Cholinergic Pharmacology Flashcards
Muscarinic R: GPCRS 3 Subtypes and targets?
M1 Gq CNS
M2 Gi Heart, Smooth Muscle, some nerves
M3 Gq exocrine glands, Sm. musc, endothelium
Nicotinic R. what types are there?
pentameric ligand-gated ion channels NA & K
- Nm= muscle type: found at neuromuscular jxn
- Nn= neuronal-type: found in nerves, autonomic ganglia
parasympathomimetic
mimic activation of PNS
cholinomimetic
mimic action of activating cholinoceptors
cholinergic
activates ach R.
Cholinomimetic (cholinergic) drugs chart
Direct Cholinomimetic action
binds to/activates ach R/
receptor agonism
eg. ach, muscarine, nicotine
Indirect cholinomimetic effect
inhibit acetylcholinesterase (AChE)
amplify action of endogenous ACh
What is the results of cholinoreceptor activation in the eye?
(alpha) sphincter muscle of iris: contrict pupils (miosis)
(M) ciliary muscle: accomodation
What is the results of cholinoreceptor activation in the heart?
SA node: decrese in rate
atria: decrease contract
AV node: decrease in conduction velocity
Ventricles: small decrease in contractile strength
What is the results of cholinoreceptor activation in the blood vessels?
arteries, veins: dilation (via EDRG). construciton (high-dose direct effect)
What is the results of cholinoreceptor activation in the lung?
bronchial muscle: contraction (bronchoconstriction)
bronchial glands: stimulation
What is the results of cholinoreceptor activation in the GI tract?
motility: increase
sphincters: relaxation
secretion: stimulation
What is the results of cholinoreceptor activation in the urinary bladder?
detrusor: contraction
trigone & sphincter: relaxation
What is the results of cholinoreceptor activation in the glands?
sweat, salivary, lacrimal, nasopharyngeal: secretion
List 3 choline esters
- Methacholine
- Carbachol
- Bethanecol
resistant to cholinesterases
not well absorbed because of charge
can be applied topically
Methacholine
Provocative asthma test
Bethanechol
Promote GI and GU motility
-for post operative ileus/ urinary retention
Carbachol
Increase aqueous humor outflow in glaucoma
Pilocarpine
Alkaloid
Muscarinic action
used for Glucoma
Indirect acting cholinenometric drugs mechanism.
Inhibit AChE
- prolong ach signaling
- occurs at muscarinic and nicotinic receptors
What two drugs are used to treat myasthenia gravis?
Neostigmine
Edrophonium
Physostigmine is used to treat?
Anticholinergic toxicity
- uncharged: cross BBB into CNS
- can reverse altered mental status from anticholinergic toxcitiy
- cannot use for MG because will cause seizures, short acting need to dose frequently.
What is carbaryl used for.
Its an insecticide poison
What is the mechanism for myesthinia gravis ?
Disease of an impaired transmission of NMJ
Autoantobodies against Nm AchR
What are some characteristics of Myasthenia Gravis?
muscle weakness
-diaphragm/ airway control muscle weakness
Eyelid ptosis
Edrophonium
SHORT Acting AChE inhibitor
- charged/quarternary ammonium
~poorly absorbed, so given IV
- Temporarily improved NMJ signaling
~tensilon test: to help diagnose
What helps diagnose Myasthenia Gravis?
Tensilon test
What are two reasons MG patients can be weak?
Myasthenic Crisis vs Cholinergic Crisis
What is the myasthenic crisis?
- disease is out of control, dose is not high enough.
tx/ w AChE inhibiors can save them
What is cholinergic Crisis?
- toxicity from AChE inhibitor
Tx w/ AChE inhibitors can kill them
What clinical test/ Drug intervention can you use to differentiated between myasthenic crisis vs cholinergic crisis?
Use Edrophonium
- if fixes them, then it was MG
- if its worse tx w/ anticholinergics
Neostigmine & Pyridostigmine: Indications?
- Myasthenia Gravis long-term therapy
- Post-operative ileus/Urinary retention
- Pyridostigmine: longer duration of action
What is special about the structure of Neostigmine & Pyridostigmine
-Charged: do not cross BBB (MG is a peripheral (non-CNS) disease
4 examples of AChE inhibitor insecticides.
very potent
- parathion
- paraoxon
- malathion
- malaxon
- carbamates
reversible AChE inhibition
“stigmine” drugs are also carbamates
Organophosphates (OPs)=
irriversible
-only rare/obsolete OP Rx drufs- _Echothiophate _
Soman
AChE inhibitor
“nerve agent”
What is the mechanism of organophosphate irreversibility? What is aging
OP drugs/ poisons fit in AChE active site
Aging: OP will enventually covalently bind to active site and irreversibily inhibit AChE.
- antidotal tx before aging occurs can regenerate enzyme
- aging DOES NOT occur in carbamates
Anticholinergic Drugs
Cholinoceptor blockers & cholinesterase regenerators
-“Anticholinergic”= “Anti-muscarinic for MDs
Nicotinic ACh receptors
if drug not muscarinis specific, increase signal at:
- autonomic ganglia (increase PNS & SNS output to effector organs)
- NMJ (muscle twitching, fasciculations, paralysis
List of anticholinergic drugs
What is the mechanism of action for Antimuscarinic Drugs?
- MOA
- Reversible bloackade of Muscarinic ACh R (Most non specific for R, R are constitutively active thus drugs are Inverse Agonist) - tertiary amines (eg. atropine) better absorbed
- qyaternary ammonium ions, used for local effect, poorly absorbed (eg. tiotripium inhaled in lungs for asthma/COPD)
What are the Antimuscarinic Clinical Effects?
Opposite of choinergic drugs
- big pupils
- increase HR
- dry you up
Antimuscarinic Clinical Effects: Eye?
dilated pupil= Mydriasis
loss of accomodation for near vision
Antimuscarinic Clinical Effects: Upper Aerodigestive Tract?
Dry mouth, Dry nose/sinuses
Antimuscarinic Drug Indications: Ocular?
Myadriatic & Cycloplegic
- dilate pupill for ophthalmologic exam or therapy
- paralyze ciliary body of eye for ophtho disease
What are the indications for tropicaminde, and cyclopentolate?
Dilate pupil for ophthal. exam or therapy
Antimuscarinic drug indications for Atropin & Glycopyrrolate?
Decrease oral/Nasal/ Airway secretions
Antimuscarinic Drug Indications: Heart?
Treats Bradycardia
-blocks vafal tone (ACh acting on M cholinoceptors) at cardiac pacemaker
Antimuscarinic Drug Indication: Lungs?
Asthma/COPR to
- decrese secretions
- decrease SM tone (Bronchospasm)
What are the indications of Ipratropium & Triotropium?
Decrease bronchial secrestion and SM tone
What are the antimuscarinic Drug Indications for Slow GI motility? Example drug?
Slow GI motility
- adjunct txt for diarrhea/ GI cramping
ex. Dicyclomine
What are the antimuscarinic Drug Indications for Urinary tract? Example drug?
Incotinence/Excess urinary frequency
ex. Oxybytynin, Tolterodine
What are the antimuscarinic Drug Indications for CNS? Example drug?
antinausea/ vertigo/ motion sickness
ex. scopolamine, dimenhydrinate
What are the anticholinergic Side Effects?
- Hot as a hare
- Dry as a bone
- Blind as a bat
- Red as a beet
- Mad as a hatter
Impiramine
anticholinergic
- TCA
- Rxn for Enuresis (Bed wetting)
- Decrease Urinary frequency
Antidotal theraphy for too much cholinergic tone
treat with anti-cholinergic drug
ex. Pyridostigmine induced cholinergic crisis can be reversed wtih Atropine
Antidotal Therapy for too much anti-muscarinic activity
treat with cholinergic agonist
ex. altered mental status from antimuscarinic side effects of diphenhydramine (Benadryl) reversed w/ Physostigmine
Can Atropine reverse Nicotinic Effects?
No, only Muscarinic
OP toxicity/ cholinergic crisis also involves?
- Hyperstimulation at nAChR in ganglia
- Hyperstimuation at nAChR at NMJ (Skeletal weakness cannot be reverse by atropine)
* need an anti-Nicotinic drug
How can we regenerate AChE?
Oximes!
-kick OP out of active site if given before “aging”
What is an example of an Oxime?
Pralidoxine
- only commercially available in US
- given along w/ atropine for OP poisoning
Ganglionic blocking drugs. 2 examples?
-very rarely used clinically
block Nicotinic R inautonomic ganglia
ex. mecamylamine
ex. trimethaphan- short acting IV for hypertensive emergencies
What are Neuromuscular Nicotinic Blockers?
for cheimcal paralysis in Anesthesia
