest; skeletal muscle end plate depolarization, which may lead to depolarization blockade and respiratory paralysis; and hypertension and cardiac arrhythmias. • Muscarinic receptor agonists are contraindicated in patients with chronic obstructive pulmonary disease (COPD) and asthma peptic ulcer disease GI or urinary tract obstructions 12/14/2023 18
- 19. II. Cholinergic Antagonists • They are commonly known as anticholinergic agents or parasympatholytics • Bind to cholinoceptors (muscarinic or nicotinic) and prevent the effects of acetylcholine (ACh) and other cholinergic agonists. • The most clinically useful of these agents are selective blockers of muscarinic receptors. • Nicotinic receptor blockers Ganglionic blockers( both sympatholytic and parasympatholytic) Neuromuscular blocker 12/14/2023 19
- 20. A. Antimuscarinic Agents • Atropine • Ipratropium • Scopolamine • Tolterodine , • pirenzepine, and • darifenacin • Antihistamines, tricyclic antidepressants, and antipsychotics 12/14/2023 20
- 21. Clinical uses • Examination of the retina and measurement of refraction; inflammatory uveitis • Excessive motility of GI and urinary tract; urinary incontinence; • irritable bowel syndrome • Chronic obstructive pulmonary disease, asthma • Motion sickness • Gastric acid secretion /PUD • Antidotes to cholinesterase inhibitors and mushrooms containing muscarine • Parkinson’s disease 12/14/2023 21
- 24. Adverse Effects • Antimuscarinic agents cause mydriasis, cycloplegia, blurred vision, dry mouth, tachycardia, urinary retention, cutaneous vasodilation, and decreased motility of the stomach and intestines with constipation. • Muscarinic antagonists that enter the brain cause sedation and interfere with memory. excitation, hallucinations, delirium, stupor, toxic psychosis, and convulsions, which may lead to respiratory depression and death. 12/14/2023 24
- 25. Adrenergic agonists and antagonists
- 26. 1. Adrenergic agonists • Also called as sympathomimetics or adrenomimetics with the exception of α2 agonists, • Sympathomimetics can be grouped in to three Direct agonists Indirect agonists Both direct and indirect (mixed action) 12/14/2023 by: Mihret Ayalew 26
- 27. A. Direct agonists Directly interact with and activate adrenoceptors. Based on receptor affinity direct agonists grouped in to: • Non-selective – Cathecolmines • Selective – α1 receptor agonists: phenylephrine and methoxamine, – β1 receptor agonist: Dobutamine – β2 receptors agonists : albuterol, bitolterol, formoterol, metaproterenol, pirbuterol, salmeterol, and terbutaline 12/14/2023 by: Mihret Ayalew 27
- 28. I. Cathecolamines • These include: • Endogenous cathecolamines epinephrine, norepinephrine, dopamine, • Synthetic cathecolamines isoproterenol • For α receptors, the rank order of potency and affinity is epinephrine ≥ norepinephrine >> isoproterenol. • For β receptors, the rank order of potency is isoproterenol > epinephrine > norepinephrine 12/14/2023 by: Mihret Ayalew 28
- 29. A.Epinephrine • Epi is the prototype direct-acting sympathomimetic • Epi is synthesized from NE • It activates all known adrenergic receptors. • Has only a brief period of action when given parenterally, • Ineffective when administered orally. • Do not readily penetrate into the CNS. • It is rapidly metabolized by MAO and COMT • The metabolites metanephrine and vanillylmandelic acid are excreted in urine. 12/14/2023 by: Mihret Ayalew 29
- 30. Major effects mediated by α- and β- adrenoceptors activation by Epinephrine. 12/14/2023 by: Mihret Ayalew 30
- 31. Therapeutic uses • Anaphylactic shock • Cardiac arrest/ asystole/pulseless arrest, • ventricular fibrillation, or pulseless ventricular tachycardia. • As a component of local anesthesia • intraocular surgery • Bradycardia unresponsive to atropine 12/14/2023 by: Mihret Ayalew 31
- 32. Adverse effects of Epi and precautions • anxiety, fear, tension, headache, and tremor. • Tachycardia. • Cardiac arrhythmias • Pulmonary edema • Hyperglycemia • Dose must be reduced in hyperthyroidism patients • Concomitant use in combination with digoxin and non- selective β-blockers should be avoided • In diabetic patients, dosages of insulin may have to be increased. 12/14/2023 by: Mihret Ayalew 32
- 33. B. Norepinephrine • Clinically relevant doses stimulate only α1 , α2 , and β1 receptors. • NE has relatively low potency at β2 receptors • In contrast to EPI, NE produces only vasoconstriction Increase total peripheral resistance and Both systolic and diastolic blood pressures increase Induces reflex bradycardia first-choice vasopressor for the treatment of septic shock. it is not useful for the treatment of anaphylactic shock has low metabolic adverse effects Has similar pK and adverse effect profile with Epi 12/14/2023 by: Mihret Ayalew 33
- 34. C. Isoproterenol (isoprenaline) • Is a very potent β-receptor agonist and has little effect on α receptors • stimulates both β1 - and β2 - adrenergic receptors. • Has positive chronotropic and inotropic actions. • It is a potent vasodilator • Reduces total peripheral resistance, • resulting in a reduction in diastolic blood pressure and increase systolic blood pressure . • Like Epi, ISO relaxes bronchial smooth muscle and induces metabolic effects. • it is rarely used therapeutically due to side effects • ISO may be used to relieve bronchoconstriction 12/14/2023 by: Mihret Ayalew 34
- 35. D. Dopamine • Is the immediate metabolic precursor of norepinephrine • DA produces complex dose-dependent peripheral actions. • Low doses of DA (0.5–2 mg/kg/min) relax smooth muscle in various vascular beds, including renal, mesenteric, and coronary. caused by D1 receptor activation and decreased NE release caused by presynaptic D2 receptor activation. • Moderate doses of DA (2–10 mg/kg/min) activate β1 receptors in addition to DA receptors elicit positive chronotropic and inotropic effects. DA has actions similar to dobutamine at these doses.. 12/14/2023 by: Mihret Ayalew 35
- 36. Cont’d • High doses of DA (>10 mg/kg/min) activate α1 receptors in addition to β1 and cognate DA receptors. • Thus the receptor activation profile of DA is similar to NE when administered at high doses, and it may be used therapeutically like NE • Dopamine can be used for cardiogenic and septic shock and is given by continuous infusion. • Dopamine is also used to treat hypotension, severe heart failure, and bradycardia unresponsive to other treatments. 12/14/2023 by: Mihret Ayalew 36
- 37. Selective α -adrenergic receptor agonists • Phenylephrine and methoxamine • Are less potent but longer acting than NE • primarily act on vascular smooth muscle • Increases total peripheral resistance • Produce a reflex bradycardia greater than for NE • Phenylephrine and methoxamine used to treat hypotension and shock. • Phenylephrine is also used in topical preparations as a mydriatic, as a nasal decongestant and for the treatment of hemorrhoids. 12/14/2023 by: Mihret Ayalew 37
- 38. β1-selective agonist • Dobutamine • a relatively β1-selective agonist • Clinical formulations of dobutamine are a racemic mixture of (–) and (+) isomers, • Each with contrasting activity at α1 and α2 receptors. The (+) isomer is a potent β1 agonist The (+) enantiomer also activates β2 receptors and inhibits α1 receptors The (–) isomer is a potent α1 agonist • Dobutamine has relatively greater inotropic than chronotropic effect compared with isoproterenol. • Peripheral resistance does not decrease significantly 12/14/2023 by: Mihret Ayalew 38
- 39. cont’d • Dobutamine is used clinically for the short-term management of cardiac decompensation in patients with refractory heart failure (American Heart Association Stage D), cardiogenic shock, and septic shock who have been adequately fluid resuscitated but have low cardiac output. 12/14/2023 by: Mihret Ayalew 39
- 40. Selective β2 -Adrenergic Receptor Agonist • Albuterol, • bitolterol, • formoterol, • metaproterenol, • pirbuterol, • salmeterol, and • terbutaline 12/14/2023 by: Mihret Ayalew 40
- 41. Cont’d • These drugs differ from ISO because they are effective orally and have a longer duration of action. • Selective β2 -receptor agonists relax vascular smooth muscle in skeletal muscle and in bronchi and the uterus. • used for the treatment of asthma and chronic obstructive pulmonary disease (COPD) • Used to prevent premature labor. 12/14/2023 by: Mihret Ayalew 41
- 42. β3 agonist • Mirabegron is a β3 agonist that relaxes the detrusor smooth muscle and increases bladder capacity. • It is used for patients with overactive bladder. • Mirabegron may increase blood pressure and should not be used in patients with uncontrolled hypertension. • It increases levels of digoxin and inhibits the CYP2D6 isozyme, which may enhance the effects of other medications metabolized by this pathway (for example, metoprolol). 12/14/2023 by: Mihret Ayalew 42
- 43. Selective α2 -Adrenergic Receptor Agonists • Clonidine, • guanfacine, and • methyldopa • evoking a sympatholytic response • decreased total peripheral resistance, heart rate, and cardiac output. • are used to lower blood pressure in patients with moderate to severe hypertension. • α-methyldopa is a first-line antihypertensive for gestational hypertension. • Clonidine is also used to ameliorate signs and symptoms that accompany withdrawal from long-term opioid use. 12/14/2023 by: Mihret Ayalew 43
- 44. Oxymetazoline • Is a direct-acting synthetic adrenergic agonist that stimulates both α1 - and α2 -adrenergic receptors. • Oxymetazoline directly stimulates α receptors on blood vessels supplying the nasal mucosa and conjunctiva • Oxymetazoline is found in many over-the-counter nasal spray decongestants, as well as in ophthalmic drops • It is absorbed in the systemic circulation regardless of the route of administration and may produce nervousness, headaches, and trouble sleeping. • Local irritation and sneezing may occur with intranasal administration. • Use for greater than 3 days is not recommended, as rebound congestion and dependence may occur. 12/14/2023 by: Mihret Ayalew 44
- 45. Indirect agonists • Their actions are dependent on their ability to enhance the actions of endogenous catecholamines by (1) inducing the release of catecholamines (eg, tyramine, amphetamine), (2) inhibiting their neuronal reuptake (eg, cocaine and tricyclic antidepressants), or (3) preventing the enzymatic metabolism of norepinephrine (monoamine oxidase and catechol-O-methyltransferase inhibitors). • The pharmacologic effects of indirect sympathomimetics are greater under conditions of increased sympathetic activity and norepinephrine storage and release. 12/14/2023 by: Mihret Ayalew 45
- 46. Reading assignment • Read on MAO and COMT inhibitors 12/14/2023 by: Mihret Ayalew 46
- 47. Mixed action agonists • Promote the cytoplasmic release of NE and directly activating adrenergic receptors Eg. ephedrine and pseudoephedrine • Similar to those of epinephrine, although less potent and and slower acting. • These drugs have a long duration of action • Ephedrine and pseudoephedrine have excellent absorption after oral administration and penetrate the CNS, • Oral pseudoephedrine is primarily used to treat nasal and sinus congestion. 12/14/2023 by: Mihret Ayalew 47
- 48. Cont’d • Ephedrine is eliminated largely unchanged in urine, and pseudoephedrine undergoes incomplete hepatic metabolism before elimination in urine. • Ephedrine raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation and it is indicated in anesthesia-induced hypotension. • Ephedrine produces bronchodilation, but it is less potent and slower acting than epinephrine or isoproterenol. • Ephedrine produces a mild stimulation of the CNS. • This increases alertness, decreases fatigue, and prevents sleep. 12/14/2023 by: Mihret Ayalew 48
- 49. Summary of the adrenergic agonists 12/14/2023 by: Mihret Ayalew 49
- 50. Cont’d 12/14/2023 by: Mihret Ayalew 50
- 51. 2. Adrenergic Antagonists • also called adrenergic blockers or sympatholytic • Numerous adrenergic antagonists have important roles in clinical medicine, primarily to treat diseases associated with the cardiovascular system • Adrenergic antagonists are classified according to their relative affinities as α-Adrenergic receptor antagonists β-Adrenergic receptor antagonists Mixed-action α1/β-adrenergic receptor antagonists 12/14/2023 by: Mihret Ayalew 51
- 52. 1. α-Adrenergic Blocking Agents • Nonselective blocker of α1 - and α2 -adrenergic receptors. Phenoxybenzamine, non competitive and irreversible antagonist Phentolamine , competitive antagonist • Selective α1 -Adrenergic Receptor Antagonists Prazosin, terazosin, doxazosin, tamsulosin ,alfuzosin , and silodosin are selective competitive blockers of the α1 receptor. • Selective competitive α2 –blocker Yohimbine works at the level of the CNS to increase sympathetic outflow to the periphery. 12/14/2023 by: Mihret Ayalew 52
- 53. Therapeutic uses of α-Adrenergic Receptor Antagonists • Benign prostatic hyperplasia and urinary retension tamsulosin ,alfuzosin , and silodosin • Pheochromocytoma phenoxybenzamine and phentolamine • Hypertension Prazosin, terazosin, doxazosin not used as monotherapy for the treatment of hypertension • Treatment of erectile dysfunction Yohimbine 12/14/2023 by: Mihret Ayalew 53
- 54. Adverse effects • Postural hypotension • Reflex tachycardia. • Dizziness and headache • Sexual dysfunction 12/14/2023 by: Mihret Ayalew 54
- 55. 2. β-Adrenergic Blocking Agents • All of the clinically available β-blockers are competitive antagonists. • Most β-blocking drugs in clinical use are pure antagonists • Some are partial agonists • some β blockers (eg, betaxolol, metoprolol) are inverse agonist • The β-receptor–blocking drugs also differ in their relative affinities for β1 and β2 receptors pharmacokinetic characteristics and local anesthetic membrane-stabilizing effects. CNS effect 12/14/2023 by: Mihret Ayalew 55
- 56. Pharmacokinetic Properties of the Beta-Receptor Antagonists • Most of the drugs in this class are well absorbed after oral administration • Propranolol undergoes extensive hepatic (first-pass) metabolism • The β antagonists are rapidly distributed and have large volumes of distribution. • Propranolol and metoprolol are extensively metabolized in the liver, with little unchanged drug appearing in the urine. • The CYP2D6 genotype is a major determinant of interindividual differences in metoprolol plasma clearance • Atenolol, celiprolol, and pindolol are less completely metabolized. • Nadolol is excreted unchanged in the urine 12/14/2023 by: Mihret Ayalew 56
- 57. Therapeutic uses of beta blockers • β-Blockers are effective in treating systemic as well as portal hypertension, angina , cardiac arrhythmias ( supraventricular cardiac arrhythmias) myocardial infarction, heart failure, hyperthyroidism, and Open angle glaucoma (timolol, carteolol, evobunolol, metipranolol,and betaxolol ). • They are also used for the prophylaxis of migraine headache (propranolol) 12/14/2023 by: Mihret Ayalew 57
- 58. Non-Selective β -Adrenergic Receptor Antagonists • propranolol • Penbutolol • Pindolol • Sotalol • Timolol • Nadolol • Labeilol • Carteolol • Carvedeilol • Levubunolol • Metiprolol 12/14/2023 by: Mihret Ayalew 58
- 59. Actions of a nonselective β antagonist • Blocks both β1 and β2 receptors with equal affinity • have both negative inotropic and chronotropic effects • Have the ability to block the actions of isoproterenol • The actions of norepinephrine on the cardiovascular system mostly remains unaffected • Triggers a reflex peripheral vasoconstriction • Causes contraction of the bronchiolar smooth muscle • Decrease glycogenolysis and decreased glucagon secretion. • Pronounced hypoglycemia may occur after insulin injection. • β-Blockers also attenuate the normal physiologic response to hypoglycemia, except diaphoresis • Increased triglycerides and reduced high-density lipoprotein 12/14/2023 by: Mihret Ayalew 59
- 60. Selective β1 -Adrenergic Receptor Antagonists • Acebutolol, • atenolol, • betaxolol, • bisoprolol, • esmolol, • metoprolol, and • nebivolol 12/14/2023 by: Mihret Ayalew 60
- 61. Actions and therapeutic uses of selective β1 antagonists • Preferentially block the β1 receptors • This cardioselectivity is most pronounced at low doses • Have fewer effects on pulmonary function, peripheral resistance, and carbohydrate metabolism. • Nebivolol releases nitric oxide from endothelial cells and causes vasodilation. • Are useful in hypertensive patients with impaired pulmonary function. • These agents are also first-line therapy for chronic stable angina • Bisoprolol and the extended-release formulation of metoprolol are indicated for the management of chronic heart failure. 12/14/2023 by: Mihret Ayalew 61
- 62. Beta antagonists with partial agonist activity • Acebutolol • pindolol • Penbutolol • Celiprolol • Carteolol • Can weakly stimulate both β1 and β2 receptors and are said to have ISA • Have a diminished effect on reduction of cardiac rate and cardiac output compared to that of β-blockers without ISA. • minimize the disturbances of lipid and carbohydrate metabolism • are effective in hypertensive patients with moderate bradycardia, and/or respiratory risk • are not used for stable angina or arrhythmias 12/14/2023 by: Mihret Ayalew 62
- 63. β blockers with local anesthetic action • Aceubutolol • Labetolol • Metoprolol • pindolol • Propranolol • This action is the result of typical local anesthetic blockade of sodium channels • The membrane stabilizing β blockers are not used topically on the eye because local anesthesia of the cornea, eliminating its protective reflexes, 12/14/2023 by: Mihret Ayalew 63
- 64. Mixed-action α1/β-adrenergic receptor antagonists • Labetalol and carvedilol • are nonselective β-blockers with concurrent α1 - blocking actions • Decrease peripheral vascular resistance • Carvedilol also decreases lipid peroxidation and vascular wall thickening, effects that have benefit in heart failure. • Labetalol is used as an alternative to methyldopa in the treatment of pregnancy-induced hypertension. • Intravenous labetalol is also used to treat hypertensive emergencies 12/14/2023 by: Mihret Ayalew 64
- 65. Properties of several beta-receptor– blocking drugs 12/14/2023 by: Mihret Ayalew 65
- 66. Indirect adrenergic antagonists • Reserpine • Block the VMAT, and inhibit storage • Causes the ultimate depletion of biogenic amines • used for the management of hypertension • It is also indicated in agitated psychotic states such as schizophrenia to relieve symptoms. 12/14/2023 by: Mihret Ayalew 66