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Cholinoceptor activating drugs. M.R. Zarrindast. Cholinergic Receptors: Where are they? . Postganglionic parasympathetic neuroeffector junctions All autonomic ganglia At the neuromuscular endplate. Cholinergic Receptors: Types. Muscarinic receptors Nicotinic receptors

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Cholinoceptor activating drugs

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Cholinoceptor activating drugs l.jpg

Cholinoceptor activating drugs

M.R. Zarrindast


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Cholinergic Receptors: Where are they?

  • Postganglionic parasympathetic neuroeffector junctions

  • All autonomic ganglia

  • At the neuromuscular endplate


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Cholinergic Receptors: Types

  • Muscarinic receptors

  • Nicotinic receptors

    Based on selective activation and antagonism.


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Subtypes and characteristic of cholinoceptors


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Muscarinic receptors(Stimulated by muscarine)

  • on cells innervated by PNS

    • smooth muscle

    • heart

    • exocrine glands

  • endothelial cells of the vascular beds (even though these are not innervated)

  • brain


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Nicotinic receptors(Stimulated by nicotine)

  • autonomic ganglia - CNS & PNS

  • neuromuscular junction (somatic nerves)

  • brain – esp. the spinal cord


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The major groups of cholinoceptor-activating drugs


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Cholinergic agonists

  • Two (2) types

    • Direct –

      • occupy and activate receptors

    • Indirect

      • inhibit acetylcholinesterase

      • levels of Ach increase

      • Ach stimulates receptors


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Esters of Choline


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Esters of Choline

  • hydrophilic

  • differ in breakdown by Ach’esterase

    • acetylcholine - very susceptable

    • methacholine - 3X less susceptible

    • bethanechol - not susceptible

  • methacholine & bethanechol

    • longer duration of action than Ach

    • mostly activate muscarinic receptors


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Direct

  • Esters of choline – mostly activate muscarinic receptors

    • methacholine

    • bethanechol

  • Alkaloids – activate both muscarinic and nicotinic receptors

    • pilocarpine

    • nicotine


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Properties of choline esters


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Alkaloids(pilocarpine and nicotine)

  • Highly lipid soluble

    • well absorbed from GI tract

    • get into brain

  • Capable of both muscarinic and nicotinic receptor activation


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Nicotinic to depolarizing blockade receptors are susceptible

  • depolarizes ganglion cell or neuromuscular endplate

  • if present in high concentration, they produce a “depolarizing block”

    • neuron or endplate stays depolarized

    • skeletal muscle relaxation

    • ganglia of both PNS & SNS systems may be paralyzed


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Effects of Muscarinic Agonists

  • Eye

  • Cardiovascular system

    • Heart

    • Blood vessels

  • Respiratory tract

  • Gastrointestinal tract


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Effect of direct-acting cholinoceptor stimulants


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Eye

  • pupillary sphincter muscle contraction (miosis)

  • ciliary muscle contraction

    • opens drainage canals in anterior chamber

    • lowers intraocular pressure

    • lens thickens for near vision


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CV Effects

  • Direct effects on heart

    • decreased SA and AV conduction velocity

    • decreased force of atrial contraction

  • Reduced vascular resistance –

    • activation of receptors on endothelium

    • generation of nitric oxide (NO)

    • NO causes vascular muscle relaxation

  • Effects on BP modified by reflexes


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Cardiac Conduction - Ach

  • Increased K+ conduction – slows conduction

    • SA node

    • AV node

  • Decreased inward Ca++ current – reduces force of contraction

  • Slowed pacemaker rate opposed by reflexes

  • Ventricles are less directly affected (parasympathetic innervation of ventricles much less than atria)


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Respiratory Effects

  • bronchial smooth muscle contraction

  • respiratory gland secretion

  • asthmatics highly sensitive


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GI Effects

  • Increased secretion

    • gastric glands

    • salivary glands

  • Increased motility - diarrhea


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Cholinergic receptors in the brain

  • Brain has muscarinic receptors

    • Esters don’t penetrate

    • Alkaloids penetrate well

  • Brainstem and spinal cord contain nicotinic receptors

    • Mild alerting from smoking

    • Seizures in overdose


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Nicotine

  • Complex effects on receptors

    • Agonist effects

      • brain nicotinic receptors

      • ganglionic nicotinic receptors – turns on both PNS and SNS

      • neuromuscular nicotinic receptors – only in overdose

    • Blockade - may produce a “depolarizing block” of nicotinic receptors in high doses


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Nicotine

  • Organ effects

    • Determined by predominate branch of the autonomic nervous system in that organ

    • CV effects - largely sympathetic

      • Increased HR, SV, CO

      • Vasoconstriction of vascular beds

    • GI & Urinary - largely parasympathetic

  • Chronic toxicity is the most serious from a societal point of view


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Indirect-Acting Agents

  • inhibit Ach’esterase

  • buildup of Ach at ganglia, neuroeffector and neuromuscular junctions

  • amplify effects of endogenous Ach

  • chief use: insecticides


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Acetylcholinesterase Inhibitors

1. simple alcohols (edrophonium)

2. carbamic acid esters (neostigmine)

3. organophosphates (isoflurophate)


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Enzyme Binding

  • simple alcohols - bind to enzyme reversibly (edrophonium)

  • carbamates - bond with Ach’ase more long-lasting e.g. 30 mins

  • organophosphates - bond irreversibly; very long acting


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Duration of Action of Cholinesterase Inhibitors

  • Determined mostly by length of binding to enzyme

    • simple alcohols - short

    • carbamates - intermediate

    • organophosphates - very long


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Therapeutic uses and durations of action of cholinesterase inhibitors


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Edrophonium (Tensilon)

  • Short acting alcohol type

  • Uses

    • Diagnosis of myasthenia gravis*

      • Muscle strength tested after administration

      • Marked improvement is a positive test

    • Adequacy of treatment

      *Look up the pathogenesis of myasthenia gravis


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Edrophonium (Tensilon)

  • Test adequacy of treatment with longer acting agents (e.g. pyridostigmine)

    • Improvement means dose of long acting agent too low

    • No improvement or worsening indicates “depolarizing block” by long-acting agent. Lower dose indicated.


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Organophosphates

  • phosphorylates Ach’esterase enzyme

  • covalent phosphorus-enzyme bond strong

  • After time the bond “ages” or gets stronger

  • enzyme may be rejuvenated with pralidoxime, esp. before “aging”


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Signs and symptoms of organophosphate poisoning


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Some Insecticides

  • Organophosphates

    • chlorpyrifos (Dursban)

    • malathion

    • diazinon

  • Carbamate

    • Carbaryl (Sevin)


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Cholinesterase Inhibitors

  • CNS - may cause convulsions

  • GI, respiratory, urinary – stimulatory, like direct-acting agents


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Cholinesterase Inhibitors

  • Cardiovascular

    • both sympathetic & parasympathetic stimulation

    • parasympathetic predominate

    • bradycardia, decreased CO, modest fall in BP


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Cholinesterase Inhibitors

  • Skeletal muscle

    • therapeutic doses -

      • moderately prolong Ach

      • intensify Ach actions

    • toxic doses

      • fibrillation of muscle fibers

      • depolarizing blockade and muscle paralysis


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Clinical Uses of Cholinergic Agonists

  • Glaucoma – physostigmine once used

  • GI and urinary stimulation - bethanechol

  • myasthenia gravis

    • edrophonium for diagnosis or testing

    • pyridostigmine for treatment


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SLUDGE: Toxicity

  • Salivation

  • Lacrimation

  • Urination

  • Defecation

  • Gastric Emptying


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Cholinesterase Inhibitor Toxicity

  • approximately 100 organophosphates & 20 carbamate insecticides available

  • SLUDGE

  • convulsions in bad toxicities

  • depolarizating nmj blockade


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Cholinergic Blockers

More selective than agonists; may block muscarinic or nicotinic receptors selectively

M.R. Zarrindast


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Cholinergic Blockers

  • muscarinic blockers - very useful in medicine

  • ganglionic blockers - not used much

  • neuromuscular blockers - used for skeletal muscle relaxation in surgery


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Antimuscarinic Drugs

  • alkaloids – naturally occurring

    • atropine

    • scopolamine

  • tertiary amines

    • dicyclomine

    • benztropine

  • quaternary amines - ipratropium


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Antimuscarinic Drugs

  • tertiary amines & alkaloids

    • lipid soluble

    • good absorption from mucous membranes and skin

    • penetration into brain

    • wide distribution e.g. brain & periphery

    • highly selective for muscarinic receptor

  • quaternary amines - opposite of above


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Antimuscarinic drugs used in gastrointestinal and genitourinary conditions


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Antimuscarinic drugs used in gastrointestinal and genitourinary conditions


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Antimuscarinic drugs used in ophtalmology


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Atropine & Scopolamine

  • plant origin

    • atropine - Atropa belladonna

    • scopolamine - Hyoscyamus niger

  • well absorbed from mucous membranes or skin

  • competes with Ach for muscarinic receptors

  • organs differ in sensitivity to these drugs


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Atropine

  • most sensitive

    • salivary glands

    • bronchial glands

    • sweat glands

  • intermediate sensitivity - heart tissues

  • least sensitive - parietal cells

  • highly selective for muscarinic receptors


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Atropine - CNS

  • sedation in therapeutic doses

  • hallucinations in toxic doses

  • bradycardia when given parenterally

  • antimotion sickness effects

  • antiparkinsonism effects


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Atropine - Eye

  • relaxes pupillary sphincter muscle

    • unopposed sympathetic effects

    • mydriasis or dilation

  • paralysis of the ciliary muscle - cycloplegia

  • reduction in lacrimal secretion - dry eye


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AtropineHeart & Cardiovascular System

  • initial bradycardia - central effect (?)

  • tachycardia due to blockade of vagal slowing

    • Opposes ach effects on SA depolarization

    • Opposes ach effects on AV conduction

  • ventricles are less affected

  • overall - little affect on BP


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Atropine

  • respiratory tract

    • some bronchodilation

    • reduction of respiratory secretions

    • a quaternary drug (Ipatropium) is given as an aerosol to patients with asthma

  • genitourinary tract - ureter and bladder relaxation

  • sweat glands - suppressed by atropine


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Atropine

  • dry mouth

  • slight, if any, decrease in gastric secretion

  • GI motility decreased

    • decreased gastric emptying

    • constipation


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Anticholinergics: Contraindications

  • Glaucoma

  • Urinary retention esp. in patients with Begnin prostatic hypertrophic


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Atropine Poisoning

  • dry as a bone

  • blind as a bat

  • red as a beet

  • very dangerous in children - hyperpyrexia


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Therapeutic Uses

  • antiparkinsonism effects

  • motion sickness - scopolamine given via transdermal patch

  • eye examinations - usually something short-acting (e.g. phenylephrine) is used rather than atropine

  • asthma - ipatropium aerosol

  • insecticide poisoning


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Ganglionic Blockers

block the action of Ach and similar agonists at nicotinic receptors at both sympathetic and parasympathetic ganglia


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Ganglionic Blockers

  • lack of selectivity

  • almost completely abandoned for clinical use

  • used for short-term reduction of BP

  • agents

    • mecamylamine – only one available in the US

    • trimethaphan


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Ganglionic Blockers

  • trimethaphan is devoid of CNS effects

  • mecamylamine is not

    • sedation, tremor, choreiform movements

  • eye

    • cycloplegia

    • pupil variously affected

  • BP decreased - highly orthostatic


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Neuromuscular Blockers


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Neuromuscular Blockers

  • interfere with transmission at the nmj

  • used as adjuncts to general anesthesia

  • 2 types

    • non-depolarizing - typified by tubocurarine

    • depolarizing - typified by succinylcholine


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Neuromuscular transmission

axon

ach’esterase

ach receptors

nerve terminal

muscle

muscle

End-plate


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Curare

  • South American Indian arrow poison

  • crude material called curare

  • active principle is tubocurarine

  • polar, water soluble

  • prevents access of ach to its receptor (competitive antagonist)

  • prevents depolarization of end-plate

  • relaxes skeletal muscles


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Tubocurarine

  • limited distribution in the body

  • acts for > 30 mins

  • jaw & eye paralyzed first

  • larger muscle (trunk & limbs) paralyzed second

  • diaphragm paralyzed last

  • releases histamine - lowers BP


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Other Non-depolarizing Agents

  • Atracurium

  • doxacurium

  • mivacurium

  • pancuronium

  • vecuronium

  • pipecuronium

  • rocuronium


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Depolarizing type: Succinylcholine

  • consists of 2 Ach molecules end-to-end

  • produces a depolarizing block

    • phase I - depolarizes the end-plate & adjacent muscle

    • phase II - with continued presence, it desensitizes the end-plate to Ach

  • metabolized by plasma pseudocholinesterases


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Succinylcholine

  • not metabolized at the nmj

  • plasma cholinesterase determines

    • concentration that reaches the nmj

    • duration of action

  • some people have atypical cholinesterase and can’t metabolize succinylcholine; they over-react to the drug

  • block lasts only 10 to 15 minutes in normal patients

  • blockade NOT overcome by Ach or ach’esterase inhibitors


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Depolarizating Blockersadverse effects

  • hyperkalemia - not well understood

  • increased intraocular pressure

  • increased intragastric pressure

  • muscle pain - presumably because of the unsynchronized contractions just before paralysis


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