ANS II Flashcards
parasympathetic effects can be mimicked by..
- muscarinic receptor agonists (carbachol, pilocarpine)
- acetylcholinesterase inhibitors (neostigmine)
parasympathetic effects can be blocked by..
- muscarinic receptor antagonists (atropine)
- skeletal neuromuscular junction blockers (D-tubocurarine)
parasympathomimetics
stimulates parasympathetic nervous system
therapeutic uses of parasympathomimetics
- reduce intraocular pressure in glaucoma; facilitate outlflow of aqueous (can cause cataracts with long term use)
- increase peristalsis of GI tract
- increase motility of urinary tracts
- increase salivary secretions
ACh released at the synapse acts for a few milliseconds before..
it is metabolized in the synapse
acetylcholinesterase (AChE)
metabolize ACh in the synaptic cleft on the outer membrane of the post junctional cell
two types of cholinesterase enzymes
- AChE
- butyrylcholinerterase (BuChE; aka plasma/pseudoChE)
BuChE
-located at non-neuronal sites; plasma and liver
Most enzyme inhibitors used clinically … discriminate between the two types of ChE
DO NOT
AChE inhibitors
increase duration of action of the released ACh at the synapse
3 types of chemical reaction that is produced by cholinesterase
- acetylation
- carbamylation
- phosphorylation
acetylation
introduce an acetyl group
-acetylated enzyme recovers rapidly
carbamylation
enzyme recovers more slowly, 3-4 hours
- reversible
- used therapeutically
phosphorylation
- poisons the enzyme
- irreversible
- 6 hours
catalytic region of cholinesterase enzyme
ser-OH
neostigmine
a reversible AChE inhibitor that causes carbamylation
diisopropyl flurophosphate
an irreversible AChE inhibitor that causes phorphorylation
2-PAM
an oxide that if administered before aging occurs, can bind to and release a phosphate moiety attached to the enzyme during phosphorylation; reversing the enzyme inhibition
donepezil and tacrine (also rivastigmine and galantamine)
ChE inhibitors in the CNS that have higher affinity and partition into lipids and cross the blood/brain barrier
ChE inhibitors in the intestine
relax sphincters to facilitate peristaltic movement (in postoperative ileum, congenital megacolon)
ChE inhibitors in the bladder
treat urinary retention due to atony of smooth muscle
ChE inhibitors in the skeletal muscle neuromuscular junction
LOW doses used to treat patients with myasthenia gravis, who have weakness of skeletal muscles
-also used to diagnose it
intermediate doses and high doses ChE inhibitors in skeletal muscle neuromuscular junction
i: fasciculations and fibrillations
h: persistent depolarization and muscle paralysis
anti-ChE agents
reverse antagonisms by competitive neuromuscular blockers but add to the depolarization and paralysis by succinylcholine and make it worse
muscarinic receptor agonists/ChE inhibitor SIDE EFFECTS
increased urinary frequency, diarrhea, vomiting, bradycardia, hypotension, increased salivation, miosis,
botulinum toxin
- blocks ACh release
- used to paralyze skeletal muscles
clinical uses of botox
- strabismus (unaligned lines of vision),
- blepharospasm (contracted eyelid)
- hemifacial spasm
cosmetic use of botox
to remove facial wrinkles
muscarinic cholinergic receptor blockers
- belladonna alkaloids (atropine, scopolamine)
- semisynthetic and synthetic (dicyclomine, ipratropium, oxybutynin)
therapeutic uses of muscarinic receptor antagonists
- to treat severe bradycardia
- cause pupil dilation (used for examination of retina)
- to treat excessive peristalsis of irritable bowel syndrome
- decrease gastric acid secretion
- to treat urinary incontinence
- block M1 receptors in vestibular apparatus to treat motion sickness
- inhibit excessive salivary and respiratory tract secretions
ipratropium and tiotropium
derivatives of atropine that treat COPD
- administered by inhalation to cause bronchodilation
- NOT absorbed into systemic circulation
trihexyphenidyl and benztropine
to treat uncoordinated muscle contraction (Parkinson’s)
scopolamine vs atropine
- scopolamine well absorbed orally and reaches brain more readily than atropine
- scopolamine 1-x more potent at producing CNS effect
- great fraction of scopolamine present in a unionized form to facilitate absorption through skin
- scopolamine used for motion sickness as a transdermal patch
muscarinic receptor antagonists SIDE EFFECTS
- urinary retention
- constipation
- tachycardia
- dry mouth
- mydriasis
nicotinic cholinergic receptor
- ACh gated sodium channel
- neuromuscular junction blockers
two types of neuromuscular junction blockers
- competitive
- depolarizing
type of neuromuscular junction blockers based on…
electrophysiological differences in their mechanisms of action
competitive NM junction blockers
- competitively antagonize the actions of ACh at nicotinic ACh receptors structure different that ACh
- ex. curare
depolarizing agents
- drug occupies and activates nicotinic receptor (agonists) for longer period of time, prevents repolarization
- structure resembles ACh
- succinylcholine
depolarizing block
when depolarizing agents makes muscle fibre refractory to further nerve impulses
South Americans and competitive NM blockers
native SAmericans used certain plant extracts (d-tubocurarine;strychnos toxifera) as arrow poison that caused muscle paralysis in animals
-curare (generic term)
neostigmine, edrophonium, pyridostigmine
ChE inhibitors that are used clinically to reverse NM block caused by competitive blockers
competitive nm blockers sequence of muscle paralysis
- small rapidly moving muscles first
- limbs, trunk
- intercostal muscles
- diaphragm (respiration stops)
*recovery in reverse
competitive nm blockers main side effects
- ganglionic blockade (fall in bp, tachycardia)
- block of vagal response (increase peristalsis)
- histamine release (bronchospasm, hypotension, increase bronchial and salivary secretions
succinylcholine
- bind to and activates muscle nicotinic receptors
- short duration of action
- not metabolized by AChE
- rapidly hydrolyzed primarily by butyrylcholinesterase in plasma
clinical problem with succinylcholine
certain patients exhibit several variants of this enzyme, which leads to prolonged and potentially dangerous duration of NM block
depolarizing blockers SIDE EFFECTS
- can release K+ rapidly from intracellular sites
- cause hyperkalemia
hyperkalemiacan be dangerous in..
heart failure patients on digoxin or diuretics
malignant hyperthermia
- side effect seen after certain anesthetics and nm blockers (succinylcholine)
- increase Ca release from SR
- rigidity, heat production from skeletal muscle, hyperthermia, accelerated muscle metabolism, metabolic acidosis, tachycardia
therapeutic uses of NM blockers
in surgical anesthesia to obtain relaxation of skeletal muscle, particularly in abdominal wall
sympathetic effects can be mimicked by..
- adrenergic receptor agonists (direct)
- NE uptake blockers (indirect)
- monoamine oxidase and COMT inhibitors
- NE releasing agents (indirect)
monoamine oxidase and COMT inhibitors
delay breakdown of NE and prolong its action
-indirect
sympathetic effects can be blocked by..
adrenergic receptor antagonists
-ex. prazosin, propranolol
termination of NE action at synapse
-released transmitter is taken up back into presynaptic nerve terminal by uptake 1
uptake 1 blocker
increase sympathetic activity
baroreceptor
control of BP and heart rate
epinephrine equipotent at..
alpha and beta receptors
NE has little activity at..
beta 2 receptors
isoproterenol
most potent sympathomimetic amine; acts exclusively on B receptors
therapeutic uses of adrenergic drugs
- allergic reactions/anaphylactic shock (EPIPEN)
- bronchodilators (asthma)
- pressor agents (hypotension)
therapeutic uses of adrenergic receptor blockers
- hypertension
- emergency treatment of hypertension
- hypertension in pheochromocytoma
- myocardial infarction
- cardiac arrhythmias
- migraines
- benign prostatic hyperplasia
- glaucoma
