Transcript Cholinergic Receptors - .:: سایت تخصصی پزشکی

Cholinoceptor activating drugs
M.R. Zarrindast
Cholinergic Receptors: Where
are they?
1. Postganglionic parasympathetic
neuroeffector junctions
2. All autonomic ganglia
3. At the neuromuscular endplate
Cholinergic Receptors: Types
1. Muscarinic receptors
2. Nicotinic receptors
Based on selective activation and
antagonism.
Subtypes and characteristic of cholinoceptors
Receptor Other
Type
Names
M 1a
M1
M2
Location
Nerves
Structual
Features
Postreceptor
Mechanism
Seven
IP3,DAG
transmembrane
cascade
segments,
G proteinlinked
M 2a, Heart,nerves,
Seven
Inhibition of
Cardiac
transmembrane
cAMP
smooth
M2
segments,G
production,
muscle
protein-linked activation of
K+ channels
Receptor
Type
M3
m41
Other
Names
Location
Structual
Features
Postreceptor
Mechanism
M2b,
Glands,
Seven
IP3 , DAG
transmemb
cascade
glandular M2 smooth
rane
muscle,
segments,
endotheli
G proteinum
linked
?CNS
Seven
Inhibition
transmemb of cAMP
rane
production
segments,
G proteinlinked
Receptor
Type
m51
NM
Other
Names
Location
?CNS
Structual
Features
Postreceptor
Mechanism
Seven
IP3 , DAG
transmem
cascade
brane
segments,
G proteinlinked
Muscle
Skeletal
Pentamer
NA+, K+
type, end muscle
( α2βδγ)2 depolarizing
plate
neuromuscular
ion channel
receptor junction
Recep
tor
Type
NN
Other
Names
Location
Neuronal Postganglionic
type, cell body,
ganglion dendrite
receptor
Structual
Features
Postreceptor
Mechanism
α and β
subunits
only as
α2β2 or
α3β3
NA+, K+
depolarizing
ion channel
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)
• autonomic ganglia - CNS & PNS
• neuromuscular junction (somatic
nerves)
• brain – esp. the spinal cord
The major groups of cholinoceptoractivating drugs
Cholinoceptor stimulants
Direct-acting
(receptor agonists)
Muscarinic
Indirect-acting
(cholinesterase inhibitors)
Nicotinic
Choline esters
Ganglionic
Alkaloids
Neuromuscular
Cholinergic agonists
• Two (2) types
– Direct –
• occupy and activate receptors
– Indirect
• inhibit acetylcholinesterase
• levels of Ach increase
• Ach stimulates receptors
Esters of Choline
O
CH3
H3 C - C - O - CH2 - CH2 - N
+
CH3
Ac e t y l c h o l i n e
CH3
O
CH3
H3 C - C - O - CH - CH2 - N
+
CH3
Me t h a c h o l i n e
CH3
CH3
CH3
H2 N - C - O - CH - CH2 - N
CH3
+
CH3
CH3
Be t h a n e c h o l
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
• Esters of choline – mostly activate
muscarinic receptors
– methacholine
– bethanechol
• Alkaloids – activate both muscarinic
and nicotinic receptors
– pilocarpine
– nicotine
Properties of choline esters
Choline Ester
Acetylcholine
chloride
Methacholine
chloride
Carbachol
chloride
Bethanechol
chloride
Susceptibility to Muscarinic
Cholinesterase
Action
Nicotinic
Action
++++
+++
+++
+
++++
None
Negligible
++
+++
Negligible
++
None
Alkaloids (pilocarpine and nicotine)
• Highly lipid soluble
– well absorbed from GI tract
– get into brain
• Capable of both muscarinic and
nicotinic receptor activation
N
N
CH
N ic o t ine
H
C CH
N
CH
O
O
N
P i loc a rp ine
CH
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
• Eye
• Cardiovascular system
– Heart
– Blood vessels
• Respiratory tract
• Gastrointestinal tract
Effect of direct-acting
cholinoceptor stimulants
Organ
•Eye
Sphincter muscle of iris
Ciliary muscle
•Lung
Bronchial muscle
Bronchial glands
Response
Contraction (miosis)
Contraction for near vision
Contraction
(bronchoconstriction)
Stimulation
Organ
•Heart
Sinoatrial node
Atria
Atrioventricular node
Ventricles
Response
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
Organ
•Blood vessels
Arteries
Veins
•Urinary bladder
Detrusor
Trigone and sphincter
Response
Dilation (via EDRF),
Constriction (high-dose effect)
Dilation (via EDRF),
Constriction (high-dose effect)
Contraction
Relaxation
Organ
•Gastrointestinal tract
Motility
Sphincters
Secretion
•Glands
Sweat, salivary, lacrimal,
nasopharyngeal
Response
Increase
Relaxation
Stimulation
Secretion
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
• 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
• 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
• bronchial smooth muscle
contraction
• respiratory gland secretion
• asthmatics highly sensitive
GI Effects
• Increased secretion
– gastric glands
– salivary glands
• Increased motility - diarrhea
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
• 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
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
• inhibit Ach’esterase
• buildup of Ach at ganglia,
neuroeffector and neuromuscular
junctions
• amplify effects of endogenous Ach
• chief use: insecticides
Acetylcholinesterase Inhibitors
1. simple alcohols (edrophonium)
2. carbamic acid esters (neostigmine)
3. organophosphates (isoflurophate)
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
• Determined mostly by length of
binding to enzyme
–simple alcohols - short
–carbamates - intermediate
–organophosphates - very long
Therapeutic uses and durations of
action of cholinesterase inhibitors
Uses
•Alcohols
Edrophonium
•Organophosphates
Echothiophate
Approximate
duration of action
Myasthenia
gravis, ileus,
arrhythmias
5-15 minutes
Glaucoma
100 hours
Uses
•Carbamates and
related agents
Neostigmine
Approximate
duration of action
Myesthenia gravis,
ileus
Pyridostigmine Myesthenia gravis
0.5-2 hours
Physostigmine
Glaucoma
0.5-2 hours
Ambenonium
Demacarium
Myesthenia gravis
Glaucoma
3-6 hours
4-8 hours
4-6 hours
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 (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 longacting agent. Lower dose indicated.
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”
Signs and symptoms of
organophosphate poisoning
Muscarinic manifestations
•Bronchoconstriction
•Increased bronchial
secretions
•Sweating
•Salivation, Lacrimation
•Bradycardia
•Hypotention
•Miosis, Blurring of vision
•Urinary incontinenc
Nicotinic
manifestations
•Muscular
fasciculation
•Tachycardia
•Hypertension
CNS
manifestations
•Restlessness
•Insomnia
•Tremors, Ataxia
•Confusion
•Convulsions
•Respiratory
depression
•Circulatory
collapse
Some Insecticides
• Organophosphates
– chlorpyrifos (Dursban)
– malathion
– diazinon
• Carbamate
– Carbaryl (Sevin)
Cholinesterase Inhibitors
• CNS - may cause convulsions
• GI, respiratory, urinary – stimulatory,
like direct-acting agents
Cholinesterase Inhibitors
• Cardiovascular
– both sympathetic & parasympathetic
stimulation
– parasympathetic predominate
– bradycardia, decreased CO, modest fall in
BP
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
• Glaucoma – physostigmine once used
• GI and urinary stimulation bethanechol
• myasthenia gravis
– edrophonium for diagnosis or testing
– pyridostigmine for treatment
SLUDGE: Toxicity
•
•
•
•
•
Salivation
Lacrimation
Urination
Defecation
Gastric Emptying
Cholinesterase Inhibitor Toxicity
• approximately 100
organophosphates & 20 carbamate
insecticides available
• SLUDGE
• convulsions in bad toxicities
• depolarizating nmj blockade
Cholinergic Blockers
More selective than agonists;
may block muscarinic or
nicotinic receptors selectively
M.R. Zarrindast
Cholinergic Blockers
• muscarinic blockers - very useful in
medicine
• ganglionic blockers - not used much
• neuromuscular blockers - used for
skeletal muscle relaxation in surgery
Antimuscarinic Drugs
• alkaloids – naturally occurring
– atropine
– scopolamine
• tertiary amines
– dicyclomine
– benztropine
• quaternary amines - ipratropium
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
Antimuscarinic drugs used in gastrointestinal
and genitourinary conditions
Drug
•Quaternary amines
Anisotropine
Clidinium
Glycopyrrolate
Isopropamide
Mepenzolate
Mthantheline
Methscopolamine
Oxyphenonium
Propantheline
Usual Dosage
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
Antimuscarinic drugs used in gastrointestinal
and genitourinary conditions
Drug
•Tertiary amines
Atropine
Dicyclomine
Oxybutynin
Oxyphencyclimin
Propiverine
Scopolamine
Tolterodine
Tridihexethyl
Usual Dosage
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
Antimuscarinic drugs used in
ophtalmology
Drug
Duration of
Effects (days)
7-10
Usual Concentration
(%)
0.5-1
Scopolamine
3-7
0.25
Homatropine
1-3
2-5
1
0.5-2
0.25
0.5-1
Atropine
Cyclopentolate
Tropicamide
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
• most sensitive
– salivary glands
– bronchial glands
– sweat glands
• intermediate sensitivity - heart tissues
• least sensitive - parietal cells
• highly selective for muscarinic
receptors
Atropine - CNS
• sedation in therapeutic doses
• hallucinations in toxic doses
• bradycardia when given
parenterally
• antimotion sickness effects
• antiparkinsonism effects
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
• 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
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
Atropine
• dry mouth
• slight, if any, decrease in gastric
secretion
• GI motility decreased
– decreased gastric emptying
– constipation
Anticholinergics:
Contraindications
• Glaucoma
• Urinary retention esp. in patients
with Begnin prostatic hypertrophic
Atropine Poisoning
•
•
•
•
dry as a bone
blind as a bat
red as a beet
very dangerous in children hyperpyrexia
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
block the action of Ach and similar
agonists at nicotinic receptors at
both sympathetic and
parasympathetic ganglia
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 Blockers
• trimethaphan is devoid of CNS effects
• mecamylamine is not
– sedation, tremor, choreiform movements
• eye
– cycloplegia
– pupil variously affected
• BP decreased - highly orthostatic
Neuromuscular Blockers
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
Neuromuscular transmission
ach’esterase
axon
ach receptors
nerve terminal
muscle
muscle
End-plate
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
•
•
•
•
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
•
•
•
•
•
•
•
Atracurium
doxacurium
mivacurium
pancuronium
vecuronium
pipecuronium
rocuronium
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
• 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
•
•
•
•
hyperkalemia - not well understood
increased intraocular pressure
increased intragastric pressure
muscle pain - presumably because of
the unsynchronized contractions just
before paralysis