PHARM 6: Cholinomimetics Flashcards
Define cholinomimetics.
Cholinomimetics = drugs that mimic the action of Ach in the body
- they are parasympathomimetic drugs
Describe the synthesis of Ach
- Ach = synthesized from acetyl CoA + choline
- via Choline Acetyltransferase (CAT)
- Ach is pumped into vesicles
- await signal
Describe the release of Ach
- depolarization causes opening of VGCC
- causes influx of Ca2+
- causes exocytosis of Ach
What enzyme breaks down Ach?
- acetylcholinesterase
Compare differences between muscarinic + nicotinic effects
Muscarinic effects:
- can be replicated by muscarine
- can be abolished by low doses of muscarinic antagonist ATROPINE
- corresponds to those of parasympathetic stimulation
- after atropine blockade, larger doses of Ach can induce effects similar to those caused by nicotine.
What are the three main receptor subtypes of muscarinic receptors and where are they located?
M1
- CNS
- Salivary Glands
- stomach
M2
- Heart
M3
- Salivary Glands
- Bronchial/ Visceral Smooth muscle
- sweat glands
note:
M4/5 = in CNS
Muscarinic Receptors are generally excitatory / inhibitory
the except is ____
Muscarinic Receptors are generally excitatory
the except is M2 (inhibitory)
All Muscarinic receptors = Type __ receptors
M1/3/5 =
M2/4 =
All Muscarinic receptors = Type 2 receptors
(G Protein Coupled)
M1/3/5 = Gq protein linked receptor —> stimulates PLC to increase production of IP3 + DAG
M2/4 = Gi protein linked receptor —> (inhibitory) reduces production of cAMP
odd = Gq even = Gi
Nicotinic Receptors =
_______ gated ion channels
with __ subunits
There are 2 main types of nicotinic receptor
in the _____ and in the _____
Nicotinic Receptors =
LIGAND gated ion channels
with 5 subunits
(ALPHA, BETA, GAMMA, DELTA, EPSILON)
There are 2 main types of nicotinic receptor
in the MUSCLE and in the GANGLION
What are the 3 main muscarinic effects on the eye?
- contraction of the ciliary muscle
(for near vision) - Contraction of sphincter papillae
(constricts pupil + increases drainage of intraocular fluid) - Lacrimation
(tears)
What is Glaucoma?
Glaucoma = Increase in Intraocular pressure
- can cause damage to optic nerves + retina
- can lead to blindness
What generates aqueous humour?
- generated by capillaries of the ciliary body
- flows into anterior chamber of eye
what is the role of the aqueous humour?
- to supply o2 and nutrients to lens + cornea
- as they don’t have a blood supply
Describe the drainage of aqueous humour
- diffuses forwards across the lens
- then across the cornea
- drains through canals of scheme
- back into the venous system
What happens in angle closure glaucoma?
angle between cornea + iris becomes narrowed
- this narrowing reduces drainage of intraocular fluid via the canals of schlemm
How would you treat angle closure glaucoma?
- give these patients a muscarinic agonist (stimulates muscarinic receptors)
- which causes contraction of the iris
- this opens up angle increases drainage of intracocular fluid through then canal of schlemm
What are muscarinic effects on the heart + cardiovascular system?
Where are M2 receptors specfically found?
- M2 receptors are inhibitory
- slows down the heart rate
- decreases cardiac output
- causes vasodilation
- -> causes drop in BP
M2 receptors found in atria + in both nodes.
What are muscarinic effects on vasculature?
- Ach acts on vascular endothelial cells –> to stimulate NO release
- via M3 receptors
- NO induces –> VSMC relaxation
- causes decrease in TPR
What are the muscarinic effect on Non vascular smooth muscle?
- Non vascular smooth muscle with parasympathetic innervation:
(OPPOSITE TO VSMC)
–> it contracts
so
LUNGS - bronchoconstriction
GUT - Increased motility
BLADDER - Increase bladder emptying
What are muscarinic effects on exocrine glands?
- Salivation
- increase bronchial secretions
- increased GI secretions
- Increased sweating
What are typical agonists at muscarinic receptors? (2)
directly acting cholinomimetic drugs
- choline esters (bethanechol)
2. alkaloids (pilocarpine)
Describe the muscarinic agonist Pilocarpine
what is it useful for?
what are some side effects?
- non selective muscarinic agonist
- good lipid solubility
- half life = 3-4 hr
USES
- useful for local treatment for glaucoma
SIDE EFFECTS
- blurred vision
- sweating
- GI disturbance
- Hypotension
- Respiratory distress
Describe the muscarinic agonist Bethanechol
what is it useful for?
what are some side effects?
- M3 AchR
- selective agonist
- produced from minot modification of Ach
USES
- assists bladder emptying
- enhances Gastric motility
SIDE EFFECTS
- sweating
- impaired vision
- bradycardia
- hypotension
- respiratory difficulty
What are indirectly acting cholinomimetic drugs?
drugs that increase effect of normal parasympathetic nerve stimulation
- inhibits acetylcholinesterase
- so therefore increases amount of Ach building up in the synapse
- -> which increases effect of normal parasympathetic nerve stimulation
What are the 2 types of anticholinesterases?
give examples
- reversible Anticholinesterases
- physostigmine
- neostigmine
- donepezil - Irreversible Anticholinesterases
- ecothiopate
- dyflos
- sarin
what is the key function of cholinesterase enzymes?
- to metabolism Ach —> choline + acetate
What are the 2 types of cholinesterase?
a) Acetylcholinesterase
b) Butyrylcholinesterase
Compare between Acetylcholinesterase and Butyrylcholinesterase
ACETYLCHOLINESTERASE:
- Found in ALL cholinergic synapses
- Very RAPID action
- highly selective for Ach
BUTYRYLCHOLINESTERASE:
- found in PLASMA + most TISSUES but NOT in cholinergic synapses
- has broad substrate specificity
- it is the principal reason for low plasma acetylcholine
- shows genetic variation
What are the effects of cholinesterase inhibitors at
Low Dose:
Moderate Dose:
High Dose:
What are the effects of cholinesterase inhibitors at
Low Dose:
- enhances muscarinic activity
Moderate Dose:
- further enhances muscarinic activity
- there is increased transmission at ALL autonomic ganglia
(due to inc in Ach conc at all cholinergic synapses)
High Dose:
- causes Depolarising block at autonomic ganglia + neuromuscular junction
- nicotinic receptors get overstimulated –> shuts down
How do reversible anti cholinesterase drugs work?
Give examples
- they compete with Ach for active site on acetylcholinesterase
- and then donates carbamyl group to the enzyme
- blocks active site
- prevents Ach from binding
- caramel groups = removed by slow hydrolysis
- INCREASES duration of Ach activity in synapse
e.g physostigmine, neostigmine
Where does physostigmine primality act at?
- primarily acts on post ganglionic parasympathetic synapse
what is the half life of physostigmine?
half life = 30 mins
what is physostigmine used for?
why?
- used in glaucoma
- -> increases drainage of intraocular fluid
- used in atropine poisoning
- -> increases conc of Ach at synapse
- -> so that Ach can outcompete the atropine
How do irreversible Anticholinesterase drugs work?
give examples + uses
- they are organophosphate compounds
- they rapidly react with the enzyme active site
- leaving a large blocking group
- blocking group = stable + resistant to hydrolysis
e.g ecothipate (clinical)
dyflos, sarin, parathion (insecticides/ nerve gas)
What is the use of ecothipate?
why?
- ecothipate = potent inhibitor of acetylcholinesterase
- used as eye drop for glaucoma treatment
- it increases drainage of intraocular fluid + has a prolonged duration of action
What are side effects of using ecothipate?
side effects –> of parasympathetic discharge
- sweating
- blurred vision
- GI disturbance + pain
- Bradycardia
- Hypotension
- respiratory difficulty
effect of Anticholinesterase drugs on CNS at
Low Dose:
High Dose:
effect of Anticholinesterase drugs on CNS at
Low Dose:
- CNS excitation with possibility of convulsions
High Dose:
- Unconsciousness, respiratory depression + death
Non polar anticholinesterases can/cannot cross the BBB
Non polar anticholinesterases can cross the BBB
What 2 anticholesterase drugs are used to treat Alzheimer’s disease?
- Donepezil
- Tacrine
How does exposure to organophosphates cause severe toxicity?
- causes increase in muscarinic activity
- causes CNS excitation
- resulting in depolarizing NM block
How would you treat exposure to organophosphate poisoning ?
TREATMENT
- IV atropine
- patient = put on respirator due to respiratory depression
- found in first few hrs: patient given Pralidoxime (IV) –> unblocks the enzymes
Why do you use Atropine to treat organophosphate poisoning?
- organophosphate poisoning results in massive reduction in activity of acetylcholinesterase
- which leads to increase in synaptic Ach conc
- to block Ach from over stimulating the receptors –> you give muscarinic antagonist (ATROPINE)
Describe the removal of Ach
- Acetylcholinesterase (bound to basement memb) breaks down Ach
- into choline + acetate
- choline is then re uptaken
and used to produce more Ach
list the distribution of muscarinic cholinergic target systems.
- eye
- salivary glands
- lungs
- bladder
- sweat glands
- gut
- heart
- vasculature
