M&R S10 - ANS and Pharmacokinetics Flashcards Preview

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Flashcards in M&R S10 - ANS and Pharmacokinetics Deck (29):

What are the 12 basic steps of neuro transmission across a synapse?

1. Uptake of precursors
2. Synthesis of transmitter
3. Storage of transmitters in vesicles
4. Degradation of transmitters
5. Depolarisation of presynaptic membrane
6. Ca2+ influx
7. Exocytotic release of transmitter
8. Diffusion of transmitter across the synaptic cleft
9. Interaction with post synaptic receptor
10. Degradation of transmitter
11. Reuptake by the presynaptic cell of transmitter/degradation products
12. Interaction of transmitter with presynaptic neurone


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)


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.

- 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

- Increase heart rate (positive chronotropy)
- Bronchodilation
- Pupillary dilation


Give examples of cholinesterase inhibitors and their uses


- 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

- 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
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

- 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:
- 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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