Lecture 8 Part 2 Flashcards
what is the action of indirect acting cholinomimetics
they prevent the hydrolysis of acetylcholine by INHIBITING ACETYLCHOLINESTERASE
Name 3 types of structures that are indirect acting cholinomimetics
simple alcohols with a quaternary ammonium group** (edrophonium)
organophosphates
carbamic acid esters of alcohols that have quaternary or tertiary ammonium gorups
what is edrophonium
a simple alcohol with a quaternary ammonium group
an indirect acting cholinomimetic
what is echothiophate
an organophosphate
indirect acting cholinomimetic
what is neostigmine
a carbamic acid ester (carbamate) of an alcohol with quaternary or tertiary ammonium groups that is an indirect acting cholinomimetic
carbaryl
cholinesterase inhibitor (indirect cholinomimetic)
physostigmine
cholinesterase inhibitor (indirect acting cholineomimetic)
what is the action of organophosphates
cause all secretions to occur - pesticides
through inhibiting acetylcholine esterase - INDIRECT acting
name 4 organophosphate cholinesterase inhibitors
sarin
paraoxon (parathion)
malaoxon (malathion)
echothiophate
true or false
organophosphates are direct acting
FALSE
indirect acting cholinomimetics - inhibit acetylcholine esterase
true or false
organophosphates inhibit acetylcholine esterase
true
indirect acting cholinomimetics target acetylcholinesterases as well as….
butyrylcholnesterases
explain the mechanism of action of quaternary alcohols and give an example of one
edrophonium
reversibly binds electrostatically and hydrogen bonds to the active site of the ACHE receptor to prevent it from accessing acetylcholine and hydrolyzing it
NOT A COVALENT BOND - short lived (2-10mins)
explain the difference in the duration of actions of:
-carbamate esters
-organophosphates
-quaternary alcohols
all bind ACHE to prevent it from accessing acetylcholine, thus having indirect cholinomimetic effects
quaternary alcohols have the shortest duration, 2-10 minutes. bond is via electrostatic and hydrogen bonds to the active site
next is carbamate esters. attaches covalently to ACHE and is considerably more RESISTANT. duration is 30mins - 6 hours
longest = organophosphates. undergo initial binding and hydrolysis by the enzyme - results in a PHOSPHORLYATED ACTIVE SITE. covalent phosphate-enzyme bond is extremely stable and hydrolyzes in water at a VERY SLOW RATE (hundreds of hours - aging)
name a carbamic acid (carbamate) ester and state its duration of action
neostigmine
30 mins - 6 hours
covalently bound to ACHE
the duration of action of carbamates is determined by…….
inhibitor-enzyme complex
what is physostigmine
a carbamate (indirect acting)
explain the absorption of quaternary carbamates
poor absorption bc of charge
a lot of dose is needed if they are to be administered orally
an exception is physostigmine, which is NO CHARGE
thus, it is well absorbed from alll sites and can be used in the eye
bad side is that it also distributes in the CNS and is thus more toxic
explain the absorption of organophosphate cholinesterase inhibitors and any exceptions
all except echothiophate is well absorbed from the skin, gut, lung, and eye
all except echothiophate are distributed to all parts of body INCLUDING CNS – thus CNS toxicity is a poisoning component
explain the half life of organophosphate cholinesterase inhibitors
short half life
therapeutic use of edrophonium
treatment of myasthenia gravis (ACH not there and degrades so quickly)
ileus, arrhythmias
approximate duration of action of edrophonium
5-15 mins
what does neostigmine treat?
also give approximate duration of action
myasthenia gravis, ileus, arrhythmias
a carbamate, duration is 0.5-4 hours
what does pyridostigmine treat and what is its duration of action
myasthenia gravis
4-6 hours (carbamate)
what does physistigmine treat?
approximate duration of action
glaucoma
contraction of ciliary body to redeuce intraocular pressure and facilitate outflow of aqueous humor and diminish its secretion
0.5-2 hours (carbamate)
what does echothiophate treat and what is its approximate duration of action
glaucoma
100 hours (organophosphate)
besides cholinesterase inhibitors, what other drugs can be used to treat glaucoma?
muscarinic stimulants
explain the mechanism of how muscarinic stimulants and cholinesterase inhibitors treat glaucoma
glaucoma symptom is INCREASED intraocular pressure
these drugs decrease the intraocular pressure by contracting the ciliary body and causing the aqueous humor to flow away and possibly shorten the rate of its secretion
direct cholino agonists and cholinesterase inhibitors have been largely replaced by…….
prostaglandin derivatives and topical beta blockers
as mentioned, cholinergic agonists and indirect cholinomimetics have been largely replaced by prostaglandin derivatives and topical beta blockers
name 1 condition that they are currently still used for
cholinomimetic agonists are used to treat esotropia - strabismus (eye misalignment) in young children
if someone suffers from dry mouth, what drug(s) should be used?
acetylcholine agonists or ACHE inhibitors
enhance activity of PSNS
specifically pilocarpine
_________ is used in dry mouth to increase salivary secretion
give brand and generic name
pilocarpine (salagen)
name 2 drugs for postoperative ileus (paralysis/atony of stomach or bowel) and for urinary retention conditions, and to increase the town of lower esophageal sphincter in pts with reflux esophagus
bethanechol and neostigmine
proton pump inhibitors preferred for reflux esophagus tho
brand name of pilocarpine
SALAGEN
Myasthenia gravis is what kind of disease and what does it affect?
autoimmune disease that affects neuromuscular junctions of skeletal muscle
name some symptoms of myasthenia gravis
ptosis
diplopia
difficulty speaking/swallowing
weakness of extremities
explain the mechanism of myasthenia gravis
antibodies produced against a1 subunits of the nicotinic receptor channel complex
not enough ACH action
what drugs are exremely valuable as therapy for myasthenia gravis?
cholinesterase inhibitors like neostigmine and edrophonium
long term with pyridostigmine or neostigmine
what drug was used to treat supraventricular tachyarrhymias?
what is used now?
edrophonium **
short acting cholinesterase inhibitor
now, calcium channel blockers are used
what drug should be administered to someone who has taken too much of an antimuscaranic drug and is now suffering toxic effects?
what are some of these toxic effects?
give 2 examples of
antimuscarinic drugs that can cause these effects
administer PHYSOSTIMGINE with close monitoring
severe behavioral disturbances
arrhythmia in adults
atropine, tricyclic antidepressants
someone has taken too much of direct acting muscarinic stimulants. name 2 potential drugs this could be.
what symptoms will be observed?
what is the treatment for this?
pilocarpine and choline esters
nausea, vomiting, diarrhea, urinary urgency, salivation, sweating, cutaneous vasodilation, bronchial constriction
treatment is ATROPINE 1-2mg parenterally — it is a cholinergic antagonist
someone has taken too much acetylcholine and is experiencing negative side effects such as vomiting and diarrhea.
what should be given
atropine 1-2mg parenterally
which is more important - acute nicotine poisoning or chronic?
chronic is more important bc of cancer risk and COPD risk
what are neonicotinoids?
synthetic compounds that cause nicotine toxicity in insects. it’s an insecticide
what is the fatal dose of nicotine?
why have more smokers not died from nicotine poisoning?
40mg or 1 drop of pure liquid
most of the nicotine in cigs is destroyed by burning or escapes via sidestream smoke
the toxic dose of nicotine is 40mg of 1 drop of pure liquid
how have more kids not died from inhaling nicotine insecticides or smoke?
vomitting immediately follows, limiting the absorption
explain 3 components of acute nicotine toxicity
it’s a CNS stimulant - causes convulsions that can bcome resp arrest/coma
respiratory paralysis - skeletal muscle depolarization blockade
hypertension and arrhythmias
name 3 things that can be used to treat acute nicotine toxicities
atropine - to reverse the muscarinic effects
diazepam (anticonvulsant)
mechanical ventilation for the neuromuscular blockade
nicotine works on what receptor
nicotinic
name 5 components of chronic nicotine toxicity
lung cancer
COPD
stroke
asthma
reproductive effects (low birth weight, premature bb)
diabetes
other cancer
name 2 drugs that can be used to stop smokine
varenicline - partial nicotinic agonist
buproprion - antidepressant
name some adverse effects of varenicline
nausea
insomnia
exacerbation of psychiatric illness - inc anx and depression
symptoms of cholinesterase inhibitor toxicity
TOO MUCH ACH
muscarinic effects: miosis (pupil constriction), salivation, bronchial constriction, vomiting, diarrhea, CNS convulsions, coma
nicotinic effects - depolarizing neuromuscular blockade
name 2 types of drugs that are available as pesticides in the US
organophosphates
cholinesterase inhibitors
what drugs were used as chemical warfare agents and why?
the cholinesterase inhibitors - soman, sarin, VX
they induced effects rapidly bc of their large concentrations
Treatment for cholinesterase inhibitor toxicity
parenteral atropine in large doses as often as required for muscarine excess
watch vital signs - respiration may be impaired
decontamination to prevent further absorption - remove clothes, wash skin, etc
what are soman, sarin, and VX
cholinesterase inhibitors used in chemical warfare
besides atropine, what other drugs may be used for cholinesterase inhibitor toxicity?
pralidoxime
benzodiazepine for seizures
what is the effect of binding to muscarinic cholinoceptors
parasympathetic nerve stimulation
what is the effect of binding to nicotinic cholinoceptors
autonomic ganglia and skeletal muscle motor end plate are stimulated
what happens when muscarinic agonists are instilled into the conjunctival sac of the eye?**
-smooth muscle of the iris sphincter contracts (pupil constriction - miosis)
-ciliary muscle contracts - resulting in accomadation, aquous humor output
USED TO TREAT GLAUCOMA
Low doses of Ach cause vaso____.
what does this result in
vasodilation
causes a reduction in blood pressure — and a reflex increase heart rate to increase it
LARGE doses of acetylcholine do what to the heart?
bradycardia (slow heart beat)
decreased AV node conduction velocity
hypotension
hyperpolarization
REDUCED action potential duration
decreased contractility of atrial and ventricular cells
as mentioned, acetylcholine in low doses causes vasodilation
this vasodilation occurs via what mechanism?
activation of M3 receptors
what is interesting about the cardiovascular effect of pilocarpine?
in general, cholinomimetics have similar effects to acetylcholine
however, pilocarpine is an exception bc when given IV it may produce HYPERTENSION after a brief initial hypotensive response
what do muscarinic stimulants do to the respiratory system
bronchoconstriction
which glands in the GI tract are stimulated the MOST when muscarinic agonists are adminsitered?
which are stimulated less?
most - salivary and gastric glands
pancreas and small intestine glands stimulated less
true or false
when muscarinic agonists are administered, peristaltic activity is decreases and most sphincters are contracted
FALSE - REST AND DIGEST
peristaltic activity is increased and most sphincters are RELAXDED
what happens to the genitourinary tract when muscarinic agonists are administered
detrusor muscle is stimulated
trigone and sphincter muscles relaxx
voiding is promoted
true or false
muscarinic agonists stimulate secretion by THERMOREGULATORY sweat glands, lacrimal, and nasopharyngeal glands
true
true or false
the CNS contains both nicotinic and muscarinic receptors.
the brain is richer in nicotinic sites and the spinal cord contains mostly muscarinic sites
FALSE
CNS does contain both but brain is richer in muscarinic sites and spinal cord in nicotinic sites
what is M1 receptor involved with in the brain
cognition
what is M2 receptor involved with in the brain
nociception and thermoregulation
what is M3 involved with in the brain
decreased appetite/body fat
_____ receptors allow ACh and nicotine to regulate the release of what 5 neurotransmitters?**
presynapticn nicotine receptors
glutamate
serotonin
GABA
dopamine
Norepinephrine
chronic exposure to nicotine has a DUAL EFFECT at nicotinic receptors
explain this statement
there is activation (depolarization) followed by DESENSITIZATION
What is the reason for nicotine addiction
activation of nicotinic receptors releases dopamine in the mesolimbic system
in high concentrations, nicotine induces ___, ____, and stimulation of the ______
tremor, emesis, and stimulation of the respiratory center
effect of nicotine on the cardiovascular system**
sympathomimetic
hypertension and increased heart rate
effect of nicotine on GI and urinary tracts**
parasympathomimetic
increased motility, nausea, vomiting, diarrhea, voiding
effect of nicotine on neuromuscular junction
depolarization of the end plate. causes muscle contraction
if the action persists, depolarization blockade, resulting in flaccid paralysis (weakness) of skeletal muscles
the nicotine action on BOTH parasympathetic and sympathetic ganglia resembles….
simultaneous discharge of of PSNS and SNS
ie: cardiovasular is sympathomimetic and GI/urinary and parasympathomimetic
