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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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cholinergic receptors where are they
Cholinergic Receptors: Where are they?
  • Postganglionic parasympathetic neuroeffector junctions
  • All autonomic ganglia
  • At the neuromuscular endplate
cholinergic receptors types
Cholinergic Receptors: Types
  • Muscarinic receptors
  • Nicotinic receptors

Based on selective activation and antagonism.

muscarinic receptors stimulated by muscarine
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
nicotinic receptors stimulated by nicotine
Nicotinic receptors(Stimulated by nicotine)
  • autonomic ganglia - CNS & PNS
  • neuromuscular junction (somatic nerves)
  • brain – esp. the spinal cord
cholinergic agonists
Cholinergic agonists
  • Two (2) types
    • Direct –
      • occupy and activate receptors
    • Indirect
      • inhibit acetylcholinesterase
      • levels of Ach increase
      • Ach stimulates receptors
esters of choline
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
direct
Direct
  • Esters of choline – mostly activate muscarinic receptors
    • methacholine
    • bethanechol
  • Alkaloids – activate both muscarinic and nicotinic receptors
    • pilocarpine
    • nicotine
alkaloids pilocarpine and nicotine
Alkaloids(pilocarpine and nicotine)
  • Highly lipid soluble
    • well absorbed from GI tract
    • get into brain
  • Capable of both muscarinic and nicotinic receptor activation
nicotinic to depolarizing blockade receptors are susceptible
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
effects of muscarinic agonists
Effects of Muscarinic Agonists
  • Eye
  • Cardiovascular system
    • Heart
    • Blood vessels
  • Respiratory tract
  • Gastrointestinal tract
slide24
Eye
  • pupillary sphincter muscle contraction (miosis)
  • ciliary muscle contraction
    • opens drainage canals in anterior chamber
    • lowers intraocular pressure
    • lens thickens for near vision
cv effects
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
cardiac conduction ach
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)
respiratory effects
Respiratory Effects
  • bronchial smooth muscle contraction
  • respiratory gland secretion
  • asthmatics highly sensitive
gi effects
GI Effects
  • Increased secretion
    • gastric glands
    • salivary glands
  • Increased motility - diarrhea
cholinergic receptors in the brain
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
nicotine
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
nicotine31
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
indirect acting agents
Indirect-Acting Agents
  • inhibit Ach’esterase
  • buildup of Ach at ganglia, neuroeffector and neuromuscular junctions
  • amplify effects of endogenous Ach
  • chief use: insecticides
acetylcholinesterase inhibitors
Acetylcholinesterase Inhibitors

1. simple alcohols (edrophonium)

2. carbamic acid esters (neostigmine)

3. organophosphates (isoflurophate)

enzyme binding
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
duration of action of cholinesterase inhibitors
Duration of Action of Cholinesterase Inhibitors
  • Determined mostly by length of binding to enzyme
    • simple alcohols - short
    • carbamates - intermediate
    • organophosphates - very long
edrophonium tensilon
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

edrophonium tensilon39
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.
organophosphates
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”
some insecticides
Some Insecticides
  • Organophosphates
    • chlorpyrifos (Dursban)
    • malathion
    • diazinon
  • Carbamate
    • Carbaryl (Sevin)
cholinesterase inhibitors
Cholinesterase Inhibitors
  • CNS - may cause convulsions
  • GI, respiratory, urinary – stimulatory, like direct-acting agents
cholinesterase inhibitors44
Cholinesterase Inhibitors
  • Cardiovascular
    • both sympathetic & parasympathetic stimulation
    • parasympathetic predominate
    • bradycardia, decreased CO, modest fall in BP
cholinesterase inhibitors45
Cholinesterase Inhibitors
  • Skeletal muscle
    • therapeutic doses -
      • moderately prolong Ach
      • intensify Ach actions
    • toxic doses
      • fibrillation of muscle fibers
      • depolarizing blockade and muscle paralysis
clinical uses of cholinergic agonists
Clinical Uses of Cholinergic Agonists
  • Glaucoma – physostigmine once used
  • GI and urinary stimulation - bethanechol
  • myasthenia gravis
    • edrophonium for diagnosis or testing
    • pyridostigmine for treatment
sludge toxicity
SLUDGE: Toxicity
  • Salivation
  • Lacrimation
  • Urination
  • Defecation
  • Gastric Emptying
cholinesterase inhibitor toxicity
Cholinesterase Inhibitor Toxicity
  • approximately 100 organophosphates & 20 carbamate insecticides available
  • SLUDGE
  • convulsions in bad toxicities
  • depolarizating nmj blockade
cholinergic blockers

Cholinergic Blockers

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

M.R. Zarrindast

cholinergic blockers50
Cholinergic Blockers
  • muscarinic blockers - very useful in medicine
  • ganglionic blockers - not used much
  • neuromuscular blockers - used for skeletal muscle relaxation in surgery
antimuscarinic drugs
Antimuscarinic Drugs
  • alkaloids – naturally occurring
    • atropine
    • scopolamine
  • tertiary amines
    • dicyclomine
    • benztropine
  • quaternary amines - ipratropium
antimuscarinic drugs52
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
atropine scopolamine
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
atropine
Atropine
  • most sensitive
    • salivary glands
    • bronchial glands
    • sweat glands
  • intermediate sensitivity - heart tissues
  • least sensitive - parietal cells
  • highly selective for muscarinic receptors
atropine cns
Atropine - CNS
  • sedation in therapeutic doses
  • hallucinations in toxic doses
  • bradycardia when given parenterally
  • antimotion sickness effects
  • antiparkinsonism effects
atropine eye
Atropine - Eye
  • relaxes pupillary sphincter muscle
    • unopposed sympathetic effects
    • mydriasis or dilation
  • paralysis of the ciliary muscle - cycloplegia
  • reduction in lacrimal secretion - dry eye
atropine heart cardiovascular system
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
atropine61
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
atropine62
Atropine
  • dry mouth
  • slight, if any, decrease in gastric secretion
  • GI motility decreased
    • decreased gastric emptying
    • constipation
anticholinergics contraindications
Anticholinergics: Contraindications
  • Glaucoma
  • Urinary retention esp. in patients with Begnin prostatic hypertrophic
atropine poisoning
Atropine Poisoning
  • dry as a bone
  • blind as a bat
  • red as a beet
  • very dangerous in children - hyperpyrexia
therapeutic uses
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
ganglionic blockers

Ganglionic Blockers

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

ganglionic blockers67
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
ganglionic blockers68
Ganglionic Blockers
  • trimethaphan is devoid of CNS effects
  • mecamylamine is not
    • sedation, tremor, choreiform movements
  • eye
    • cycloplegia
    • pupil variously affected
  • BP decreased - highly orthostatic
neuromuscular blockers70
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
slide71

Neuromuscular transmission

axon

ach’esterase

ach receptors

nerve terminal

muscle

muscle

End-plate

curare
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
tubocurarine
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
other non depolarizing agents
Other Non-depolarizing Agents
  • Atracurium
  • doxacurium
  • mivacurium
  • pancuronium
  • vecuronium
  • pipecuronium
  • rocuronium
depolarizing type succinylcholine
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
succinylcholine
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
depolarizating blockers adverse effects
Depolarizating Blockersadverse effects
  • hyperkalemia - not well understood
  • increased intraocular pressure
  • increased intragastric pressure
  • muscle pain - presumably because of the unsynchronized contractions just before paralysis
ad