M&R S10 - ANS and Pharmacokinetics Flashcards
How do drugs affect neurotransmission? (In general)
Via interaction with any of the steps of neurotransmission
We will primarily consider drugs that act via step 9 (interaction of transmitter and post synaptic receptor)
What are the 12 basic steps of neuro transmission across a synapse?
- Uptake of precursors
- Synthesis of transmitter
- Storage of transmitters in vesicles
- Degradation of transmitters
- Depolarisation of presynaptic membrane
- Ca2+ influx
- Exocytotic release of transmitter
- Diffusion of transmitter across the synaptic cleft
- Interaction with post synaptic receptor
- Degradation of transmitter
- Reuptake by the presynaptic cell of transmitter/degradation products
- Interaction of transmitter with presynaptic neurone
Where and how is acetylcholine synthesised?
In the cytoplasm of cholinergic synaptic axon terminals
Synthesised by choline acetyltransferase from choline and AcetylCoA
What is the fate of acetylcholine after synthesis and before release from the axon?
Transported into vesicles by indirect active transport mechanism
Stored in vesicles (>100mM Ach in vesicle)
Some degraded by cytoplasmic cholinesterase
What is the fate of Ach after release from the presynaptic axon terminal?
Released via exocytosis
Diffuses across synaptic cleft
Can interact with pre and post synaptic receptors
ACh degraded by acetylcholine esterase in the cleft into choline and acetate (more Ach esterase in nicotinic/fast clefts)
Re uptake of degradation material by presynaptic neurone
How do agents that interfere with cholinergic transmission typically act?
Interaction with cholinoceptors
Notable exception is the use of cholinesterase inhibitors (decrease rate of Ach degradation)
What are the two common classes of nicotinic cholinoceptor antagonists?
Give examples of agents and uses
Those with preferential ganglion:
- E.g. Trimethaphan
- Rarely used clinically
Neuromuscular blockers:
- E.g. Tubocurarine, pancuronium
- Muscle paralysis during anaesthesia
Describe muscarinic cholinoceptor agonists
Give an example and its uses
They vary in their selectivity to muscarinic and nicotinic receptors and resistance to degradation
No agent has significant muscarinic selectivity
Have different actions depending on whether they’re acting on the peripheral or central nervous system.
Pilocarpine:
- Major clinical use is in the treatment of glaucoma
- Is usually applied in the form of eyedrops.
- Also suppresses atrial tachycardia
Describe muscarinic cholinoceptor antagonists
Give 1 example
Little to no receptor subtype selectivity however vary in central and peripheral actions
Atropine:
- Increase heart rate (positive chronotropy)
- Bronchodilation
- Pupillary dilation
Give examples of cholinesterase inhibitors and their uses
Physostigmine
Dyflos
Edrophonium
- Vary in longevity of action and peripheral versus central actions
- Acutely reverse effects of myasthenia gravis and no non-depolarising neuromuscular blocking agents used in anaesthesia
- Topical treatment of glaucoma
- New drugs treat of early Alzheimer’s (E.g. tacrine)
Describe the synthesis of dopamine from tyrosine
Tyrosine taken up by presynaptic adrenergic axon terminals
Cytoplasmic tyrosine hydroxylase converts tyrosine to DOPA, this is the rate limiting step
DOPA is converted to Dopamine by DOPA decarboxylase
Dopamine is transported into vesicles and converted to noradrenaline via dopamine-B-hydroxylase
How is adrenaline synthesised in the adrenal glands?
Chromaffin cells of the adrenal medulla can synthesise noradrenaline
NA can be converted to adrenaline via phenylethanolamine-N-methyl transferase
Describe the fate of NA after packaging into vesicles
Ca2+ mediated exocytosis upon action potential
Interacts with pre and post synaptic receptors as it diffuses through the cleft
Uptake 1:
- NA actions terminated by presynaptic uptake via Na+ dependent, high affinity transporter
Uptake 2:
- Non neuronal, low affinity mechanism
Degradation:
- Within the presynaptic axon terminal
- Two enzymes
- Monoamine oxidase (MAO)
- Catechol-O-methyltransferase (COMT)
Or can be re-vesiculated and reused
Describe NA vesicles intracellularly
Present in adrenergic pre-synaptic axon terminals
Contain NA and Dopamine-B-hydroylase that converts Dopamine to NA
NA conc = 0.5 - 1.0M
Exploits a H+ gradient that is ATPase generated to move catecholamines against concentration gradient (Dopamine and NA can be taken up)
Give a list of drug/drug categories that can be used to modulate adrenergic neurotransmission
Adrenoceptor agonists Adrenoceptor antagonists Alpha-methyl-tyrosine Alpha-methyl-DOPA CarbiDOPA Adrenergic blocking drugs Indirectly acting sympathomimetic agents (IASAs) Uptake 1 inhibitors
Describe the action of Alpha-methyl-tyrosine
Give it’s use
Competitively inhibits tyrosine hydroxylase and therefore blocks de novo synthesis of NA
Only clinical use is to inhibit NA synthesis in pheochromocytoma
Describe the action of Alpha-methyl-DOPA`
Give an example of its use
Taken up by adrenergic neurones and converted to Alpha-methyl-noradrenaline via normal NA synthesis pathway
Unlike NA, AMNA is poorly metabolised and therefore accumulates in vesicles
When released preferentially activates presynaptic A2 adrenoceptors, reducing transmitter release
Has been exploited in treatment of hypertension
Describe the action of CarbiDOPA
Give an example of use
Inhibits DOPA decarboxylase in the periphery but not in the CNS (Doesn’t cross blood-brain barrier)
Used in combination with L-DOPA in the treatment of Parkinson’s disease
What are adrenergic blocking drugs?
Give a few examples
Selectively concentrated in terminals via Uptake 1
Then act via a variety of mechanisms:
- Reduce impulse conduction and Ca2+ mediated endocytosis (local anaesthetic)
- Partial blocking of reuptake of neurotransmitter
- Depletion of NA from vesicles
Rarely used clinically, severe side effects (orthostatic hypotension)
E.g. Guanethidine, Bretylium
Describe the action of Indirectly acting sympathomimetic agents
Give some examples
Weak adrenoceptor agonists
Exert actions via other/additional mechanisms:
- IASAs are subject to uptake 1 into pre-synaptic neurones and into vesicles
- Cause NA to leak from the vesicles which can leak into the cleft
- This leaking effect is enhanced by monoamine oxidase inhibitors (MAOIs)
E.g. Amphetamine, tyramine, ephedrine
Describe the action of Uptake 1 inhibitors
Give an example
Central and possible peripheral actions (can cause tachycardia, dysrhythmia)
Tricyclic antidepressants E.g. Amitriptyline
What is the major therapeutic difference between muscarinic and adrenoceptor agonists
Highly subtype specific agents available for adrenoceptors, not muscarinic receptors
Give a brief description of beta adrenoceptor agonists
Give examples
B1 agonists:
- Positive ionotropy and chronotropy
- Prone to cause cardiac arrhythmia
- E.g. Dobutamine
B2 agonists:
- Reverse bronchoconstriction in asthmatics
- E.g. Salbutamol
Give a brief description of alpha adrenoceptor agonists
Give examples
A1 agonists:
- Nasal decongestant
- Local vasodilation
- Given in conjunction with local anaesthetic to prevent anaesthetic dissipation
- E.g. Phenylephrine, adrenaline
A2 agonists:
- Anti-hypertensives
- E.g. Clonidine
Give a brief description of adrenoceptor antagonists
Widely used
Most are Alpha or Beta selective, this reduces side effects
Give a description of alpha adrenoceptor antagonists
Give examples
Alpha agonists:
- A1 and A2
- Peripheral vasodilatation
- Treat peripheral vascular disease
- E.g. Phentolamine
Selective A1:
- Treat hypertension
- Orthostatic hypotension and impotence side effects
- E.g. Prazosin
Give a description of beta adrenoceptor antagonists
Give examples
B1 selective or general (B1 and B2):
- Treat hypertension, arrhythmia, angina and MI
- Bronchoconstriction, bradycardia, cold extremities, insomnia as side effects
- Partial agonists cause fewer side effects
Examples:
- Non selective = Propanolol
- B1 selective = Atenolol
- Partial - Alprenolol
What are NANCs?
Give some examples
‘Non-adrenergic Non-cholinergic’ transmitters
NANC transmitters found in the ANS are often co-released with Ach or NA
Examples include:
- ATP
- 5-HT
- Nitric oxide
- Neuropeptide Y
- Substance P
Make sure to revise the basics on ANS from semester 1 and CVS!
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