4.2 Cholinomimetics &Cholinoceptor Antagonists Flashcards
Acetylcholine is synthesised from choline (absorbed into the neurone from the bloodstream via an energy-dependent Na+/choline carrier) and acetyl-CoA by _________________:
• _______________ is the rate-limiting step in ACh synthesis
• Packaged into vesicles (along with _______________ → increases or decreases effect of primary neurotransmitter) near the surface of the neurone. Acetylcholine is protected from degradation in the vesicle.
• Arrival of action potential leads to large-scale Ca2+ influx that promotes exocytosis of synaptic vesicles → release of ACh into the synapse (binds postsynaptic receptors). Release is blocked by ____________, _______ causes release of acetyl choline.
• Postsynaptic receptor is activated by binding of the neurotransmitter.
• Rapidly degraded by _______________ into acetate and choline (reabsorbed into presynaptic cell to make more ACh)
• Choline is taken up by the neuron. this transport is inhibited by ____________.
choline acetyltransferase;
Uptake of choline;
ATP and proteoglycan;
botulinum toxin;
spider venom;
acetylcholinesterase;
hemicholinium
The two main families of cholinoceptors (muscarinic and nicotinic) have different ACh effects in the body, and are distinguished by _________________:
Nicotinic receptors
- _______________ receptors
- Highest affinity for nicotine (low-dose stimulates receptor, high-dose blocks it)
- ACh effects are relatively weak
- Found in the __________________
different affinities for cholinomimetic agents;
Type I (ionotropic);
CNS, adrenal medulla, autonomic ganglia, NMJs in skeletal muscles (also affects the somatic response);
Muscarinic receptors - \_\_\_\_\_\_\_\_\_\_\_ receptors - Highest affinity for muscarine (mushroom poison found in Amanita muscaria) *ACh effects are stronger - All subtypes are found on neurones M1: \_\_\_\_\_\_, \_\_\_\_\_\_\_\_\_\_ M2: \_\_\_\_\_\_\_, \_\_\_\_\_\_\_\_\_ M3 \_\_\_\_\_\_\_, \_\_\_\_\_\_\_\_, \_\_\_\_\_\_\_\_, \_\_\_\_\_\_\_\_\_\_\_
Muscarinic effects are replicated by muscarine and abolished by low doses of ________________ → correspond to those of parasympathetic stimulation:
• After atropine blockade of muscarinic actions, larger doses of ACh can induce effects similar to those caused by nicotine (binding to nicotinic receptors instead)
Type II (G-protein coupled);
gastric parietal cells, salivary glands;
cardiac cells and smooth muscles;
bladder, exocrine glands (sweat, salivary), smooth muscles, eyes;
atropine (antagonist)
Aqueous humour is produced by the _____________, and passes through the lens and lines the part of the eye between the _________________ (protects the eye):
• Rate of production of aqueous humour is matched by the rate of drainage (by the venous drainage channels/ ______________)
Effect
- Contraction of ___________: Accommodation for near vision → _______________ slacken to a certain degree → lens fattens → focus on near objects
- Contraction of _______________ (circular muscle of the iris): Constricts the pupil (_________) and improves drainage of intraocular fluid:
• Contraction of sphincter papillae causes it to elongate → ________________ becomes smaller
• Helps to focus image of near object on the fovea
• Drawing of the muscle towards the centre of the eye → less blockage of the venous drainage channels → drainage via canals of Schlemm → reduced intraocular pressure (used in ____________) - Lacrimation: Secretion of tears from the lacrimal glands
ciliary body;
lens and cornea;
canal of Schlemm;
ciliary muscle;
suspensory ligaments holding the lens;
sphincter pupillae;
miosis;
gap between iris muscles (pupil);
glaucoma
The cardiac tissues contain __________________ (mainly in the atria and nodal tissue), which are activated by ACh and are coupled negatively to __________:
• Mainly helps to elicit a fall in blood pressure (reduces CO and HR)
Tissue Effects
- Atrial: Decreased ___________ → decreased ___________ → decreased ____________
- Nodal: Increased _________________ → decreased nodal firing rate → decreased ____________
M2 ACh receptors;
cAMP;
Ca2+ entry; contractility; cardiac output
K+ efflux (hyperpolarisation); heart rate
Most blood vessels do not have parasympathetic innervation, but those with _______________ are acted on by ACh:
• Stimulates _____________ in vascular endothelial cells to induce vascular smooth muscle relaxation → decreases total peripheral resistance → decreases blood pressure
• More relevant to the clinical use of cholinomimetics than normal physiology
M3 muscarinic receptors;
NO release
Smooth muscles which have parasympathetic innervation respond in the opposite way to vascular smooth muscles → contraction rather than relaxation:
- Lungs: _______________
- Gut: _________________
- Bladder: Increased __________________
Bronchoconstriction ;
Increased peristalsis (enhanced gut motility);
bladder emptying (micturition)
ACh binding to muscarinic receptors (especially _______________) promotes exocrine secretion:
• Increased salivation
• Increased bronchial secretions (e.g. mucus)
• Increased gastrointestinal secretions (including ______________ → M1 receptor)
• Increased ______________ (sympathetically-mediated)
M3 subtype;
gastric HCl production ;
sweating
what is the definition of affinity?
- Capacity of a drug to bind to its receptor (mediated by electrostatic forces, hydrogen bonding, van der Waals forces, hydrophobic interactions)
- Agonists and antagonists possess affinity
What is the definition of efficacy?
- Ability of a drug (once bound to its receptor) to produce a response
- Only agonists possess efficacy
How is the selectivity of Pilocarpine?
Non-selective agonist (binds to all muscarinic receptors)
What is the half life of pilocarpine?
3 – 4 hours
What is the administration of Pilocarpine?
Good lipid solubility
How is the brain penetration of Pilocarpine?
Relatively effective
What are the uses of Pilocarpine?
Local treatment for glaucoma
What are the side effects of Pilocarpine?
Due to leakage into systemic circulation from highly vascular eye: Blurred vision Sweating GI disturbance and pain Hypotension Respiratory distress
How is the selectivity of Bethanechol?
M3-selective agonist
What is the half life of Bethanechol?
3 – 4 hours
What is the administration of Bethanechol?
Resistant to degradation
Orally active
How is the brain penetration of Bethanechol?
Limited
What are the uses of Bethanechol?
Assist bladder emptying
Enhance gastric motility
Glaucoma, Sjogren (dry mouth)
What are the side effects of Bethanechol?
Impaired vision Sweating Nausea Hypotension Respiratory difficulty Bradycardia
Latrotoxin toxicity: latrotoxin is produced by the black widow spider and does not directly interact with the muscarinic receptor
- Diffuses into the___________ –> promotes massive ACh exocytosis –> Immediately causes excessive stimulation of muscarinic receptor –> overactivation
- Very little ACh left in the synaptic terminal –> subsequent stimulation of presynaptic neurone leads to ______________
- ______________ are the most sensitive (controlling breathing diaphragmatic muscles
and movement skeletal muscles) –> paralysis (reduced capacity to mov_______________ and
parasympathetic nerve terminal;
little ACh release and activation of ACh receptor;
Motor neurones
Acetylcholinesterase (true/specific cholinesterase)
- Found in _____________________
- Very rapid action (> 10000 hydrolysis reactions per second)
- Highly selective for ACh
- Possesses an important ______________ (interacts with acetyl group on ACh to remove the group and liberate choline)
all cholinergic synapses (peripheral and central nervous systems);
serine-hydroxyl group
Butyrylcholinesterase (pseudocholinesterase)
- Found in ______________ (not cholinergic synapses)
- Results in __________________ (vs high plasma NA → no enzyme in blood for NA)
- Broad substrate specificity (hydrolyses other esters like suxamethonium)
- Shows genetic variation
-
plasma and most tissues;
low plasma ACh
Indirectly acting cholinomimetic drugs promote a build-up of ACh (do not work directly on the muscarinic receptors) by ____________:
• ______________ (stops breakdown of ACh) → increases the effects of normal parasympathetic nerve stimulation
• Effects differ depending on the dose used:
increasing ACh levels in the synapse;
Inhibits acetylcholinesterase enzyme
What is the effect of low dose cholinesterases?
Enhanced muscarinic activity
What is the effect of moderate dose cholinesterases?
Further enhancement of muscarinic activity Increased transmission at all autonomic ganglia (nicotinic)
What is the effect of High (toxic) dose of cholisterinases
Depolarising block at autonomic ganglia and NMJs
Reversible anticholinesterases
- Carbamoyl donors which compete for the cholinesterase enzymatic active site by ________________ to block the site
- Carbamoyl group is removed by
____________ (minutes rather than msecs) → increases duration of ACh activity
donating carbamoyl group;
slow hydrolysis
Irreversible anti cholinesterases
- _______________ which rapidly react with the active site and leave a large blocking group
- Stable and resistant to hydrolysis → recovery requires production of new enzymes (days to weeks)
- Only _______________ is in clinical use (may still be removed after a considerable period of time) → others are used as insecticides and nerve gas (sarin) as they are irreversible
Organophosphate compounds;
ecothiopate
What is the selectivity of physostigmine
Postganglionic parasympathetic synapse (muscarinic)
What is the half life of physostigmine
30 minutes
How is the administration of physostigmine
IV, IM, eye drops
how is the brain penetration of phyostigme
Crosses blood-brain barrier
what are the uses of physostigmine
Glaucoma (increase IOF drainage) Atropine poisoning (esp. children)
What are the side effects of physostigmine
- Low doses: excitation (possibility of convulsions)
- High doses: unconsciousness, respiratory depression, death
What is the selectivity of physostigmine
Potent inhibitor of acetylcholinesterase
What is the half life of physostigmine
Several days (slow reactivation)
How is the administration of physostigmine?
Eye drops
How is the penetration of Ecothiopate?
NA
What are the uses of Ecothiopate?
Glaucoma (increase IOF drainage; prolonged duration of action)
What are the side effects of Ecothiopate?
Sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty
Organophosphate toxicity: accidental exposure to organophosphates used in insecticides or deliberate use as nerve agents may lead to severe toxicity –> ages the ACh esterase
- Treated using _______________, combination of all3 improves the survivability of the patient) –> must be given within 5 hours
- _______________ liberates the serine hydroxyl group on the cholinesterase enzyme –> removes the irreversible inhibitor
o Recovered enzyme ages quickly and has a shorter half life
IV atropine , artificial respiration and IV pralidoxime;
Pralidoxime
_______________ are used to treat Alzheimer’s disease as ACh is important in the protection against the development of Alzheimer’s (for learning and memory): • Potentiation of central cholinergic transmission _______________ but not the degeneration of the nerves
Donepezil and tacrine;
relieves Alzheimer’s disease symptoms
NICOTINIC RECEPTOR ANTAGONISTS: Classical receptor antagonists
- degree of antagonism vs concentration of agonists?
Degree of antagonism is inversely proportional to the amount of agonists present (compete for the same site)
NICOTINIC RECEPTOR ANTAGONISTS: Ion channer blockers
- degree of antagonism vs concentration of agonists?
- Use-dependent block: degree of antagonism is directly proportional to amount of agonists present (ion channel is opened when agonists are present, allowing access for the antagonists)
- |Incomplete block (do not completely prevent ion passage)
What are the effects of nAChR antagonists on kidneys?
reduction in renin (reduced blood volume)
What are the effects of nAChR antagonists on vessels ?
reduction in vasoconstriction (fall in TPR)
What are the effects of nAChR antagonists on smooth muscles ?
- Parasympathetic system predominates at rest to maintain a degree of tone within the smooth muscles
• Blocking this effect leads to pupil dilation, bronchodilation, bladder dysfunction (less capable on emptying), reduced GI tone (constipation)
What are the effects of nAChR antagonists on exocrine secretions?
• Parasympathetic predominates to increase secretions • Blocking this effect leads to reduced secretions (e.g. bronchial, saliva, sweat, GI)
what are the uses of hexamethonium?
First antihypertensive drug (numerous side effects → e.g. bladder dysfunction, constipation)
what are the uses of trimetaphan
Short-acting antihypertensive used during surgery to reduce the likelihood of blood loss
why is bunarus cereus (1 of the most venemous snakes in the world) so dangerous?
• Common krait (Bungarus caeruleus) is one of the most venomous snakes in the world, producing a toxin called α-bungarotoxin (irreversible nAChR antagonist) • Very dangerous as nAChR also mediate the action of skeletal muscles → irreversible antagonists will lead to paralysis and inability to breathe
What are the effects of atropine?
Less M1 selective (M1 receptors prevalent throughout the brain):
• Normal dose: little effect
• Toxic dose: mild restlessness → agitation
What are the effects of hyoscine?
Possesses greater ability to permeate into the CNS:
• Normal dose: sedation, amnesia
• Toxic dose: CNS depression or paradoxical CNS excitation (associated with pain)
how are muscarinic receptor antagonists used for ophthalmic (retinal examination)?
- ______________ is used (similar to atropine and hyoscine):
• Blocks muscarinic receptors in the iris (prevents _____________ and facilitates _____________)
Tropicamide;
pupil constriction;
dilation
how are muscarinic receptor antagonists used for anaesthesia?
• Bronchodilation: blocks _______________ (allows better access for anaesthetic)
• Decreased _______________ (reduces risk of aspiration)
• Heart: both parasympathetic system and anaesthetics slow down the heart (drugs block muscarinic effect so that the heart rate does not fall too drastically)
• Sedative (e.g. hyoscine)
tracheal/bronchiolar constriction;
saliva production
how are muscarinic receptor antagonists used for motion sickness ?
- Motion sickness is caused by ___________________ (signals sent to the vomiting centre are mediated by cholinergic nerves and muscarinic receptors):
• _______________ prevents sensory mismatch from being relayed to the vomiting centre (anti-emetic)
sensory mismatch between information from the visual pathways and labyrinth;
Hyoscine patch
how are muscarinic receptor antagonists used for Parkinson’s disease ?
- Normally: substantia nigra neurones release dopamine which binds to _______________________ (important for normal motor function)
• ________________ have inhibitory effects on D1 receptors → massive reduction in number of substantia nigra neurones (85%) in Parkinson’s disease → already very little dopamine production → already diminished motor function
• Muscarinic receptor antagonists block _______________ to reduce D1 inhibition → D1 function is enhanced → preserves certain amount of normal motor function
D1 receptors present on neurones originating in the striatum;
M4 receptors;
M4 receptors
how are muscarinic receptor antagonists used for respiratory (asthma/ obstructive airway disease)?
- Muscarinic receptor antagonists block the parasympathetic constriction of the lungs (causing dilation):
• __________________ has a large quaternary amine group which traps it in lungs (prevents diffusion into bloodstream → reduces side effects)
• Administered ________________
Ipratropium bromide (similar to atropine) ;
locally via an inhaler
how are muscarinic receptor antagonists used for IBS ?
Irritable bowel syndrome is characterised by increased motility and secretion (unpleasant symptoms): Blockage of these effects decreases associated symptoms
What are the side effects of muscarinic receptors antagonists
- hot as hell: Decreased sweating, thermoregulation
- dry as a bone: Decreased secretions
- blind as a bat: Cycloplegia (paralysis of ciliary muscles)
- mad as a hatter: CNS disturbance (especially at high doses)
Anticholinesterases are used in the treatment of muscarinic receptor antagonist overdose
- Physostigmine prevents ACh breakdown and causes build up of ACh in the synapse –> ACh ______________ atropine (present due to ingestion of deadly nightshade
- More normal AChR complexes –> normal function is restored
outcompetes
Botulinum toxin: one of the most potent toxins (1g of crystalline toxin can kill more than 1 million people when evenly dispersed and inhaled)
- Interferes with __________________ (allows exocytosis of vesicles) at nerve terminals –> prevents exocytosis of ACh –> impaired skeletal muscle function–> paralysis and death
- Used at very low doses in Botox (localised as best as possible; directly into _______________ –> paralysis of that muscle –> anti wrinkling effect ) –> last up to 6 months
SNARE complex;
skeletal muscle
