Pharmacology 6 - Cholinomimetics Flashcards
What are the two classes of cholinomimetic drugs?
- Directly acting (choline esters and alkaloids)
- Indirectly acting
Why is acetylcholine of no therapeutic use?
- It doesn’t differentiate between nicotinic and muscarinic receptors
- It is rapidly degraded
What does muscarine cause?
Mushroom poisoning
Give an example of a choline ester
- Bethanechol
Give examples of alkaloids
- Pilocarpine (of pilocarpus)
What are the uses of bethanechol?
- A modified acetylcholine resistant to degradation - limited acess to brain, orally active
- Selective for muscarinic M3 receptors
- Used to assist bladder emptying and stimulate gastrointestinal motility
What is the use of pilocarpine?
- Selective for muscarinic receptors (not selective between the subtypes of receptors)
- Given locally to treat glaucoma (causes pupil constriction and fluid drainage)
- Applied topically (eye drops)
What drugs are indirectly acting cholinomimetics?
Anticholinesterase drugs
What is the mode of action of anticholinesterase drugs?
- Produces pharmacological actions by inhibiting acetylcholinesterase and preventing breakdown of acetylcholine
- Potential to increase cholinergic activity at all cholinergic synapses
What are the two types of cholinesterases and where are they found?
- Acetylcholinesterase (true) is found in all cholinergic synapses in the PNS and CNS
- Butyrylcholinesterase (pseudocholinesterase) is found in tissues and plasma
How does butyrylcholinesterase differ from acetylcholinesterase?
- Butyrylcholinesterase has a broader substrate specificity and hydrolyses other esters such as suxamethonium
- Shows genetic variance, which influences the duration of action of drugs it normally metabolises
- Acetylcholinesterase has a rapid hydrolysis action and is highly selective
Describe the mechanism of hydrolysis by acetylcholinesterase
- Acetylcholine + enzyme
- Choline + acetylated enzyme
- Acetate + free enzyme
How are anticholinesterase drugs classified?
- Reversible
- Irreversible
Give examples of reversible anticholinesterase drugs
Alkaloids (physostigmine - postganglionic parasympathetic synapse - and neostigmine)
What is the mechanism of reversible antichonesterase drugs?
- Carbamyl esters (physostigmine and neostigmine) inactivate the enzyme by transferring their carbamyl group and blocking the active site
- Carbamyl group removed by slow hydrolysis (minutes)
Give examples of irreversible anticholinesterase drugs
Organophosphate compounds (eg. ecothiopate)
How do irreversible anticholinesterase drugs work?
- They inactivate the enzyme by leaving a large blocking group
- The inactive phosphorylated enzyme is stable (recovery depends upon synthesis of a new enzyme - could take weeks)
List the effects of anticholinesterase drugs on the autonomic nervous system
- Low dose results in enhanced muscarinic activity
- Moderate dose results in enhancement of muscarinic activity and enhanced transmission at all autonomic ganglia
- High doses cause sepolarising block at ganglia
What is physostigmine used to treat?
- Glaucoma (eye drops)
- Atropine poisoning (I.V)
What is ecothiopate used to treat?
- Glaucoma (eye drops)
How does organophosphorous poisoning occur?
- Compounds used in agriculture/horticulture
- Nerve agents
- Highly lipid soluble so readily absorbed through the nasal mucosa, skin and lungs
What are the signs and symptoms of organophosphorus poisoning?
- Increased muscarinic activity (seizures)
- CNS excitation
- NM block
- Cessation of respiration
What are the potential treatments of organophosphorous poisoning?
- Atropine IV
- Artificial respiration
- Pralidoxime
Define cholinomimetic drug
A drug that mimics acetylcholine
What is the characteristic of muscarinic receptor structure?
7 transmembrane components
What are the second messengers of M1, M2, M3, M4 and M5
M1, M3, M5 Gq protein - increases IP3 and DAG
M2 and M4 Gi protein - reduces cAMP
List the subunits of nicotinic receptors, and compare composition of the muscle and ganglion type
5 subunits - alpha beta gamma delta and epsilon
- Muscle type 2alpha, beta, delta, epsilon
- Ganglion type 2alpha, 3beta
What are the main effects of the muscarinic receptors in the eye?
- Contraction of the ciliary muscle (convex, allows near vision)
- Contraction of the spincter pupillae (constricts pupil and improves drainage of intraocular fluid)
- Lacrimation (tears)
How does intraocular drainage occur following contraction of sphincter pupillae?
- Opens the pathway for the aqueous humour, produced by the ciliary body
- This drains via the canals of schlemm
- Reduces intra-ocular pressure
Describe how muscarinic receptors affect the heart
- M2 AChR in atria and nodes cause decreased cAMP
- This deacreases Ca2+ entry (decreased CO) and increases K+ efflux (decreased HR)
How does ACh affect vascular endothelial cells?
- Binds to M3 in endothelial cells stimulating NO release
- This induces smooth muscle relaxation, decreasing TPR
List the side effects of pilocarpine
- Blurred vision
- Sweating
- Gastro-intestinal disturbance and pain
- Hypotension
- Respiratory distress
List the side effects of bethanechol
- Sweating
- Impaired vision
- Bradycardia
- Hypotension
- Respiratory difficulty
What is the principal reason for low plasma acetylcholine?
Butyrylcholinesterase
