University:
Michigan State University
Course:
PHM 430 | Human Pharmacology
Academic year:

2020
Views:

437

Pages:

50
Author:

Caroline Mcfarland

Chapter 4: Cholinergic system Overview • Drugs affecting the ANS are divided into 2 groups according to the type of neurons involved in the MOA: 1. Cholinergic drugs: they act in receptors that are activated by acetylcholine (Ach). 2. Adrenergic drugs: they act in receptors that are activated by norepinephrine or epinephrine. • Cholinergic & Adrenergic drugs both act by either stimulating or blocking receptors of the ANS. Cholinergic Receptors ( Cholinoceptors) • Cholinoreceptor denotes receptors that respond to Ach. • Two families/subtypes of Cholinoreceptor were named after the alkaloids originally used in their identification: Muscarinic (M) & nicotinic (N). 1. Muscarinic: ▫ These receptors in addition to binding to Ach, also recognize muscarine, but show a weak affinity for nicotine. ▫ These receptors have been found in organs innervated by parasympathetic nerves as well as some tissues that are not innervated by these nerves, e.g. endothelial, & on those tissues innervated by postganglionic sympathetic cholinergic nerves. Cholinergic Receptors ( Cholinoceptors) 1. Muscarinic: ▫ Five subclasses of these receptors: M1, M2, M3, M4, & M5 . ▫ Muscarinic receptors are G-coupling protein receptors (seven transmembrane domains) ▫ These receptors have different signal transduction mechanisms based on the G-protein to which they are coupled. • M1, M3, M5 activations stimulate IP2 & DAG. These receptors are primarily responsible for activating Ca+2-dependent responses, such as secretion by glands & the contraction of smooth muscle. • M2, M4 activation inhibits adenylyl cyclase leading to decrease cAMP. Cholinergic Receptors ( Cholinoceptors) 1. Nicotinic: ▫ These receptors in addition to binding to Ach, also recognize nicotine, but show a weak affinity for muscarine. ▫ N receptors are transmembrane polypeptide whose subunits form cation-selective ion channels. ▫ N receptors are located on plasma membrane of postganglionic cells in all autonomic ganglia of muscles innervated by somatic motor fibers à Neuromuscular junctions & of some CNS neurons. Cholinergic Receptors ( Cholinoreceptors) 1. Nicotinic: • When the Nicotinic AchR is stimulated à the channel opens & allows Na+ to rush into the cell. • This triggers depolarization of the cell & elicits a neuronal action potential in postganglionic nerves or muscle contraction ( skeletal MS). • Nicotinic AchR located at the neuromuscular junction are sometimes designated NM & the ganglionic neuronal receptors are designated NN . Sites of actions of cholinergic agonists in ANS & somatic system Cholinergic Drugs • Nonselective Cholinergic stimulants in sufficient dosage can produce very diffuse & marked alterations in organ system functions. • Selectivity of action is based on several factors: 1. Receptor selectivity: Nicotinic or Muscarinic 2. Pharmacokinetic selectivity: using appropriate routes of administration so that desired effects can often be achieved while minimizing systemic effects. Cholinomimetic Drugs • Cholinomimetic Drugs can elicit some or all of the effects that Ach produces. • Include agents that act directly (cholinoceptor agonists/stimulants) or indirectly acting mechanism (cholinesterase inhibitors). Cholinomimetic Drugs Direct acting Cholinomimetics Direct acting Cholinergic Drugs • Cholinergic receptor agonists mimic the effects of Ach by binding directly to cholinoceptors. • They differ in their spectrum of action (Nicotinic vs. Muscarinic stimulation) & in their pharmacokinetics. • The direct acting cholinomimetics can be subdivided into: 1. Parasympathomimetic drugs: agents that exert their effects primarily through stimulation of muscarinic receptors at parasympathetic neuroeffector junctions. 2. Agents that stimulate nicotinic receptors in autonomic ganglia & at the neuromuscular junction. Direct acting Cholinergic Drugs • These agents can be divided into 2 groups: a. Choline esters (Ach, methacholine, carbachol, bethanechol). b. Naturally cholinomimetic occurring alkaloids (muscarine, nicotine, pilocarpine, & lobeline) Direct acting Cholinergic Drugs 1. Choline esters: • Poorly absorbed & poorly distributed into the CNS cause they are hydrophilic & susceptible to esterase hydrolysis in the GIT. • Methacholine is more resistant to hydrolysis, & the carbamic acid ester carbachol & bethanechol are still more resistant to hydrolysis by cholinesterase & have correspondingly longer duration of action. 2. Natural cholinomimetic alkaloids: • Tertiary amines (pilocarpine, nicotine, lobeline) are well absorbed from the GIT from most sites of administration, & it can cross the BBB. • Quaternary amines (Muscarine) is less completely absorbed from the GIT than tertiary amines but is toxic when ingested & it even enters the brain. Muscarine agonists: Parasympathomimetic • Cholinergic receptor agonists ( also called Ach-like agonists) mimic the effects of Ach by binding directly to cholinoceptors. • They show relatively few selectivity for M2, M4 vs. M1,M3, M5 . • Methacholine, pilocarpine& bethanechol are selective agonists of M receptors. • Carbachol & Ach can activate both M & N receptors: at usual therapeutic doses, the effects of Carbachol & Ach are entirely due to the activation of M receptors b/c of greater accessibility of the M receptors compared with the N receptors. Direct acting Cholinergic stimulantsMechanism of Action • Activation of the parasympathetic NS modifies organ functions by to major mechanisms: 1. Directly: by activation of muscarinic receptors on effector cells to alter organ function directly. 2. Indirectly: by modulating the effects of the parasympathetic & sympathetic NS. Direct acting Cholinergic stimulantsOrgan system effect A. Cardiovascular system: - Ach has four primary effects on the CVS: 1. Vasodilation by activating the endothelial M3. 2. Decrease the heart rate (negative chronotropic effect) by activating M2 receptors. 3. Decrease in the conduction velocity in the atrioventricular (AV) node by activating M2 receptors (negative dromotropic effect). 4. Decrease in the force of cardiac contraction (negative inotropic effect) by activating M2 receptors. Direct acting Cholinergic stimulantsOrgan system effect A. Cardiovascular system: - This result in marked reduction in the peripheral vascular resistance, bradycardia, & decrease AV node conduction velocity in addition to hypotension. - This direct slowing effect is often opposed by reflex sympathetic discharge, elicited by the decrease in blood pressure. - The net effect on heart rate depends on: a. local contractions of the agonist in the heart & in the vessels b. And on the level of reflex responsiveness. Direct acting Cholinergic stimulantsOrgan system effect Direct acting Cholinergic stimulantsOrgan system effect B. Eye system: - Muscarinic agonists cause contraction of the smooth muscle: 1. Iris sphincter: resulting in miosis by activating of M3 receptor. 2. Ciliary muscle: resulting in accommodation of the eye for the near vision by activating of M3 receptor. Direct acting Cholinergic stimulantsOrgan system (eye) effect Direct acting Cholinergic stimulantsOrgan system effect C. Other organ systems: à Respiratory system *: Bronchoconstriction & increase tracheobronchial secretions. à GI tract ***: Stimulation of salivation & acid secretion, increased intestinal tone & peristaltic activity, & relaxation of most sphincters. à Genitourinary tract: stimulation of the detrusor muscle * & relax the trigone & sphincter muscles of the bladder **, thus promoting urination. * M3 activation, ** M2 activation, *** M2 & M3 activation Direct acting Cholinergic stimulantsOrgan system effect C. Other organ systems: à Miscellaneous Secretory glands*: Stimulation secretion by thermoregulatory sweat, lacrimal, & nasopharyngeal glands. àCNS: Muscarinic agonists are able to produce marked CNS effects owing to activation of M1-receptors in the brain areas responsible for cognition. * M3 activation Direct acting Cholinomimetics- Clinical uses 1. Glaucoma: these agents reduce the intraocular pressure by causing the contraction of the ciliary body so as to facilitate outflow of aqueous humor (e.g. pilocarpine & carbachol). 2. Bladder & bowel atony after surgery: Bethanechol. 3. Xerostomia associated with Sjögren’s syndrome & that caused by radiation damage of the salivary glands: pilocarpine & cevimeline. Direct acting Cholinomimetics- Toxicity à Potentially severe adverse effects can result from systemic administration of Cholinomimetics & the consumption mushrooms of genus lnocybe (muscarine). à Overdosage is characterized chiefly by exaggeration of various parasympathomimetic effects: NVD, urinary urgency, salivation, sweating, hypotension with reflex tachycardia, cutaneous vasodilation, & bronchial constriction. Direct acting Cholinomimetics- Toxicity • Pilocarpine can cross the BBB & affect cognitive functions especially among elderly. ▫ It also can cause blurred vision, night blindness, & brow ache. àCholinomimetics elicits miosis & spasm of accommodation, both of which disturb vision. àTreatment consists of the parenteral administration of atropine in doses sufficient to cross the BBB & measures to support the respiratory & CV systems & to counteract pulmonary edema (Pilocarpine toxicity). Indirect acting CholinomimeticsAnticholinesterase Agents Indirect Acting Cholinomimetics- Anticholinesterase Agents (Reversible) - Acetylcholinesterase (AChE) is an enzyme that specifically cleaves Ach to acetate & choline, & thus terminates its action. • Inhibitors of AChE indirectly provide a cholinergic action by preventing the degradation of Ach & prolonging the lifetime of it in synapses where Ach is released physiologically (i.e. they have both muscarinic & nicotinic effects. Indirect Acting Cholinomimetics- Mechanism of action • The active site of AChE enzyme comprises two distinct regions: an anionic site & esteratic site. • In the initial catalytic step: ACh binds to the enzyme’s active site & is hydrolyzed, yielding free choline & the acetyl-enzyme. • In the 2nd step: the covalent acetyl-enzyme bond is split, with the addition of water (hydration). Indirect acting CholinomimeticsMechanism of action Indirect Acting Cholinomimetics- Mechanism of action • There are 3 chemical groups of AChE inhibitors: 1. Simple alcohols bearing a quaternary ammonium grp: Edrophonium: reversibly bind electrostatically & by hydrogen bonds to the active site & correspondingly short-lived (on the order of 2-10 minutes). 2. Carbamates: Neostigmine: the carbamylated enzyme is considerably more resistant to hydrolysis, & this step is correspondingly prolonged ( on the order of 2 to 6 hours). 3. Organophosphates: Echothiophate à irreversible binding (not included). Indirect Acting Cholinomimetics- Pharmacokinetics 1. Carbamates: ▫ Quaternary carbamates: Pyridostigmine & Neostigmine: are polar compounds & relatively insoluble in lipids. Therefore, absorption is predictably poor & distribution into the CNS is neglectable. ▫ Tertiary carbamates: Physostigmine: is well absorbed from all sites & it distributes into the CNS (toxic effects). Indirect Acting Cholinomimetics ▫ Inhibition of the AChE potentiates & prolong the stimulation of cholinoceptors resulting from Ach released at the synapses found at the different regions including: skeletal muscle NMJ, adrenal medulla, autonomic ganglia, cholinergic neuroeffector junctions of the ANS, & cholinergic synapses in the CNS. ▫ Because the primary action is to amplify the actions of endogenous ACh, the effects are similar (but not always identical) to the effects of the direct-acting cholinomimetic drugs. Indirect Acting Cholinomimetics ▫ The anti-AChE agents potentially can produce all the following effects: 1. Stimulation of muscarinic receptors responses at the autonomic effector organs. 2. Stimulation, with occasional subsequent depression of cholinergic receptor sites in the CNS. 3. Stimulation, followed by depression or paralysis of all autonomic ganglia & skeletal MS (nicotinic actions). Indirect acting CholinomimeticsOrgan system effects Indirect Acting Cholinomimetics Organ system effect 1. CNS: ▫ In low concentration à lipid-soluble cholinesterase inhibitors cause diffuse activation on the electroencephalogram & a subjective alerting response. ▫ In high concentration à they cause generalized convulsions, which maybe followed by coma & respiratory arrest. Indirect Acting Cholinomimetics Organ system effect 2. Eye, respiratory tract, GIT, & UT: ▫ The effects are qualitatively quite similar to the effect of the direct acting cholinomimetics. 3. Cardiovascular system: ▫ They are quite complex à in the heart, the effects of the parasympathetic stimulation predominate (bradycardia with a consequent decrease in cardiac output & blood pressure). Indirect Acting Cholinomimetics Organ system effect 3. Cardiovascular system: ▫ At moderate doses, cholinesterase inhibitors cause an increase in systemic vascular resistance (vasoconstriction). 4. Neuromuscular junctions: ▫ Low therapeutic doses moderately prolong & intensify the action of physiologically released Ach à This increase the strength of contraction. ▫ Higher doses, with marked inhibition of acetylcholinesterase à depolarizing NM blockage occurs & that maybe followed by a phase of nondepolarizing blockage (i.e. nicotinic receptors can quickly desensitized). Indirect acting CholinomimeticsClinical uses Indirect Acting Cholinomimetics-Clinical uses a) Glaucoma: Physostigmine, Demecarium, Echothiophate, Isoflurophate. b) GIT &UT: Neostigmine is most commonly used among others in the treatment of adynamic ileus & atony of the urinary bladder, both of which may result from surgery. c) Myasthenia gravis: (long-term neuromuscular disease that leads to varying degrees of skeletal muscle weakness) These agents help to relieve the weakness by elevating & prolonging the concentration of Ach in the synaptic cleft, producing a greater activation of the remaining nicotinic receptors. They also play a role in the diagnosis & therapy of this disease, cause they increase MS strength. Indirect Acting Cholinomimetics-Clinical uses c) Myasthenia gravis: (long-term neuromuscular disease that leads to varying degrees of skeletal muscle weakness) Carbamates (Pyridostigmine, neostigmine, & ambenonium): these agents are used in the long term treatment of this disease. • Edrophonium (I.V): is used for the diagnosis & in differentiating myasthenic crisis from cholinergic crises. Indirect Acting Cholinomimetics-Clinical uses c) Anti-muscarinic drug intoxication: ▫ To treat overdoses of drugs with antimuscarinic actions, such as Atropine. ▫ Physostigmine: has been used for this application because it can enter the CNS & reverse the central as well as the peripheral signs of muscarinic blockade. d) Alzheimer’s disease: ▫ Tacrine, donepezil, rivastigmine, & galantamine are approved for the palliative treatment of AD. These agents can cross the BBB to produce a reversible inhibition of AChE in the CNS. They produce modest but significant improvement in the cognitive function of mild to moderate AD pts, but don’t delay the progression of the disease. Direct acting Cholinomimetics- Nicotinic drugs • Drugs that modulate Nicotinic Receptors have very limited application because of the localization of these receptor subtypes. • Pharmacological stimulation of ganglionic neuronal receptors (NN) has limited utility because this receptor affect both branches of the ANS. • The tissue & organ effect depend on the autonomic innervation of the organ involved. Direct acting Cholinomimetics- Nicotinic drugs àIn the brain: the most abundant nicotinic receptor is ɑ4β2 oligomer. àChronic exposure to nicotine has a dual effect at nicotinic receptors: depolarization followed by desensitization. àActivation of ɑ4β2 NR is associated with greater release of dopamine in the mesolimbic system. This effect is thought to contribute to the mild altering action & the addictive property of nicotine absorbed from tobacco. Direct acting Cholinomimetics- Nicotinic drugs • Caution: Excessive stimulation of NM receptors can cause depolarization blockage à loss of electrical excitability due to inactivation of voltage-gated Na+ channels. If repeated doses of the agonist is used, the nicotinic cholinergic receptors can quickly become desensitized leading to fasciculation & paralysis.

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