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
