ANS: Presynaptic Drugs Flashcards
Mecamylamine MOA
Noncompetitive antagonist of Nn receptors (no effect on Nm)
Mecamylamine therapeutic use
Antihypertensive, tobacco smoking cessation
Mecamylamine blocks…
Both PNS and SNA postganglionic
Reveals dominant ANS division
Side effects Mecamylamine
- tachycardia
- mydriasis
- cycloplegia
- constipation
- urinary retention
- dry mouth
- increased BT
- peripheral pooling in veins
- vasodilation
Vesamicol
- experimental
- inhibit ACh storage
- fusion of empty vesicles with PM
OnabotulinumtoxinA MOA
- Inhibit Ach release
- inactivate SNAP-25
- temporary state of cholinergic denervation
SNAP-25
Required for docking of vesicle (ACh) with presynaptic membrane
Drug action of OnabotulinumtoxinA
- flaccid paralysis of skeletal muscle
- inactivate sweat gland
Restoration of function from OnabotulinumtoxinA
- requires sprouting of new nerve terminals
- 3-4 months
Therapeutic uses of OnabotulinumtoxinA
- cosmetic
- muscle spasms/dystonias
- axillary hyperhidrosis,
Overactive bladder
Side effects of OnabotulinumtoxinA
- dysphagia (BOXED warning)
- breathing difficulties (BOXED warning)
- muscle weakness (ptosis)
- pain
- allergic reaction rare
Muscarine
- Prototype agonist of muscarinic receptors
- mushroom
Atropine
Prototype antagonist
- belladona (deadly nightshade)
- blocks all subtypes equally
What are the two drugs that affect M cholinergic receptors?
Muscarine, atropine
What are the drugs that affect N receptors
- nicotine
- mecamylamine
- d-tubocurarine
All muscarinic receptors have ______ response. All nicotinic have _______ response
GPCR
Ligand gated ion channels
Which drugs affect the Nn receptor
Nicotine
Mecamylamine
Which drugs affect the Nm receptor?
Nicotine
D-tubocurarine
Nicotine in Nn
- prototype agonist (high affinity)
- causes receptor desensitization
Mecamylamine of Nn
Prototype antagonist
Nn structure
2a, 3b
Nm structure
2a, b, y, d
Nicotine Nm
Prototype agonist (low affinity) - desensitization, skeletal muscle paralysis
D-tubocurarine Nm
- Prototype antagonist
- (Curare)
- Non-depolarizing (competitive) Nm blockade
Termination of cholinergic transmission
- AChE rapidly terminates by hydrolysis of transmitter
- allows for next depolarization and prevent lateral diffusion
Inhibition of AChE
- accumulation of Ach in synapse
- increased receptor stimulation and desensitization
BuChE
- plasma, glial cells, liver
- drug metabolizing enzyme
- deficient in some
Succinylcholine-induced apnea is prolonged in those deficient in what?
BuChE
Where is NE formed?
Adrenergic postganglionic neurons
Where is DA formed?
Basal ganglia & renal vasculature
Where is Epi formed?
Adrenal medulla
Formation of catecholamines
Tyrosine —> DOPA —> DA —> NE —> Epi
What is the rate limiting step of synthesis of catecholamines?
Tyrosine —> DOPA
Tyrosine hydroxylase
- regulated by stress
What is the synthesis of Epi increased by?
PNMT
What dose vesicular storage protect DA, NE, and Epi from?
Degradation by MAO
What are DA, NE and Epi transported into storage vesicles by?
VMAT-2
What drug is an inhibitor of NE transmitter storage?
Reserpine
MOA of reserpine
- irreversible inhibitor of VMAT-2 (prevents uptake of DA and NE)
- depletes catecholamines from all terminals
- decreases CO & peripheral resistance —> lowers BP
Therapeutic use of reserpine
Antihypertensive
Antipsychotic
Side effects of reserpine
- sedation
- unopposed cholinergic effects (cramping, diarrhea)
- psychotic depression (high doses)
- orthostatic hypotension
Release of catecholamines
- AP, Ca2+ influx, exocytosis
Negative feedback inhibition of catecholamines
- NE stimulation of presynaptic a2 autoreceptors
- occurs via Gi mediated inhibition of Ca influx
Which drug stimulates NE release?
Tyramine
Which drug inhibits NE release?
Methyldopa
Where is tyramine found?
Fermentation byproduct of tyrosine in protein rich foods
- aged cheese, beer/wine, soy/fish sauce, sauerkraut/kimchee, cured meats
Why is there low oral bioavailability of tyramine?
GI/hepatic MAO
- systemic abs can occur in patients taking MAOI (avoid taking)
MOA of tyramine
- displaces NE from vesicles
- causes non-vesicular release from nerve terminals by REVERSE transport through NET
High systemic exposure of tyramine can cause what?
Hypertensive crisis (abrupt NE release) - dietary restrictions for those on MAOIs prevent this
Where does methyldopa come from?
Prodrug converted to methyl-NE (mNE, active form) by DBH
MOA of methyldopa
A2 receptor agonist
- reduces sympathetic outflow to periphery
Therapeutic use of methyldopa
Gestational HTN
Side effects of methyldopa
- sedation
- dry mouth
- edema
- autoimmune hemolytic anemia (Coomb’s test positive) with long term use
Drug that affects termination of NE
Cocaine
Synaptic NE termination
- re-uptake via NET
- diffusion away from adrenergic receptors
Termination of circulating NE and Epi
- ENT in smooth muscle and glands
- metabolism (liver, kidney)
Stimulant effects from cocaine are due to what?
Excess NE remaining in synapse
3 metabolism mechanisms of catecholamines
- MAO
- COMT
- VMA
Where are MAO?
Mitochondrial
Where are COMT?
Cytosolic (liver, kidney)
What is the major metabolite excreted in urine?
VMA
MAO
- deaminates catecholamines, tyramine, histamine
- clear catecholamines in nerve terminals
What are MAOIs used for ?
Depression
COMT
- o-mthylates catecholes
- clearence of circulating catecholamines
What are COMT inhibitors used for?
Parkinson’s
Significance of VMA
Clinical test of fractional metanephrines used to diagnose pheochromocytoma
RLS of synthesis of Ach
Choline transported into pre-synaptic nerve ending by high affinity Na choline co-transporter
Hemicholinium
- Experimental
- inhibit Ach synthesis
- inhibit choline uptake
- depletes Ach from nerve terminal
Cocaine action
Inhibits NE re-uptake
Therapeutic use of cocaine
Anesthetic/vasoconstrictor
Action of amphetamine
Promote NE release/inhibits re-uptake
Therapeutic use of amphetamine
ADHD
Narcolepsy
Where does onabotulinumtoxin A come from?
Protein neurotoxin (protease) from C. Botulinum
