Cholinoceptor activating drugs

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Cholinoceptor activating drugs

• M.R. Zarrindast

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Cholinergic Receptors Where are they?

1. Postganglionic parasympathetic neuroeffector
   junctions
2. All autonomic ganglia
3. 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
Receptor Type Other Names Location Structual Features Postreceptor Mechanism
M1 M 1a Nerves Seven transmembrane segments, G protein-linked IP3,DAG cascade
M2 M 2a, Cardiac M2 Heart,nerves, smooth muscle Seven transmembrane segments,G protein-linked Inhibition of cAMP production, activation of K channels
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Receptor Type Other Names Location Structual Features Postreceptor Mechanism
M3 M2b, glandular M2 Glands, smooth muscle, endothelium Seven transmembrane segments, G protein-linked IP3 , DAG cascade
m41 ?CNS Seven transmembrane segments, G protein-linked Inhibition of cAMP production
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Receptor Type Other Names Location Structual Features Postreceptor Mechanism
m51 ?CNS Seven transmembrane segments, G protein-linked IP3 , DAG cascade
NM Muscle type, end plate receptor Skeletal muscle neuromuscular junction Pentamer ( a2ßd?)2 NA, K depolarizing ion channel
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Receptor Type Other Names Location Structual Features Postreceptor Mechanism
NN Neuronal type, ganglion receptor Postganglionic cell body, dendrite a and ß subunits only as a2ß2 or a3ß3 NA, K depolarizing ion channel
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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 Achesterase
• 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
Choline Ester Susceptibility to Cholinesterase Muscarinic Action Nicotinic Action
Acetylcholine chloride
Methacholine chloride None
Carbachol chloride Negligible
Bethanechol chloride Negligible None
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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
Organ Response
Eye Sphincter muscle of iris Ciliary muscle Contraction (miosis) Contraction for near vision
Lung Bronchial muscle Bronchial glands Contraction (bronchoconstriction) Stimulation
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Organ Response
Heart Sinoatrial node Atria Atrioventricular node Ventricles Decrease in rate (negative chronotropy) Decrease in contractile strength (negative ionotropy),Decrease in refractory period Decrease in conduction velocity, Increase in refractory period Small decrease in contractile strength
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Organ Response
Blood vessels Arteries Veins Dilation (via EDRF), Constriction (high-dose effect) Dilation (via EDRF), Constriction (high-dose effect)
Urinary bladder Detrusor Trigone and sphincter Contraction Relaxation
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Organ Response
Gastrointestinal tract Motility Sphincters Secretion Increase Relaxation Stimulation
Glands Sweat, salivary, lacrimal, nasopharyngeal Secretion
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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 dont 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 Achesterase
• 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 Achase 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
Uses Approximate duration of action
Alcohols Edrophonium Myasthenia gravis, ileus, arrhythmias 5-15 minutes
Organophosphates Echothiophate Glaucoma 100 hours
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Uses Approximate duration of action
Carbamates and related agents Neostigmine Pyridostigmine Physostigmine Ambenonium Demacarium Myesthenia gravis, ileus Myesthenia gravis Glaucoma Myesthenia gravis Glaucoma 0.5-2 hours 3-6 hours 0.5-2 hours 4-8 hours 4-6 hours
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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 Achesterase 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
Muscarinic manifestations Nicotinic manifestations CNS manifestations
Bronchoconstriction Increased bronchial secretions Sweating Salivation, Lacrimation Bradycardia Hypotention Miosis, Blurring of vision Urinary incontinenc Muscular fasciculation Tachycardia Hypertension Restlessness Insomnia Tremors, Ataxia Confusion Convulsions Respiratory depression Circulatory collapse
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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
Drug Usual Dosage
Quaternary amines Anisotropine Clidinium Glycopyrrolate Isopropamide Mepenzolate Mthantheline Methscopolamine Oxyphenonium Propantheline 50 mg tid 2.5 mg tid-qid 1 mg bid-tid 5 mg bid 25-50 mg qid 50-100 mg qid 2.5 mg qid 5-10 mg qid 15 mg qid
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Antimuscarinic drugs used in gastrointestinal and
genitourinary conditions
Drug Usual Dosage
Tertiary amines Atropine Dicyclomine Oxybutynin Oxyphencyclimin Propiverine Scopolamine Tolterodine Tridihexethyl 0.4 mg tid-qid 10-20 mg qid 5 mg tid 10 mg bid 15 mg bid-tid 0.4 mg tid 2 mg bid 25-50 mg tid-qid
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Antimuscarinic drugs used in ophtalmology
Drug Duration of Effects (days) Usual Concentration ()
Atropine 7-10 0.5-1
Scopolamine 3-7 0.25
Homatropine 1-3 2-5
Cyclopentolate 1 0.5-2
Tropicamide 0.25 0.5-1
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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
achesterase
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 gt 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
  cant metabolize succinylcholine they over-react
  to the drug
• block lasts only 10 to 15 minutes in normal
  patients
• blockade NOT overcome by Ach or achesterase
  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