Cholinomimetics Flashcards
What are cholinomimetics?
Drugs that mimick ACh
What are the three main types of muscarinic receptors?
M1 - salivary glands, stomach and CNS
M2 - heart (inhibitory - Gi cAMP))
M3 - salivary and sweat glands, bronchial/visceral SM, eye
others are excitatory (1/3 are Gq- IP3 and DAG)
What type of receptors are nicotinic and how many subunits are they made of?
faster ligand gated ion channels
5 - alpha, beta, gamma, delta, epsilon
What does the subunit combination of the nicotinic receptor determine?
the ligand binding properties of the receptor - ACh has weak effects on these receptors
Where are muscarinic receptors found?
effector organ of parasympathetic nervous system
and on effector organs e.g. sweat gland
What is the bodily distribution of muscarinic receptors?
eye, salivary gland, bladder, sweat glands, lungs, heart, gut and vasculature
What are the muscarinic effects in the eye?
- contraction of ciliary muscle so lens bulges allowing near vision
- contraction of sphincter pupillae of the iris which constricts the pupil (misosi) abd improves the drainage of intraocular fluid
- lacrimation (tear production)
What is the importance of muscarinic agonists in the eye?
In glaucoma - contraction of sphincter pupillae opens pathway for aqueous humour allowing drainage via the canals of Schlemm and reducing intraocular pressure. The iris may narrow the drainage angle in glaucoma and intraocular pressure will build and can lead to blindness.
What are the muscrainic effects in the heart?
The M2 AChR are located mainly in the atria and the nodes. The depressing effect on the heart (GI muscarinic receptors) is mediated by:
- Reduction of cAMP 2. Decreased Ca2+ entry - decreased CO
- Increased K+ efflux - decreased HR.
What are the muscarinic effects on the vasculature?
Most blood vessels do not have parasympathetic innervation.
- ACh acts on the vascular ednodthelial cells to stimulate NO release via M3
- NO acts on VSMC and relaxes it resulting in decreases TPR
What are the muscarinic effects on non vascular smooth muscle?
SM with PNS innervation contracts (instead of relax)
- Lungs – bronchoconstriction
- Gut – increased peristalsis (can cause pain)
- Bladder – increased bladder emptying
What are the muscarinic effects on exocrine glands??
- Salivation
- Increased bronchial and GI secretions (including gastric HCl production)
- Increased sweating
What are directly and indirectly acting cholinomimetics?
directly - act on the receptor (agonists)
indirectly - affect the enzymes involved
Give examples of the two types of directly acting cholinomimetics
bethanechol -choline ester
pilocarpine - alkaloid
What does bethanechol do?
Side effects?
Selectivity?
- M3 AChR selective agonist
- Used to aid bladder emptying and enhance GI motility
- Side effects: blurred vision, sweating, nausea, hypotension, respiratory distress, bradycardia
Pharmakokinetics of bethanechol
Resistant to degradation, orally active, limited access to brain, t1/2 ~ 3-4hrs
What is pilocarpine?
What is it used for?
Side effects?
Non-selective (attaches to only muscarinic receptors but any sub-types) muscarinic agonist
- glaucoma
- SE: blurred vision, sweating, GI pain, hypotension, respiratory distress
Pharmakokinetics of pilocarpine
- Good lipid solubility - t1/2 ~ 3-4hrs
What are the two types of cholinesterases?
- acetylcholinesterase (true/specific)
- butyrylcholinesterase (pseudo)
Where is acteylcholinesterase found, how fast does it act and what is its selectivity?
- Found in synapses
- Rapid action
- Highly selective for ACh
Where is butyrylcholinesterase found and what is its selectivity?
- Found in plasma and most tissues but not in synapses
- Broad substrate specificity
- Is the principal reason for low plasma ACh
- Shows genetic variation
What are the effects of low, moderate and high dose of cholinesterase inhibitors?
Low dose – enhanced muscarinic activity
Moderate dose – further enhancement, increased transmission at all ANS ganglia (Inc. nAChRs)
High Dose (toxic) – depolarising block at ANS ganglia and NMJ
What are the two types of indirectly acting cholinomimetics?
reversible
irreversible
Give examples of reversible indirectly acting cholinomimetics
physostigmine, neostigmine, donepezil
How do reversible indirectly acting cholinomimetics work?
- They donate a carbamyl group to the enzyme active site, blocking the active site (competitive)
- The carbamyl group is then removed via slow hydrolysis (minutes)
Describe the structure of physostigmine, where it works and what it is used to treat
- A tertiary amine
- Acts at the postganglionic PNS synapse
- Used to treat glaucoma (aids IOP reduction)
- Used to treat atropine poisoning
Give examples of irreversible indirectly acting cholinomimetics
Ecothiopate, dyflos, sarin (organophosphates)
How do irreversible indirectly acting cholinomimetics work?
Rapidly react to enzyme active site and leave a large blocking group – stable and resistant to hydrolysis
What does ecothiopate do, what does it treat and the side effects?
- Potent inhibitor of acetylcholinesterases
- Slow reactivation of the enzyme by hydrolysis takes several days
- Used to treat glaucoma (eye drops) with a prolonged duration of action
- Side effects – sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty
Which type of anticholinesterase can cross the BBB and give an example?
Non-polar anticholinesterases (e.g. physostigmine)
Which drugs are used to treat Alzheimers?
Donepezil and Tacrine are used to treat Alzheimer’s disease (which proves ACh is important in learning and memory)
Potentiation of central cholinergic transmission relieves and symptoms but does not affect degeneration
What is organophosphate poisoning?
Treatment?
- Severe toxicity is caused by accidental exposure to organophosphates used in insecticides/nerve gas
- Treatment = IV atropine, artificial respiration, IV pralidoxime
- The phosphorylated enzyme ‘ages’ within a few hours – just keep them alive until then
- Pralidoxime can cause anticholinesterases to unbind.
What do low and high doses of anticholinesterases do in the brain?
Low doses – excitation with possibility of convulsions
High doses – unconsciousness, respiratory depression, death
