Chapter 6:  Autonomic Pharmacology: Cholinergic Drugs

 

 

.

• Location of cholinergic synapses mainly determine the spectrum of action of acetycholine and choline esters.

• Cholinergic Synaptic Sites

  • autonomic effector sites: innervated by post-ganglionic parasympathetic fibers

  • some CNS synapses

  • autonomic ganglia and the adrenal medulla

  • skeletal muscle motor endplates (motor nerves)

• Systemic administration of acetylcholine (ACh) may theoretically act at these sites, but poor CNS penetration (ACh is a charged, quaternary nitrogen compound) and plasma butyrylcholinesterase which hydrolysizes ACh limit systemic effects.

• Acetylcholine (and other choline esters) effects are initiated by interaction with cholinergic receptors, designated either as muscarinic or nicotinic.

  • Muscarinic receptors (so defined based of their response to muscarine) are found not only at post-ganglionic parasympathetic effector sites but also at autonomic ganglion cells and adrenal medulla where they modulate nicotinic receptor-mediated effects.

  • Nicotinic receptors are the primary cholinergic receptors at autonomic ganglia and skeletal muscle neuromuscular junctions. These receptors were named because of their responsiveness to the alkaloid nicotine.

• Cholinergic influences are prominent in many organ systems:

1. Modified from Table 7-1: Brown, J.H. and Taylor, P. Muscarinic Receptor Agonists and Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p 143

2. Brown, J.H. and Taylor, P. Muscarinic Receptor Agonists and Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, p 142-143.

Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms

Muscarinic Receptor Coupling Mechanisms

• Five types of cholinergic receptors have been identified by molecular cloning methods.

• The possibility of multiple forms was suggested by the pharmacology of piprenzipine which is an effective antimuscarinic in blocking gastric acid secretion, but was not effective in blocking other responses to muscarinic agonists.

• The five muscarinic receptor subtypes, M₁ - M_5, are associated with specific anatomical sites. For example:

  • M₁ -ganglia; secretory glands

  • M₂ - myocardium, smooth muscle

  • M₃ , M₄ :smooth muscle, secretory glands

Adapted from Table 6-2: Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, p119.

• Signal Transduction: Comparison of Muscarinic and Nicotinc Receptors

  • Nicotinic Receptors

    •  Ligand-gated ion channels

    •  Agonist effects blocked by tubocurarine

    •  Receptor activation results in:

      • rapid increases of Na⁺ and Ca²⁺ conductance

      • deplorization

      • excitation

    •  Subtypes based on differing subunit composition: Muscle and Neuronal Classification

  • Muscarinic Receptors

    •  G-protein coupled receptor system

    •  Slower responses

    •  Agonist effects blocked by atropine

    •  At least five receptor subtypes have been described by molecular cloning. Variants have distinct anatomical locations and differing molecular specificities

Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.112-137.

• Direct vs. Indirect-Acting Cholinomimetics

  • A direct-acting cholinomimetic drug produces its pharmacological effect by receptor activation.

  • An indirect-acting drug inhibits acetylcholinesterase, thereby increasing endogenous acetylcholine levels, resulting in increased cholinergic response.

Pharmacological Effects of Cholinomimetics

Cardiovascular: Four major effects

• Vasodilation may also occur due to ACh inhibition of N.E. release from post-ganglionic sympathetic fibers.

• Damaged endothelium can result in ACh causing vasoconstriction by direct action on vascular smooth muscle.

• Negative chronotropic effect (Decrease in heart rate)

  •  Decreases phase 4 (diastolic depolarization)

    • As a result, it takes longer for the membrane potential to reach threshold.

  •   Mediated by M₂ muscarinic receptors

• Decreased SA nodal and AV nodal conduction velocity

  • Excessive vagal tone may induce bradyarrhythmias including partial or total heart block (impulses cannot pass through the AV node to drive the ventricular rate; in this case, the idioventricular or intrinsic ventricular rate must maintain adequate cardiac output)

  • Transmission through the AV node is especially dependent on Ca2⁺ currents.

    •  ACh decreases calcium currents in the atrioventricular node.

• Negative inotropism (decreased myocardial contractility)

  • more prominent in atrial than ventricular tissue.

  • due to a decrease in I_Ca2+ inward current

  • in the ventricle, adrenergic tone dominates;

    • at higher levels of sympathetic tone, a reduction in contractility due to muscarinic stimulation is noted.

    • Muscarinic stimulation reduces the response to norepinephrine by opposing increases in cAMP in addition to reducing norepinephrine release from adrenergic terminals

• Effect of muscarinic receptor activation on cardiac currents

  • increase in I _{K (Ach)} in atrial muscle and in SA and AV nodal tissue

  • decrease in slow, inward calcium (I_Ca2+) current (decreased atrial contractility; decreased AV nodal conduction)

  • decrease in diastolic depolarizing current (I_f)--decreases heart rate, because it takes longer for the membrane potential to reach threshold (less depolarizing I_f current)

• Gastrointestinal and Urinary Tracts

  • Muscarinic agonists increase intestinal peristalsis, tone, and contraction amplitude.

  • Carbachol and bethanecol (not ACh or methacholine) stimulate the urinary tract by increasing ureteral peristalsis and by contraction of the urinary bladder detrusor muscle.

Cellular Events following Cholinergic Receptor Activation

• Nicotinic Muscle Receptor

  • Response:

    • Membrane Depolarization leading to muscle contraction

  • Molecular Aspects:

    • Nicotinic (muscle) receptor's cation ion channel opening

• Nicotinic Neuronal Receptor

  • Responses:

    • Depolarization: postsynaptic cell activation

    • Catecholamine secretion

  • Molecular Aspects

    • Nicotinic (muscle) receptor's cation ion channel opening

• Muscarinic Type M₁

  • Response:

    • Depolarization (late EPSP)

  • Molecular Aspects

    • Stimulation of Phospholipase C (PLC) with formation of inositol-1,4,5 triphosphate (IP₃ ) and diacylglycerol (DAG)resulting in increased cytosolic Ca²⁺

• Muscarinic Type M₂

  • SA node

    • Responses: decreased phase 4 depolarization; hyperpolarization

    • Molecular Aspects: K⁺ channel activation through ß-gamma G_i subunits.

  • Atrium 

    • Responses: decreased contractility; decreased AP duration

    • Molecular Aspects: G_i -mediated inhibition of adenylyl cyclase which decreases intracellular Ca²⁺ levels (reduces contractility);(G_i can inhibit directly Ca²⁺ channel opening)

  • AV node

    • Responses: decreased conduction velocity

  • Ventricle:

    • Responses: decreased contractility

    • Molecular Aspects: G_i -mediated inhibition of adenylyl cyclase which decreases intracellular Ca²⁺ levels (reduces contractility);(G_i can inhibit directly Ca²⁺ channel opening)

Adapted from Table 6-2: Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p119

Muscarinic Receptors: Second Messenger Systems

• Activation of IP₃, DAG cascade

  • DAG may activate smooth muscle Ca²⁺ channels

  • IP₃ releases Ca²⁺ from endoplasmic and sarcoplasmic reticulum

• Increase in cGMP

• Increase in intracellular K⁺ by cGMP-K⁺ channel binding

• inhibition of adenylyl cyclase activity (heart)

Pappano, A.J. Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs, In Basic and Clinical Pharmacology, 7th Edition, (Katzung, B.G.,ed) Appleton & Lange, 1998, p. 93-94

• Nitric Oxide and Muscarinic Receptor Activation

  • Activation of salivary gland and intestinal parasympathetic systems produce significant vasodilation.

  • This effect depends on nitric oxide (EDRF) release and subsequent guanylate cyclase activation. (NO binding to the heme group of guanylate cyclase).

  • Increased levels of cGMP results in stimulation of ion pumps which lower intracellular Ca²⁺ promoting relaxation.

  • Increased nitric oxide production may be mediated by:

    • acetylcholine

    • substance P

    • bradykinin

    • direct mechanical (shear forces) on endothelial membranes.

• Nitric oxide synthase²

  • Nitric oxide synthase catalyzes the conversion of L-arginine and molecular oxygen to nitric oxide.

  • Three forms of nitric oxide synthase

    • form 1 (constitutive): release nitric oxide over short time periods in response to increase in intracellular Ca²⁺ .

    • form 2: responsible for Ca²⁺ - dependent nitric oxide neuronal release.

    • form 3: induced following cytokine or endotoxin cellular activation. This form catalyzes nitric oxide synthesis for an extended time. This form is Ca²⁺ - independent and is responsible for some pathophysiological responses to endotoxin (hypotension, e.g.).

¹Granger,D.N., Regulation of Regional Blood Flow, In Essential Physiology,(Johnson, L.,ed) Lippincott-Ravin,1998, p. 231.

²Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.136-137

• Cholinergic Agents

  • Choline Esters

    • Acetylcholine

    • Bethanechol (Urecholine)

    • Carbachol

    • Methacholine (Provocholine)

  • Alkaloids

    • Muscarine

    • Pilocarpine (Pilocar)

• Gastrointestinal & Genitourinary

  • Bethanechol (Urecholine) 

    •  GI smooth muscle stimulant

      • postoperative abdominal distention

      • paralytic ileus

      • esophageal reflux; promotes increased esophageal motility (other drugs are more effective, e.g. dopamine antagonist (metoclopramide) or serotonin agonists (cisapride)

    •  Urinary bladder stimulant

      • post-operative; post-partum urinary retention

    • alternative to pilocarpine to treat diminished salivation secondary e.g. to radiation

    • Carbachol not used due to more prominent nicotinic receptor activation

  • Methacholine used for diagnostic purposes.

    • testing for bronchial hyperreactivity and asthma

• Opthalmological Uses 

  • Acetylcholine and Carbachol may be used for intraocular use as a miotic in surgery

  • Carbachol may be used also in treatment of glaucoma. 

  • Pilocarpine is used in management of glaucoma and has become the standard initial drug for treating the open-angle form.

  • Sequential adminstration of atropine (mydriatic) and pilocarpine (miotic) is used to break iris-lens adhesions.

• Major contraindication to the use of muscarinic agonists

  • Asthma: Choline esters (muscarinic agonists) can produce bronchoconstriction. In the predisposed patient, an asthmatic attack may be induced.

  • Hyperthyroidism: Choline esters (muscarinic agonists) can induce atrial fibrillation in hyperthyroid patients.

  • Peptic ulcer: Choline esters (muscarinic agonists), by increasing gastric acid secretion, may exacerbate ulcer symptoms.

  • Coronary vascular disease:  Choline esters (muscarinic agonists), as a result of their hypotensive effects, can further compromise coronary blood flow.

•   Adverse Effects: Muscarinic Agonists 

  • salivation

  •  diaphoresis

  •  colic

  •  GI hyperactivity

  •  headache

  •  loss of accommodation

 Indirect-acting Cholinomimetic Drugs

• Acetylcholinesterase Inhibitors

  • Overview

    • Three domains describe the acetylcholinesterase active site: an acyl binding region, the choline binding region, and a peripheral anionic site.

    • There are three classes of anticholinesterase agents

  • Reversible, Short-Acting Anticholinesterases

    • Reversible inhibitors, edrophonium (Tensilon) and tacrine (Cognex), associate with the choline binding domain.

      • The short duration of edrophonium (Tensilon) action is due to its binding reversibility and rapid renal clearance.

      • Tacrine (Cognex), being more lipophillic, has a longer duration.

    • Some reversible inhibitors, propidium and fasiculin, a toxic peptide, bind at the peripheral anionic site.

  • Carbamylating Agents: Intermediate-Duration Acetylcholinesterase Inhibitors

    • Physostigmine and Neostigmine are acetylcholinesterase inhibitors that form a moderately stable carbamyl-enzyme derivative.

    • The carbamyl-ester linkage is hydrolyzed by the esterase, but much more slowly compared to acetylcholine.

    • As a result, enzyme inhibition by these drugs last about 3 - 4 h (t _½ = 15 - 30 min).

    • Neostigmine possesses a quaternary nitrogen and thus has a permanent positive charge.

    • By contrast, physostigmine is a tertiary amine

  •  Phosphorylating Agents: Long-Duration Acetylcholinesterase Inhibitors

    • Organophosphate acetylcholinesterase inhibitors, such as diisopropyl fluorophosphate (DFP) form stable phosphorylated serine derivatives.

    • For DFP the enzyme effectively does not regenerate following inhibition.

      • Furthermore, in the case of DFP, the loss, termed "aging", of an isopropyl group, further stabilizes the phosphylated enzyme.

      • The application of the terms "reversible" and "irreversible" depends on the duration of enzyme inhibition rather than strictly based on mechanism. (see above)

    • Examples of "reversible" acetylcholinesterase inhibitors that may be used clinically include both carbamylating agents and those that associate only with the choline binding domain.

  • "Reversible" Anticholinesterases Used Clinically

    • edrophonium

    • pyridostigmine-Used in treatment of myasthenia gravis

    • neostigmine

    • physostigmine

    • demecarium

    • ambenonium-Used in treatment of myasthenia gravis

• Pharmacokinetics of Acetylcholinesterase Inhibitors

  • Duration of Action: Principles

    • Anticholinesterase duration of action: based on rate of disappearance from plasma.

    • Clinical Anesthesia Context:

      • Anticholinesterase drugs are administered when effects of nondepolarizing neuromuscular-blocking agents are diminishing

      • Note: duration of action of edrophonium is approximately the same compared to that of neostigmine in anesthetized patients. (edrophonium had been usually considered a short-acting agent)

  • Renal Clearance: anticholinesterase drugs

    • Actively secreted into renal tubule lumen

    • Renal clearance:

      •  50% for neostigmine elimination

      •  75% for edrophonium and pyridostigmine elimination

      •  Elimination halftimes -- significantly prolonged in renal failure

        • In renal failure, plasma clearance of anticholinesterase drugs is prolonged more substantially than plasma clearance of neuromuscular-blocking agents-- making recurarization

    • In the absence of renal clearance (renal insufficiency), hepatic metabolism is involved to the following extents::

      • Neostigmine -- 50%

      • Edrophonium -- 30%

      • Pyridostigmine -- 25%

  • Carbamates

    •  Physostigmine, a tertiary amine, is readily absorbed following systemic administration and may be absorbed systemically after conjunctival use.

    •  Neostigmine, also a carbamylating inhibitor, is a quaternary nitrogen compound and, as a result, is poorly absorbed.

    •  Neostigmine is hydrolyzed by plasma esterases with metabolites excreted in the urine.

     

  •  Organophosphates

    • Most organophosphorous acetylcholinesterase inhibitors are well- absorbed lipophillic agents.

    • Organophosphates are generally hydrolyzed by serum and tissue esterases and hydrolytic products are renally excreted.

    • Some organophosphorus chemicals are substrates for mixed-function oxidases that convert phosphorothioates (P=S) to phorphorates (P=O).

    • Organophosphate anticholinesterases are themselves hydrolyzed by liver esterases also called A-esterases or paraoxonases. The extent of paraoxon toxicity in humans is dependent on an A-esterase genetic polymorphism.

    • Lipophillicity and intrinsic reactivity (phosophorylation rate constant) are two important factors in determining the lethality of human exposure to organophosphate inhibitors.

Stoelting, R.K., "Anticholinesterase Drugs and Cholinergic Agonists", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 224-237;  Taylor, P. Anticholinesterase Agents, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.161-174.

• Differences between Parathion & Malathion

  • Parathion

    • Parathion, a low volatility and aqueous-stable, organophosphate is used as an agriculural insecticide.

    • Parathion is converted to paraoxon by mixed function oxidases. Both the parent compound and its metabolite are effective acetylcholinesterase inhibitors (P=S to P=O).

    •  Parathion probably is the most common cause of accidental organophosphate poisoning and death.

    • The phosphothioate structure is present in other common insecticides: dimpylate, fenthion, and chlorpyrifos.

  • Malathion

    • Malathion is converted to the oxygen form (P=S to P=O).

    • Inactivation rates (hydrolysis) vary between species.

    • Inactivation rates are much higher in mammals and birds than insects.

    • Accidental poisoning and death is not observed with malathion with acute toxicity seen in suicide or deliberate poisoning. (lethal dose in man is about 1g/kg)

    • Spraying over populated areas with malathion has been used in control of Medierranean fruit flies and mosquitoes.

    • Malathion is used in treatment of lice infestations.

Taylor, P. Anticholinesterase Agents, In Goodman and Gillman's The Pharmacologial Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p. 167.

• Inhibition Mechanisms

  • Overview: 

    • Inactivation of acetylcholinesterase by organophosphates or carbamates requires either carbamylation or phosphorylation of an active-site reactive serine.

    • Phosphorylation of this serine leads to a very stable acyl-enzyme complex.

    • Deacylation (dephosphorylations) reactions may occur very slowly, thus effective inhibiting enzyme activity for long periods.

    • Reactivation of phosphorylated enzyme may be possible using a nucleophile such as pyridine-2-aldoxime (2-PAM).

    •  2-PAM reactivation may be not be possible, depending on the stability of the phosphoryl enzyme derivative.

     

• Acetylcholinesterase Locations

  • Acetylcholinesterase: post-synaptic cholinergic membranes.

  • Inhibition of acetylcholinesterase with subsequent acetylcholine accumulation causes:

    1. enhanced muscarinic responses at parasympathetic effector sites.

    2. nicotinic receptor stimulation and then paralysis (depolarization block) at autonomic ganglia and skeletal muscle.

    3. CNS cholinergic neuronal stimulation

  • Effects of increased acetylcholine levels can be blocked or reduced by atropine (muscarinic antagonist) at:

    • parasympathetic effector sites

    • autonomic ganglia (muscarinic receptor population)

    • subcortical CNS sites.

     

• Organ Systems Affected by Anticholinesterase Agents

  • Opthalmological Uses of Anticholinesterase Drugs

    • When applied to the conjunctiva, acetylcholinesterase inhibitors produce:

      • constriction of the pupillary sphincter muscle (miosis)

      • contraction of the ciliary muscle (paralysis of accommodation or loss of far vision).

    • Loss of accommodation disappears first, while the miotic effect is longer lasting.

    • During miosis, elevated intraocular pressure (glaucoma) declines due to enhanced flow of aqueous humor.

    •  In glaucoma, elevation of intraocular pressure can cause damage to the optic disc and blindness.

    • There are three types of glaucoma:

      • primary

      • secondary (aphakic (no lens) glaucoma, following cataract removal)

      • congenital.

      • Of the three, primary glaucoma responds to anticholinesterase treatment.

    • Primary glaucoma may either be narrow angle (acute, congestive) or wide-angle (chronic, simple) depending on the angle configuration of the anterior chamber.

    • Narrow angle glaucoma, a medical emergency, may rely on drug treatment to control the attack, although surgery may be required for long-term management (iridectomy, peripheral or complete).

    • Anticholinesterase used for management of glaucoma or accommodative esotropia (esotropia (eso- (inward) + Gr. trepein to turn) [Deviation of visual axis toward that of the other other when fusion is possible]

    • Anticholinesterases Used in Treating Glaucoma

      1. Physostigmine (eserine)

      2. Demecarium (Humorsol)

      3. Echothiophate (Phospholine)

      4. Isoflurophate (Floropryl)

       

  • Gastrointestinal and Urinary Bladder

    • Neostigmine is the anticholinesterase agent of choice for treatment of paralytic ileus or urinary bladder atony.

    • Direct acting cholinomimetic drugs are also useful.

     

  • Myasthenia Gravis

    • Myasthenia Gravis appears to be caused by the binding of anti-nicotinic receptor antibodies to the nicotinic cholinergic receptor.

    • Binding studies using snake alpha-neurotoxins determined a 70% to 90% reduction of nicotinic receptors per motor endplate in myasthenic patients. Receptor number is reduced by:

      • increased receptor turnover (rapid endocytosis)

      • blockade of the receptor binding domain

      • antibody damage of postsynaptic muscle membrane

    • A related disease, Lambert-Eaton syndrome, is a presynaptic disorder in which acetylcholine release is impaired due to autoantibodies against P/Q type calcium channels.

      • Most patients with this syndrome have a malignancy, usually small cell lung carcinoma.

      • Treatment includes immunosuppression and plasmapheresis.

    • Anticholinesterase, edrophonium (Tensilon), is useful in differential diagnosis for myasthenia gravis.

      • In this use, edrophonium (Tensilon) with its rapid onset (30 s) and short duration (5 min) may cause an increase in muscle strength.

      • This change is due to the transient increase in acetylcholine concentration at the end plate.

      • Edrophonium (Tensilon) may also be used to differentiate between muscle weakness due to excessive acetylcholine (cholinergic crisis) and inadequate drug dosing.

    • Anticholinesterase drugs provide partial improvement in myasthenia gravis by increasing the amount of acetylcholine available at neuromuscular junctions.

    • Of the anticholinesterases listed below, pyridostigmine (oral) is the one most widely used in the U.S.

      • Anticholinesterases Used in Treating Myasthenia Gravis

        • Neostigmine (Prostigmin)

        • Pyridostigmine (Mestinon)

        • Ambenonium

         

    • Conditions that resemble myasthenia gravis include:

      • Lambert-Eaton myasthenic syndrome, a presynaptic disorder. (NEJM 332: 1467, 1995 review)

        • Patients with Lambert-Eaton disorder have depressed or absent reflexes, show autonomic changes such as xerostomia and impotence and incremetal responses to repetitive nerve stimulation. Treatment includes plamapheresis and immunosupression.

      • Neurasthenia

        • muscle testing indicates a nonorganic disorder, characterized by feelings of fatigue rather than by a loss of muscle power.

      • Thyroid abnormalities (either hyper or hypo- thyroidism) can increase myasthenic weakness.

        • Thyroid testing is definitive.

      • Associated Disorders:

        •  Myasthenia gravis patients often have associated disorders including:

          •  thymic abnormalities: >70%

          •  hyperthyroidism 3% - 8%

          •  other autoimmune disorders--test for rheumatoid factor and antinuclear antibody

          •  ventilatory dysfunction

        •  Thymic abnormalities: about 35% of patients with epithelial thymoma have myasthenia gravis; furthermore, acetylcholine receptor autoantibody secretion by thymocytes have been reported {Yoshikawa, H and Lennon, V.A. Acetylcholine receptor autoantibody secretion by thymocytes: Relationship to myasthenia gravis, Neurology, 49:562-567,1997}

        •  Of the patients who do not have thymomas, most of the rest have thymic hyperplasia (germinal follicles in the thymus)

          • Most thymomas express acetylcholine receptor epitopes on the surfaces of the neoplastic cells (Lancet 339: 707, 1992; Am. J. Path. 148: 1359 & 1839, 1996). This expression may trigger the disease.

          • Seronegative myasthenia gravis patients do not have thymoma: Neurology 42: 586, 1992.

          • Extended thymectomy is the procedure of choice (Ann. Thoracic Surg. 62: 853, 1996).

Sites of Drug Intervention in Management of Myasthenia Gravis

Drachman, D.B. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction , In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 2469-2472.: Figure adapted from Figure 382-2, p. 2471

• Alzheimer's Disease

  • Tacrine (Cognex) or other cholinesterase inhibitiors are useful in treating mild to moderate Alzheimer's dementias.

1. Taylor, P. Anticholinesterase Agents, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 172-173.;

2. Moroi, S.E. and Lichter, P.R. Ocular Pharmacology In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p. 1634;

3. Drachman, D.B. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction , In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 2469-2472

• Adverse Effects: Overstimulation of Muscarinic and Nicotinic Receptors

  • miosis

  • salivation

  • sweating

  • bronchial constriction

  • vomiting and diarrhea

  • myasthenia gravis

  • neuromuscular blockade (nicotinic effect)

  • CNS effects: high doses

Indirect Cholinomimetic Agents

Acetylcholinesterase Inhibitors ("Reversible")	Acetylcholinesterase Inhibitors ("Irreversible")
Neostigmine (Prostigmin) Physostigmine (Antilirium) Edrophonium (Tensilon)	Soman Parathion Malathion Isoflurophate (Diisopropylflurorphosphate DFP) Echothiophate

 

 

 

 Cholinoceptor-Blocking Drugs

• Introduction: Muscarinic Receptor Antagonists

  • Antimuscarinic agents were of plant origin.

  • Belladonna (beautiful woman, a reference to the drug's mydriatic effects,) are found in many plants.

  • Atropa belladonna (Solanaceae) or the deadly nightshade contains atropine (dl-hyoscyamine) as does Datura stramonium (Jamestown or jimsonweed, thorn-apple, etc.)

  • Scopolamine, also an alkaloid, is found in the shrub Hyosyamus niger and Scopolia carniolica.

    • An alkaloid is one of a large group of organic, basic plant substances. They are usually pharmacologically active and bitter in taste

    • Alkaloids

      • atropine

      • caffeine

      • morphine

      • nicotine

      • quinine

      • strychnine

  • Tertiary and Quaternary Antimuscarinic Agents

    • Atropine, scopolamine, and the semisynthetic agent homatropine (Isopto Homatropine) are tertiary amines, generally well-absorbed and able to penetrate the CNS.

    • Each drug can be converted to a quaternary form by addition of a methyl group to the nitrogen, resulting in methylatropine nitrate, methscopolamine bromide and homatropine methybromide.

    • Quaternary muscarinic receptor antagonists tend to be more potent as muscarinic blockers and have increased ganglionic blocking action.

    • Quaternary (permanently charged) antagonists do not penetrate the CNS to a significant extent. Therefore, CNS activity is limited.

Brown, J.H. and Taylor, P. Muscarinic Receptor Agonists and Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.149-150