Cholinergic Pharmacology I Flashcards
Cholinoreceptor-activatnig and cholinesterase-inhibiting drugs
mimic acetylcholine
-muscarinic or nicotinic receptors
direct acting cholinomemetic agents
-directly bind and activate muscarinic or nicotinic receptors
indirect acting agents
inhibit acetylcholinesterase
- reduce hydrolysis of acetylcholine, inc endogenous Ach concentration in synaptic cleft, excess ach stimulates cholinoreceptors to evoke increased responses
- drugs act primarily where acetylcholine is physiologically released
Cholinoreceptors are either
g protein linked (muscarinic) or ion channel (nicotinic)
G protein linked receptors
- muscarinic
- 7 transmembrane domains
- located in CNS, tissues targeted by PNS, vascular endothelium
Ion channel (nicotinic)
four subunits form cation-selective ion channels
-located on all ANS post ganglionic cells, muscles (neuronal type), muscles innervated by somatic motor fibers (NMJ type), some CNS neurons
direct acting cholinoreceptor agonists are classified as
esters of choline (including Ach) or alkaloids (such as muscarine and nicotine)
choline esters
- acetylcholine, methacholane, carbachol, and bethanechol
- poorly absorbed and poorly distributed into CNS
- adding a methyl group reduces potency at nicotinic receptors (methacholine, bethanechol)
Methacholine
-Add methyl group to first carbon of choline, which makes it resistant to hydrolysis and gives it muscarinic specificity
Acetylcholine
rapidly hydrolyzed and active towards both muscarinic and nicotinic
Carbachol and Bethanochol
-adding a nitrogen to acetate, makes it even very resistant to hydrolysis
Bethanochol
-Has nitrogen group, making it resistant to hydrolysis and has a methyl group, making it muscarinic specific
Tertiary natural cholinomimetic alkaloids
Muscarine (quaternary amine), nicotine
- Pilocarpine, lobeline
- A lot more lipophilic
Muscarinic receptors
- G protein coupled
- Activates IP3, DAG cascade, increases potassium flux, some tissues will inhibit adenylyl cyclase activity and open K channels (Gi)
Nicotinic receptor activation
- electrical and ionic changes
- depolarization of nerve cell or neuromuscular end plate membrane
- prolonged agonist occupancy can abolish effector response, cause depolarizing blockade, and can produce muscle paralysis
Prolonged nicotinic agonist occupancy can
abolish effector response, cause depolarizing blockade, and can produce muscle paralysis
Muscarinic cholinoreceptor effects
- parasympathetic nerve stimulation
- At the distribution of muscarinic receptors
Nicotinic agonist effects
-autonomic ganglia and skeletal muscle motor end plate
Eye- muscarinic agonists produce
contraction of iris sphincter (miosis), contraction of ciliary muscle (accomodation) which facilitates acqueous humor outflow
Muscarinic agonist affect CV system by
- reducing peripheral vascular resistance (if delivered IV; via release of NO)
- direct effect is to slow heart rate
IV infusions of ACh
- Cause vasodilation and reduce blood pressure
- ACh induced vasodilation requires intact endothelium which releases NO (relaxes smooth muscle)
-This will evoke a SNS reflex and result in tachycardia; larger ACh will mask this reflex (bradycardia)
Respiratory system cholinergec effects
- Contracts smooth muscle of bronchial tree, glands of mucosa stimulated to secrete
- Exacerbates symptoms of asthma
GI tract
- Increases secretion, increase peristaltic activity
- Contraction of longitudinal muscle, relaxation of sphincters
GU tract
Contracts detrusor muscle, relaxes trigone and sphincter muscles
-promotes voiding (but micturition is it’s own reflex, so may just make it easier)
Secretory glands
- sympathetic
- stimulates secretion of sweat from thermoregulatory sweat glands
Nicotinic agonists
- Autonomic ganglia are major site of action
- Simultaneous SNS and PNS discharge
- Tissue where effects are balanced (like eye)- may intermediate response
- Peripheral vasculature, which has no parasympathetic innervation, will have solely sympathetic effect
- GI tract- cholinergic ending of myenteric plexus, will inhibit parasympathetic outflow–> see GI motility and secretion
Effects on NMJ by nicotinic agaonists
- produce muscle fasciculations because it’s an overall increase in activity, not specifically one muscle
- subsequent development of depolarization blockage (flaccid paralysis)
Low dose Ach
- only activates vascular muscarinic receptors (endothelium)
- not high enough of a dose to escape peripheral vasculature
- evokes synthesis and release of NO, produces vasodilation (decrease in BP), reflex tachycardia
Direct effect of Ach on muscarinic receptors on vascular smooth muscle is
contraction (usually masked by effects of NO)
-Can be seen in vasculature stripped of endothelium
Effects of low dose Ach blocked by
atropine (muscarinic antagnost)
In the presence of ganglionic blockade or other elimination of baroreceptor mediated reflexes, a low dose ACh might
decrease both blood pressure and heart rate
only direct effects of drugs observed with ganglionic blockade
HIgh dose ACh
- high enough dose to escape vascular space and affect muscarinic and nicotinic receptors
- muscarinic receptors on vascular endothelial cells are activated evoking synthesis and release of NO and producing vasodilation (dec BP)
- cardiac muscarinic receptors activated- produces direct bradycardia, slows rate of diastolic depol of SA node, slows AV conduction, reduces force of myocardial contractions, shortened atrial refractory period which can lead to atrial flutter
Indirect acting cholinomimetics
ACh effects terminated by acetylcholinesterase
-these inhibit this enzyme
-acetylcholinesterase and butyrylcholinesterase inhibited
3 groups:
-simple alcohols (brief overactivity) , carbamic acid esters of alcohols (longer duration effect), organic derivatives of phosphoric acid (organophosphates)
simple alcohol -cholinesterase inhibitor
Edrophonium
- bears quaternary ammonium group
- reversibly bind to active site, inhibition is short lived (2-10 mins)
Carbamic acid esters of alcohol- cholinesterase inhibitors
- neostigmine (quaternary, not lipid soluble)
- physostigmine and carbaryl (high lipid solubility, will have CNS effects)
- undergo two step hydrolysis: covalent bond of carbamoylated enzyme resistant to hydration, inhibition is longer (30 min- 6 hrs)
organophosphates- cholinesterase inhibitors
- echothiophate, soman, sarin, malathion, parathion
- malathion and parathion are used as insecticides
- well absorbed topically and distributed to all parts of body, including CNS
- organophosphates bind and are hydrolyzed– results in phosphorylated AChE active site
- inhibition lasts hundreds of hours (lifetime of enzyme protein)
- aging strengthens phosphorous-enzyme bond
Pralidoxime (2-PAM)
restores AChE function when given before aging caused by organophosphates
cholinesterase inhibitors- organ system effects
CV and GI systems mainly effected, eye and skeletal muscle as well
- actions amplify endogenous acetylcholine
- little effect on vascular smooth muscle and blood pressure
- modifies tone of PNS (not peripheral vasculature because it is not innervated by PNS)
Effects of cholinesterase inhibitors on NMJ
low (therapeutic) concentrations increase force of contraction
-higher doses produce depolarizing neuromuscular blockade
Clinical use of cholinesterase inhibitors on eye
Eye: closed angle glaucoma, promotes outflow of aqueous humor by reducing intraoculuar pressure and contraction of ciliary body
Clinical use of cholinesterase inhibitors on GI and UT
- disorders related to inactivity of smooth muscle
- postop ileus, congenital megacolon, urinary retention, neurogenic bladder, reflux esophagitis, insufficient salivary secretion
Clinical use of cholinesterase inhibitors at NMJ
For myasthenia gravis
Can be used as therapy and
-Edrophonium as diagnostic test–> improvement in muscle strength
Clinical use of cholinesterase inhibitors - atropine and other anticholinergic intoxication
-reversal of competitive blockade by cholinomimetics
Clinical use of cholinesterase inhibitors- CNS
Alzheimer’s
Toxicity of cholinesterase inhibitors
SLUDGE Salivation Lacrimation Urinary incontinence Diarrhea Gastrointestinal cramps Emesis
- Parasympathetic like activities
- Can be reversed by atropine (muscarinic agonist)
Cholinesterase inhibitor poisoning treated by
large doses of Atropine
- Maintenance of vital signs (respiration- because it causes paralysis of diaphragm), decontamination,
- pralidoxime to rescue unaged inhibited enzyme
Nicotinic toxicity
- usually produced by nicotine
- fatal dose is 440 mg
- amt in 2 regular cigarettes but most is destroyed by burning
- ingestion is usually followed by vomiting (emesis)
- limits absorbed dose
effects: overactivity of entire ANS, and stimulation of CNS- convulsions, coma,respiratory arrest
- htn, cardiac arrythmias,
Tx of nicotinic toxicity
-symptom mediated
-muscarinic and adrenergic antagonists and mechanical respiration
Most significant toxicity is due to chronic use
Choline esters
ACh, bethanechol, carbachol, cevimeline
Alkaloids
muscarine, pilocarpine
direct nicotinic agonist
nicotine, varenicline
Carbamates
neostigmine, physostigmine, pyridostigmine, rivastigmine, ambenomium, demecarium, carbaryl
simple alcohol ester cholinesterase
edrophonium
organophosphates
echothiophate, soman, sarin, parathion, malathion, isoflurophate, diisopropylfluorophosphate
other cholinesterase inh
donepezil, tacrine, galantamine
