Pharmacology - Autonomics II and III Flashcards
M1/M3/M5 receptors couple to:
phospholipase C
M2/M4 receptors couple to:
adenylyl cyclase and/or K+ channels
Are M2 autoreceptors excitatory or inhibitory?
Inhibitory
utilize signaling pathways identical to M2 receptors in the heart - cAMP reduction and K+ channel activation
*decreases HR
Pilocarpine is a nonselective muscarinic ______.
agonist
Direct-acting cholinomimetic agents bind to and directly activate muscarinic or nicotinic receptors. The indirect agents act by:
inhibiting the action of acetylcholinesterase –> increase endogenous ACh in the synaptic clefts and neuroeffector junctions
Some cholinesterase inhibitors have a moderate direct action, for example some quaternary carbamates like ____
Neostigmine
active NM nicotinic cholinoceptors in addition to blocking cholinesterase
Bethanechol is used for:
postoperative and neurogenic ileus and urine retention
relieves paralysis of GI/GU tract
carbamic acid ester
Direct muscarinic effects of direct-acting choliniceptor stimulants:
Eye - sphincter muscle of iris
contraction (miosis)
muscarinic agonists can reduce intraocular pressure by causing contraction of the ciliary body so as to facilitate outflow of aqueous humor and perhaps also its rate of secretion…Pilocarpine, a well-absorbed, tertiary amine, can be used for this.
Direct muscarinic effects of direct-acting choliniceptor stimulants:
Eye - ciliary muscle
contraction for near vision
muscarinic agonists can reduce intraocular pressure by causing contraction of the ciliary body so as to facilitate outflow of aqueous humor and perhaps also its rate of secretion…Pilocarpine, a well-absorbed, tertiary amine, can be used for this.
Direct muscarinic effects of direct-acting choliniceptor stimulants:
Heart - SA node
Negative chronotropy
HR down
M2
Direct muscarinic effects of direct-acting choliniceptor stimulants:
Heart - Atria
decrease in contractile strength - negative inotropy
_______ in refractory period
M2
Direct muscarinic effects of direct-acting choliniceptor stimulants:
Heart - AV node
decrease in conduction velocity - negative dromotropy
increase in refractory period
M2
Direct muscarinic effects of direct-acting choliniceptor stimulants:
Heart - ventricles
small decrease in contractile strength
M2
Direct muscarinic effects of direct-acting choliniceptor stimulants:
Arteries and veins
dilation via NO (EDRF)
constriction is high dose direct effect
Direct muscarinic effects of direct-acting choliniceptor stimulants:
Bronchial muscle
contraction/bronchoconstriction
Direct muscarinic effects of direct-acting choliniceptor stimulants:
GI tract - motility
increase
Direct muscarinic effects of direct-acting choliniceptor stimulants:
GI sphincters
relaxation
Direct muscarinic effects of direct-acting choliniceptor stimulants:
GI secretion
stimulation
Direct muscarinic effects of direct-acting choliniceptor stimulants:
Urinary bladder - detrusor muscle
contraction
Direct muscarinic effects of direct-acting choliniceptor stimulants:
Urinary bladder - Trigone and sphincter
relaxation
Direct muscarinic effects of direct-acting choliniceptor stimulants:
sweat, salivary, lacrimal, nasopharyngeal
secretion (SLUDGE)
M3
Neostigmine Tacrine Donepezil Edrophonium Physostigmine Pyridostigmine
These drugs are examples of:
cholinesterase inhibitors
Isoflurophate Sarin Echothiophate Parathion Paraoxon
These drugs are examples of:
Organophosphate cholinesterase inhibitors
Poisons, insecticides and nerve gases
Sarin gas poisoning can be reversed by pralidoxime because:
Pralidoxime (PAM) is a strong nucleophile that regenerates acetylcholinesterase
**must work before “aging” which makes acetylcholinesterase permanently/irreversibly inactive
Sarin gas takes only 2 minutes to age, so administer quickly
Explain the effect of Neostigmine on muscle strength at LOW doses.
Increases ACh level
Under or overdoses in MG patients cause paralysis
Explain the effect of Neostigmine on muscle strength at HIGH doses.
Depolarizing block
Under or overdoses in MG patients cause paralysis
Major uses for cholinomimetics:
diseases of the eye ie glaucoma;
GI and urinary tension (is post-surgical atony, neurogenic bladder, impaired salivation);
NMJ issue ie MG, reversal of non-depolarizing blocker-induced neuromuscular paralysis;
cognitive enhancement in Alzheimer’s
What drug can be used as a diagnostic tool for confirming MG in patients?
Edrophonium
transiently increases muscle strength, can be given IV to test
SLUDGE effects can be reversed by administering:
Atropine (and pralidoxime (PAM))
SLUDGE plus what symptoms characterize major cholinomimetic toxicity (as with suicide attempts)?
Respiratory collapse from CNS effects;
skeletal muscle paralysis;
bronchospasm
Duration of action:
Edrophonium - MG and Ileus
5-15 minutes
Duration of action:
Neostigmine - MG and Ileus
30 min to 2 hours
Duration of action:
Pyridostigmine - MG
3-6 hours
Duration of action:
Physostigmine - Glaucoma
30 min to 2 hours
Duration of action:
Echothiophate - Glaucoma
100 hours
What are the sites of action of the ganglionic blockers, Nn?
Adrenal medulla;
Norepi nicotinic receptor;
ACh nicotinic receptor
Does atropine bind to nicotinic receptors?
No, while it is structurally similar to ACh, it binds only at muscarinic GPCRs.
In general, tertiary amines are better absorbed and _______ than quaternary amines
penetrate the CNS better
have more central effects
Give an example of a quaternary amine that has local effects but is too big to diffuse and affect the CNS.
Glycopyrrolate
0.5mg of atropine has what effects?
slight cardiac slowing
drymouth
inhibition of sweating (cholinergic)
5mg of atropine has what effects?
rapid HR palpitations market drymouth dilation of pupil (mydriasis) --> "belladonna" blurring of near vision
10mg and up of atropine has what effects?
hallucinations and delirium
coma
Effects of Muscarine BLOCKING drugs:
CNS
–muscarinic subtypes unknown
sedation anti-motion sickness action anti-Parkinsonian action amnesia delirium
Effects of Muscarine BLOCKING drugs:
Eye
M3 receptors
Cycloplegia - paralysis of the ciliary muscle of the eye, resulting in a loss of accommodation;
mydriasis
Effects of Muscarine BLOCKING drugs:
Bronchi
M3 receptors
Bronchodilation, especially if constricted
Effects of Muscarine BLOCKING drugs:
GI
M1 and M3 receptors
relaxation
slowed peristalsis
Effects of Muscarine BLOCKING drugs:
GU tract
M3 receptors
relaxation of bladder wall
urinary retention
Effects of Muscarine BLOCKING drugs:
Heart
initially slight bradycardia at low doses - block of inhibitory presynaptic receptors
then tachycardia - block M2 receptors at SA node
Effects of Muscarine BLOCKING drugs:
Blood vessels
M3 receptors on endothelium
block muscarinic vasodilation with NO
will not manifest unless a muscarinic agonist is present
Effects of Muscarine BLOCKING drugs:
Glands
M1 and M3 receptors
reduction in salivation, lacrimation, sweating,
Effects of Muscarine BLOCKING drugs:
Skeletal muscle
NONE!!! This is NMJ
Hexamethonium
Mecamylamine
these drugs are:
Ganglion-blocking drugs
not really used therapeutically anymore
used to be used to prevent bleeding out by dropping BP on the battlefield
Ganglionic blockers competitively inhibit Nn receptors at both sympathetic and parasympathetic ganglia. Lack of selectivity –> side effects
NMJ blockers inhibit what kind of receptor?
Nm
Give an example of a nondepolarizing NMJ blocker.
Tubocurarine
Mivacurium
prevents opening of the end plate channel
Give an example of a depolarizing NMJ blocker.
Succinylcholine
“desensitize” the end plate by causing persistent depolarization
flaccid paralysis
Succinylcholine is made up of:
2 molecules of acetylcholine linked
AGONIST of NMJ (initial contractions)
**action is brief - 5-10 min
Hydrolyzed by butyrylcholinesterase in the plasma en route to site of action
Uses for NMJ blockers:
surgery prep
intubation prep
Length of effects - Tubocurarine
30-60 min
Mivacurium is much shorter bc hydrolyzed more rapidly
Toxic effects of NMJ blockers:
Tubocurarine
Succinylcholine
respiratory paralysis
disturbance of autonomic function (Nn overlap effects)
Pancuronium used in:
lethal injection. It’s a NMJ blocker
used with sodium thiopental and potassium chloride
Botulinim Toxin A degrades what protein?
SNAP-25 which mediates fusion of synaptic vesicles with the presynaptic terminal membrane –> AP can’t get ACh released
useful in treating diseases with pathologic muscular tone (locally injected) - ie achalasia, strabismus, oromandibular dystonia (spasms of face/jaw/neck)
