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CHOLINERGIC TRANSMISSION - Coggle Diagram
CHOLINERGIC TRANSMISSION
CHOLINERGIC DRUGS
-
ACETYLCHOLINE Prototype
ACTIONS :check:
MUSCARINIC ACTIONS
HEART: M2 1. Hyperpolarizes SA node
- → ↓ rate of diastolic depolarization
- → bradycardia or even cardiac arrest may occur
2. AV node & His-purkinje fibers
- → Refractory period ↑
- → Conduction slowed
3. PR interval ↑, partial to complete AV block
4. Force of atrial contraction markedly reduced
5. D/t non uniform vagal innervation, intensity of effect on RP & conduction of different atral fibers varies
- → inhomogenity predisposes to atrial fibrillation & flutter
6. Ventricular contractility also ↓ but no marked effect
BLOOD VESSELS (M3) 1. BV dilation
- →Release of EDRF
- → Activates endothelial NO synthase via Ca-calmodulin mechanism
- If endothelium damaged by disease
○ ACh diffuses to vascular smooth muscle→ vasoconstriction
2. Fall in BP, blushing
3. Erection of penis
- → Release of NO
- → Dilate cavernosal vessels
- → Minimal with injected cholinomimetics
SMOOTH MUSCLES (M3) 1. Tone & peristalsis in GIT ↑
- → Sphincters relax
- →Abdominal cramps & evacuation of bowel
2. Perstalsis in ureter ↑
- →Detrusor muscle contracts
- →Bladder trigone & sphincter relaxes
- →Voiding of bladder
3. Bronchial muscles constrict
- → Asthmatics highly sensitive
- Bronchospasm, dyspnea, precipitation of attack
EYE (M3) 1. Miosis
- Contraction of circular muscle
2. Spasm of accommodation
3. Increased aquous outflow
4. Reduction in IOT
GLANDS (M2) 1. Parasympathetic gland secretions ↑
- →Sweating, salivation, tracheobronchial & gastric secretion ↑
2. Effect on intestinal/ pancreatic glands not marked
3. Secr. of milk & bile not aff.
-
SYNTHESIS
ATP + acetate + CoEn-A
↓
Acetyl CoEn-A + Choline
↓
Acetylcholine + CoEn-A
- Choline actively taken up by axonal membrane
○ Na⁺ ChT : Na⁺ choline cotransporter
○ Rate limiting step: choline uptake
- Acetylated by Choline acetyl transferase (ChAT) in axoplasm
○ Hemicholinium (HC3) blocks choline uptake & depletes Ach
STORAGE
- Ach stored in small clear synaptic vesicles
- Active transport of Ach to synaptic vesicles by VAT- vesicle associated transporter
○ Blocked by Vesamicol
- Large dense core vesicles contain peptide cotransmitters such as VIP
RELEASE
- Release of Ach in small quanta
- Extruded in pulses by exocytosis
- Toxins affecting release:
○ Botulinum toxin: inhibits release
○ Black widow spider toxin: induces massive release and depletion
BOTULINUM TOXIN
- Clostridium botulinum
- Highly potent exotoxins: Type A & B
- Neurotoxins→ long lasting loss of cholinergic transmission
BOTOX
- Localized inj. of minute quantity of bot. toxin A: Botox
+ Or its hemagglutinin complex: Dysport
- Trt of various spastic & other neurological conditions
○ Blepharospasm, spastic cerebral palsy, strabismus
○ Spasmodic torticollis, nystagmus, hemifacial spasm
○ Post stroke spasticity
○ Spasmodic dysphonia
○ Axillary hyperhydrosis
○ Beauty trt. for age related wrinkles
- Incorrect inj. / overdose causes
○ Ptosis/ diplopia
○ Facial swelling, dry mouth
○ Dysphagia, dysarthria, muscular weakness, respiratory paralysis
CHOLINESTERASE AchE
- Hydrolyzes Ach & choline is recycled
- AchE is true cholinesterase
- Does not hydrolyse benzoylcholine & butyrylcholine
- Located at sll cholinergic sites , RBC, gray matter
Butyrylcholinesterase (BuChE)
- Pseudocholinesterase
- Present in plasma, liver, intestine, white matter
- Slow ACh hydrolysis
- Methacholine not hydrolysed
- Butyrylcholine & benzoylcholine hydrolysed
CHOLINOCEPTORS
MUSCARINIC RECEPTORS
- GPCR
- Present on postganglionic cholinergic N. endings
M1 :check: Location
- Autonomic ganglia
○ Depolarization
- Gastric glands
○ Histamine release, acid secretion
- Enteric neurones
○ ↑ intestinal secr.
- CNS
○ Learning, memory, motor activity
- Relaxation of LES by vagal stimulation
Nature
Transducer mechanism
- IP3/DAG→ ↑ cytocolic Ca²⁺
- PLA₂↑ → PG synthesis
Agonists
Antagonistss
M2 :check: Locations
- SA node
○ Hyperpolarization, ↓ rate of impulse generation
- AV node
○ ↓ velocity of conduction
- Atrium:
○ Shortening of APD
○ ↓ contractility
- Ventricle
○ ↓ contractility slightly
- Cholinergic nerve endings
○ ↓ ACh release
- CNS:
○ tremor, analgesia
- Visceral smooth muscle
○ Contraction
Nature
Transducer mechanism
- K⁺ channel opening, ↓ cAMP
Agonists
Antagonists
- Methoctramine
- Tripitramine
M3 :check:
Location
- Visceral & bronchial smooth muscle
○ contraction
- Iris
○ Constriction of pupil
- Ciliary muscle
○ Contraction
- Exocrine glands
○ secretion
- Vascular endothelium
○ release of NO→ vasodilation
Nature
Transducer mechanism
- IP₃/DAG -↑ cytosolic Ca²⁺
- PLA₂ ↑ - PG synthesis
Agonist
Antagonists
M4
- Facilitation/ inhibition of transmitter release in certain areas of brain
M5
- Dilate cerebral arterioles
- Facilitate dopamine release & mediate reward behaviour
Nₘ :check:
Location
- NM jn.
○ Depolarization of muscle end plate- contraction of skeletal muscle
Nature
- Has intrinsic ion channel
○ Pentamer of α₂, ß, ε or γ and 𝛿 subunits
○ Each subunit has 4 TM subunits
Transducer mechanism
- Opening of cation (Na/K channels)
Agonists
Antagonists
- Turbocurarine
- α bungarotoxin
Nₙ :check: Location
- Autonomic ganglia:
○ depolarization- postganglionic impulse
- Adrenal medulla
○ Catecholamine release
- CNS
○ site specific excitation or inhibition
Nature
- Intrinsic ion channel
- Pentamer of only α or α,ß subunits , each subunit has 4 TM sefments
Transducer mechanism
- Opening of cation channels
Agonists
Antagonists
- Hexamethonium
- Trimethaphan