cholinomimetics Flashcards
muscarinic and nicotinic effects
replicated by muscarine, but is abolished by a small dose of antagonist atropine once this blockade occurs, larger doses of ACH are needed to cause the effects of nicotine
location and types of muscarinic receptors
M1 is present in salivary glands (produce saliva), stomach (produce acid) and CNS M2 is in heart (slows it down) M3 is in salivary glands, bronchi, sweat glands and eye
comparing muscarinic subtypes and general rule
apart from M2, they are excitatory- they are all G protein coupled M1/3 stimulate GQ, which increases IP3 and DAG, but M2 stimulates the inhibitory Gi, which lowers cAMP
nicotinic receptors and
ligand gated ion channels with 5 subunits- ACH arrives and causes Na+ influx- large DOSE of ACH needed
different types of nicotinic receptors and clinical relevance
two main types are those on skeletal muscles, and on PNS organds, they have different subunit combinations, so can be targeted by different drugs ganglion has 2 alpha 3 beta, muscle has epsilon and delta
main location of muscarinic receptors
eye, salivary glands, lungs, heart, sweat glands, gut, bladder and vasculature
muscarinic effects of eye
contraction of ciliary muscle- causes lens to buldge to allow near vision contraction of sphincter pupillae- constricts pupil (miosis) and supports drainage of intraocular fluid lacrimation (tears)
aqueous humour production and glaucoma DIAGRAM
aqueous humour is produced by ciliary bodys, which moves forward to iris when sphincter pupillae contracs, and into canal of schlemm where it drains back into venous system in glaucoma the iris is ruffled, so less drainage occurs, increasing intra-ocular pressure, which could cause blindness
muscarinic effects of heart
M2 ACHr receptors in atria and nodes, decreasing cAMP, decreasing Ca2+ entry (= lower CO ie negative inotropic effect, and decreasing K+ (=lower HR ie negative chonotropic effect)
muscarinic effects of vasculature
most blood vessles don’t have direct PNS innervation, although they have muscarinic receptors, so can be targeted by drugs ACH acts of M3 receptors on endothelial cells, NOT VCSM, causing NO production= muscle relaxation= lower TPR
overall effect on CVS
lower BP due to lower CO, HR and TPR
muscarinic effects on non-vascular muscles
this muscle does not have PNS innervation, so it contracts: lungs (bronchoconstriction), gut (more peristalsis/motility) and bladder (emptying)
muscarinic effects on exocrine glands
more salivation, bronchial secretions, GI secretions (acid) and sweating (SNS) can lead to difficulty breathing (constriction of airways) and GI pain
types of directly acting cholinomimetics
agonists at muscarinic receptors are choline esters (bethanechol) and alkaloids (pilocarpine), whuch are similar in structure to ACH bethanecol has an extra methyl group, enhancing its selectivity compared to ACH
pilocarpine: selectivity, use and side effects, and half life
non selective against muscarinic subtypes, so affects M1-3 useful for glaucoma as it flattens the iris however can cause blurred vision, GI pain, hypotension, although it is only applied locally to eye, hence low doses suffice half life of 3-4hrs
bethanechol (compárison with pilocarpine)
unlike pilocarpine, it’s selective for M3, and is resistance to degradation unlike ACH supports bladder emptying and gastric motility, with a similar half life to pilocarpine side effects include bradycardia, respiratory problems and sweating (like ACH would do), and are more serious as applied systemically, not locally like pilocarpine
indirectly acting cholinomimetic drugs
they don’t directly act on muscarinic receptor, but act on acetylcholineterases, increasing ACH ie NORMAL PNS stimulation
types of indirect drugs
reversible anticholinesterase eg physostigmine irreversible include ecothiopate
cholinesterase enzymes types
they make ACH go to choline and acetate there is acetylcholinesterase (true) and butyrylcholinesterase (pseudo)
acetylcholinesterase
found in all cholingergic synapses with a rapid reaction, and is very selective to ACH OH group attached to serine helps break ACH
butyrylcholinesterase
buty is found in plasma and tissues but not cholinergic synapses, and has a broad specificity, so hydrolyses other esters as well it makes sure there is low ACH, although there is genetic variation between people
effects of cholinesterase inhibitors (doses)
low dose enhances muscarinic activity, moderate dose even more as well as increasing transmission of all ganglia high dose is toxic and causes depolarising block at ganglia, where receptors desensitised= respiratory failure
reversible anticholinesterases
compete with ACH for active site by donating carbamyl group to enzyme, preventing ACH from binding carbamyl group is removed by slow hydrolysis and ACH broken down, but done in minutes rather than ms, increasing ACH duration
physostigmine- half life, where it acts, uses
acts on post ganglionic PNS synapse, NOT effector organ, and has a short half life treats glaucoma by supporting circular muscle contraction to allow intraocular fluid drainage also treats atropine poision- this is a competitive antagonist of ACH, so by increasing ACH, inhibition is less
irreversible anticholinesterases and nonhuman use
phosphorylate enzyme active site, leaving a large blocking group which is resistant to hydrolysis, so recovery takes weeks can be used as insectidies
ecothiopate
treats glaucoma like physostigmine, but with a longer duration has systemic side effects by overstimulate of PNS: sweating, bradycardia, respiratory problems, blurred vision, GI pain
anticholinesterases and CNS
they are non polar so can cross blood brain barrier low doses cause excitation, high can cause unconciousness and even death
treatment of organophosphate poisoning
organophosphates in insecticides/nerve agents can be very toxic and cause CNS failure treatment involves atropine, artificial respiration, and pralidoxime (unblocks the enzyme)
