s2-L22-Autonomic pharmacology Flashcards
(21 cards)
Why is Autonomic pharmacology important?
- ANS innervates (almost) all viscera - ANS innervates(almost)/ controls/regulates the function of nearly all internal organs without conscious effort. ANS is responsible for involuntary process like heart rate, digestion, respiration, blood pressure, and glandular secretion.
- Unlike CNS, not protected by the blood-brain barrier, and so exposed to many chemical compounds.
- Widespread therapeutic use
- Important toxicology
- Similar methods and mechanisms of
transmission in multiple different tissues
Outline an overview of the Autonomic nervous system(ANS) - 8 major things that ANS do
- Synthesis of catecholamines - NTMs & hormones that play a role in stress response, CV function, metabolism.
- Storage and Packaging of noradrenaline (NAd) and adrenaline (Ad)
- Exocytosis
- Prejunctional regulation of exocytosis
- Uptake (recycling)
- Degradation
- Noradrenergic neuron blockers & indirectly acting catecholamines
- Parasympathetic pharmacology
Describe the anatomical organisation of the ANS and some process that it regulates
-Part of the peripheral nervous system
-Conveys all outputs from the CNS to the rest of the body, except the motor innervation of skeletal muscle.
-Largely outside voluntary control- all involuntary
-3 main anatomical divisions:
Sympathetic
Parasympathetic
Enteric
-Regulation of several processes:
smooth muscle tone
all exocrine secretions
some endocrine secretions
heart rate and force
certain metabolic processes
Describe 1. Synthesis of catecholamines - NAd and adrenaline
Tyrosine
👇 Tyrosine hydroxylase
Dihydroxyphenylalanine (DOPA)
👇 DOPA decarboxylase
Dopamine
👇 Dopamine-ß-hydroxylase
Noradrenaline
👇 Phenylethanolamine
👇 N-methyl transferase
Adrenaline
Name Drugs affecting the NAd synthesis
- alpha-methyl tyrosine
- inhibits tyrosine hydroxylase
- uses: phaeochromocytoma - Carbidopa
- inhibits DOPA-decarboxylase
- works in periphery, not CNS
- uses: Parkinson’s disease (with L-dopa)
- reduces unwanted peripheral actions of
administered L-dopa - Methyldopa
- taken up by sympathetic neurons
- converted to alpha-methylnoradrenaline
- displaces noradrenaline from vesicles
- acts as ‘false transmitter’
- uses: hypertension in pregnancy - 6-OH dopamine
- neurotoxin; experimental use only
Describe 2.Storage and Packaging of noradrenaline (NAd) and adrenaline (Ad)
NAd and Ad are not free in the cytoplasm, but are stored in subcellular membrane-limited particles.
Ad & NAd stored in chromaffin granules (300 nm diameter)
Sympathetic terminals:-
Large dense-core vesicles (80 nm diameter)
- found in cell body, axon and varicosities
Small dense-core vesicles (50 nm diameter)
- found in varicosities
Describe 3.Exocytosis from sympathetic nerves
- Arrival of action potential causes depolarisation of varicosity.
- This results in opening of voltage-gated Ca2+ channels. Ca2+ entry causes an increase in the concentration of free Ca2+ in the varicosity.
3.This activates Ca2+-sensitive proteins that initiate the process of exocytosis, i.e. fusion of vesicles with the nerve terminal membrane, and release of contents.
Describe 4. Prejunctional regulation of exocytosis - modulation of exocytosis
-Sympathetic nerve terminals contain receptors for many different mediators
-A variety of substances can act on these prejunctional receptors to regulate release of noradrenaline.
-Some of these facilitate release of noradrenaline.
-Others inhibit release of noradrenaline.
Presynaptic modulation by endogenous mediators is not restricted to sympathetic nerves, but is an important mechanism for controlling transmitter release from many
different types of nerve terminal.
Describe autoinhibition of noradrenaline release.
-Noradrenaline, released from sympathetic varicosities, can act locally on presynaptic receptors to inhibit its own release, and also that of ATP.
-The presynaptic receptors involved are alpha 2-adrenoceptors, which are negatively coupled to adenylyl cyclase.
-This autoinhibitory feedback mechanism was demonstrated in studies of overflow of radioactively-labelled noradrenaline
from tissues: alpha2-adrenoceptor antagonists were shown to substantially increase noradrenaline overflow, due to enhanced release from sympathetic nerves.
-Clonidine is a selective alpha-2-adrenoceptor agonist - was used to treat hypertension.
- Name few other mediators that can affect the NAd release
1)Acetylcholine
- inhibits release
- via muscarinic receptors
- produces lateral inhibition from
parasympathetic nerves.
- facilitatory nicotinic receptors also.
2)Adenosine - inhibits release (A1 receptors)
3)Opioids - inhibit release (μ-receptors)
4)Angiotensin II
- facilitates release
- via AT1 receptor
Describe 5. Uptake (recycling)
Uptake into sympathetic nerve terminals and into other cells.
1). Uptake 1 = neuronal
-Neuronal due to the 2o active transporter NAT.
-Main way to terminate actions of NAd, highly affinity for NAd (NAd>Ad>isoprenaline)
-Cotransports Na+, Cl- and catecholamine.
Uptake 1 is inhibited by :
Desipramine - tricyclic antidepressant
- major action is on CNS
- adverse effects: tachycardia,
dysrhythmia
Cocaine - euphoria and excitement (CNS
action)
- tachycardia and increased BP
(peripheral)
- also a local anaesthetic
2). Uptake 2 = non-neuronal
-cardiac, smooth muscle, endothelium
-low affinity for NAd, high maximal rate of uptake.
-not particularly selective for NAd(Ad>NAd>ISO)
Uptake 2 is inhibited by :
-normetanephrine
-steroid hormones
-phenoxybenzamine
Both are saturable active transport mechanisms.
Describe 6. Metabolic degradation of Ad and NAd
Degradation by 2 main intracellular enzymes —monoamine oxidase (MAO)
-catechol-O-methyl transferase (COMT)
2 other enzymes involved:
- aldehyde dehydrogenase (ADH); mainly in periphery.
- aldehyde reductase (AR); mainly in CNS
Explain MAO - the intracellular enzymes for degradation of Ad and NAd
-Bound to surface membrane of mitochondria.
-Found in many tissues, including nerve terminals.
-Converts catecholamines to aldehydes.
-Aldehydes then metabolised by aldehyde dehydrogenase (periphery) or aldehyde reductase (CNS).
-Inhibited by several drugs which are used therapeutically for their effects on the CNS (treatment of depression.
Describe the Mono-amine oxidase inhibitor
- Most block MAO irreversibly
Used clinically as antidepressants
Increase levels of noradrenaline, dopamine and 5-HT in the
brain and peripheral tissues
Adverse effects include postural hypotension, atropine-like
effects, weight gain, restlessness, insomnia, cheese reaction
(hypertensive episode following ingestion of tyramine-
containing food, e.g. cheese; flushing)
Examples - phenelzine, tranylcypromine, iproniazid - moclobemide (reversible, competitive inhibito
Describe 7. Noradrenergic neuron blockers & indirectly acting catecholamines
-Inhibit noradrenaline release from sympathetic nerve terminals.
Examples: guanethidine, bretylium*
-Complex actions: Enter nerve terminals through NET and inhibit action potentials (via ion channels) or exocytotic proteins.
-No longer used clinically to treat hypertension.
-Severe adverse effects include postural hypotension, diarrhoea, nasal congestion and failure of ejaculation.
- indirectly acting catecholamines ( ie: amfetamine)
Describe 8. Parasympathetic pharmacology
Steps of the nicotinic receptor agonist
ie:- nicotine
- receptors rapidly desensitise,
and so these agonists can end-up inhibiting
ganglionic transmission if given at
low concentrations for a ‘long time”
(eg. longer than a second)
- Ganglia are no longer targeted
clinically.
Steps of the nicotinic receptor antagonist
-Selectively antagonised by:
1. Autonomic ganglia (and CNS):
2. hexamethonium
-Non-specific antagonist: d-tubocurarine
As a ganglion blocking drug :- Explain the 😊 and 😔 of Hexamethonium.
😊
-Hexamethonium was used to treat high blood pressure (hypertension).
-blocks the ion channel, uses a dependent block, block becomes more effective as membrane hyperpolarized.
😔
- very poorly absorbed from gut; have to be given by
injection.
- not only blocks sympathetic ganglia, but also parasympathetic ganglia, to give unpredictable side-effects.
Examples of muscarinic agonists
ACh
carbachol
muscarine
pilocarpine
Describe the effects and uses of Parasympathomimetics
Effects
* Cardiovascular - decreased heart
rate, cardiac output
* Exocrine glands - secrete -
sweating, lacrimation, salivation,
bronchial secretion
Uses:
-Rarely used due to widespread
side effects
* May be used for the treatment of
glaucoma (pilocarpine topically
applied to the eye)
