Noradrenaline

What are the effects of sympathetic stimulation?

Increased HR/force of contraction. Bronchodilation. Decreased peristalsis/luminal secretions, increase vasoconstriction in GI organs. Pupil dilation (mydriasis), glycogenolysis, lipolysis, renin secretion, vasodilation of skeletal muscle

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What are the major targets for therapeutic intervention - agonists?

Asthma (increased bronchodilation for enhanced gas exchange) e.g. salbutamol, salmeterol (b2-adrengeric agonist). Premature labour - uterine relaxation e.g. IV salbutamol (b2-adrenergic agonist)

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What are the major targets for therapeutic intervention - antagonists?

Hypertension (decrease bp e.g. propanolol - non-selective b-adrenergic antagonist). Angina (decreased HR e.g. propanolol). Benign prostatic hypertrophy (decrease size of prostate gland e.g. prazosin, tamsulosin - a-adrenergic antagonist)

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Describe features of drugs in the sympathetic nerves in the CNS

All drugs would need to penetrate the BBB, all effects are likely to be widespread

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Describe features of the sympathetic ganglion

Transmission is similar (ACh mediated) at all autonomic ganglia - effects likely to be widespread and non-specific

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Describe the effect of drugs on the NMJ

Allows for specific targeting of function, minimal off target effects

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What are the five target areas for signalling at sympathetic post ganglionic junction?

Synthesis, storage, release, interaction with receptors and transmitter inactivation

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Outline the process of noradrenaline synthesis

Tyrosine (tyrosine hydroxylase) - DOPA (dopa decarboxylase) - dopamine (dopamine b-hydroxylase) - noradrenaline (phenylethanolamine-N-methyltransferase) - adrenadline

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Describe features of the false substrate a-methyl-tyrosine

Tyrosine hydroxylase (ate limiting enzyme in NA synthesis). A-methyl-tyrosine (tyrosine analogue) inhibits tyrosine hydroxylase/blocks formation of DOPA. Used to decrease bp in phaechromocytoma. Side effects: sedation, Parkinsonism, diarrhoea

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Describe features of the false neurotransmitter methyldopa

2 mechanisms of action. Production of a2-selective agonist a-methylnoradrenaline. Competitive inhibitor of DOPA decarboxylase (decrease dopamine/NA). Lowers bp/stimulate inhibitory a2-adrenoceptors in brainstem - decrease sympathetic NS activity

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Describe features of reserpine inhibiting NA storage

Unprotected monoamines (NA/dopamine/serotonin), metabolised by MAO. Normal conditions - NA taken up by VMAT. Reserpine blocks VMAT, prevent uptake of NA/metabolism by MAO. Nerve depleted of NA within 24h. No longer used in clinic (anti-hypertensive)

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What are the side effects of reserpine?

Profound CNS depression, diarrhoea and nasal congestion

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Describe features of drugs inhibiting NA release

After release, NA can be taken up by 'uptake 1' channels. Drugs inhibit NA release by entering varcosity through channels/displace NA in vesicles. Leads to metabolism of NA e.g. Guanethidine/Debrisoquine - benefits for stimulating controlled release

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Describe how clonidine inhibits NA release

NA release is inhibited by NA activation of a2-adrenergic receptor on presynaptic terminal in negative feedback mechanism. Clonidine (a2-adrenergic receptor specific agonist - inhibits NA release by activating receptors)

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What are the uses and side effects of clonidine?

Uses - hypertension and tachycardia. Side effects - postural hypotension, headaches, diarrhoea, fluid retention

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Describe how amphetamine promotes NA release (1)

Amphetamine/tyramine/ephedrine enter varicosity through uptake 1 channel. Drugs compete with NA to enter vesicles through VMAT. Drug displaces NA from storage, NA leakage into synaptic gap where it activates receptors

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Describe how amphetamine promotes NA release (2)

Amphetamine has secondary effects, inhibits MAO, increases free NA concentration for release into synaptic gap. Ephedrine (nasal decongestant/bronchodilator). Amphetamine/speed (used in ADHD)

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What are the side effects of amphetamine?

Side effects - tachycardia, restlessness, insomnia, dry mouth, tolerance, rebound effects

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Describe features of adrenergic receptors

Vascular smooth muscle (a) - NA - A - isoprenaline. Cardiac muscle (b) - isoprenaline - A - NA. a receptors (a1A, a1B, a1D and a2A, a2B, a2C). b receptors (b1, b2, b3) - sub-types discovered in cloning

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Describe features of a1 adrenergic receptors (postsynpatic) (1)

Vascular smooth muscle contraction (vasoconstriction, reduced blood flow, increased bp). Relaxation of longitudinal muscle in GIT, anal sphincter contraction (reduced GI motility, constipation). Bladder relaxation/sphincter contraction (retention)

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Describe features of a1 adrenergic receptors (postsynpatic) (2)

Pregnant uterine muscle contraction. Radial muscle contraction in the eye (pupil dilation). Increased secretion from salivary glands. Increased glycogen metabolism in liver. Vas deferens contraction (***********)

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Describe features of a2 adrenergic receptors (presynaptic)

Widespread distribution, inhibition of transmitter release

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Describe features of b1 adrenergic receptors (postsynaptic)

Predominantly located in cardiac muscles. Increased HR. Increased force of contraction

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Describe features of b2 adrenergic receptors (non-synaptic sites)

Relaxation of bronchial smooth muscles (bronchodilation). Vascular smooth muscle relaxation. Skeletal muscle, coronary/hepatic arteriole vasodilation. Uterine smooth muscle relaxation. Glycogen metabolism in liver

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What are sympathomimetics?

Drugs which mimic the action of endogenous sympathetic nervous system agents

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Describe features of non-selective sympathomimetics

NA (a1 +++, a2 +++, b1 ++, b2 +) - emergency treatment of acute hypotension/cardiac arrest. A (a1 ++, a2 ++, b1 +++, b2 +++) - emergency treatment for acute hypotension/cardiac arrest, anaphylactic shock/local anaesthetic (vasoconstriction limits F)

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Describe features of directly acting sympathomimetics - a-selective

Phenylephrine (a1 ++, a2 0, b1 0, b2 0) - acute hypotension/nasal congestion). Clonidine (a1 0, a2 +++, b1 0, b2 0) - hypertension/migraine

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Describe features of directly acting sympathomimetics - b-selective

Isoprenaline (a1 0, a2 0, b1 +++, b2 +++) - heart block (acute/pending pacemaker). Salbutamol (a1 0, a2 0 , b1 +, b2 +++) - asthma (inhaled), premature labour (uterine relaxation). Dobutamine (a1 0, a2 0, b1 +++, b2 +) - cardiogenic shock/increase CO

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Describe features of a-adrenoceptor antagonists (a-blockers) - non-selective

Block sympathetic vasoconstrictor tone (decrease bp). Non-selective (a1/a2) - phenoxybenzamine (irreversible competitive antagonist - not used). Phentolamine (reversible competitive antagonist - not used) - cause severe reflex tachycardia

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Describe features of a-adrenoceptor antagonists (a-blockers) - selective

Selective blockers (a1) - prazosin, doxazosin - decreased risk of reflex tachycardia, used as antihypertensive agents and used for benign prostatic hyperplasia. Side effects - postural hypotension, nasal congestion, impotence, priapism, diarrhoea

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Describe features of b-adrenergic antagonists (b-blockers)

Block sympathetic nervous input into heart. Decreased force of contraction/frequency of contraction/vascular tone (mechanism unknown). Decreased CO/bp. No longer recommended by NICE as first line of treatment

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Describe features of b-adrenergic antagonists (b-blockers) - selectivity

Non-selective (a1/b1) - labetalol, carvedilol (reduce arterial bp, fewer side effects than a-blockers, used for stable congestive heart failure). B-selective (b1/b2) - propanolol, timolol (use - treatment of disturbances in cardiac rhythm, MI/angina)

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Describe features of b-adrenergic antagonists (b-blockers) - cardioselective

b1-subtype selective - metoprolol, atenolol (uses - treatment of disturbances in cardiac rhythm, MI/angina)

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What are the adverse effects of b-blockers?

Fatigue (reduced CO/muscle perfusion). Reduced peripheral blood flow (Reynaud's phenomenon). Bronchoconstriction. Increased risk of cardiac failure. Risk of hypoglycaemia (reduce warning signs for patients with diabetes). Rebound effects (withdrawal)

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Endogenous and exogenous catecholamines are metabolised by which two enzymes?

MAO (within cells bound to surface membrane of mitochondria). COMT (widespread enzyme in neuronal/non-neuronal tissues)

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What is the function of MAO?

Converts NA to NA aldehyde (then ADH used to convert it to DOMA)

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What are the two isoforms of MAO?

MAOA - in CNS, liver, pulmonary vascular endothelium, GIT and placenta. MAOB - in CNS, systemically in blood platelets

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Give examples of MAOIs

Phenylzine (irreversible non-selective inhibitor, inhibits both isoforms). Moclobemide (short acting MAOA selective inhibitor). Selegiline (irreversible MAOB selective inhibitor - selective for dopamine, used in PD)

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What are the side effects of MAOIs?

Urinary retention, headache, insomnia, postural hypotension, diarrhoea

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Describe features of tyramine and the cheese effect

Tyramine found in cheese/wine/yoghurt is normally degraded by MAO. But when patients take MAOIs, tyramine is not metabolised and can lead to a hypertensive crisis

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Why do drugs acting on NA have limited success as a treatment for hypertension?

They act at all the sympathetic neuro-effector junctions (non-selective) and have a wide range of side effects

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Summarise the drugs acting on NA synthesis, storage, release and inactivation

Synthesis (a-methyltyrosine, carbidopa, a-methyldopa, decrease). Storage (reserpine, decrease). Release (guanethidine/clonidine decrease, tyramine/amphetamine/ephedrine increase). Inactivation (cocaine/MAOIs/phenylzine/mocloemide/selegiline increase)

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What is the effect of phentolamine on the sympathetic NS on the CVS?

Non-selective a-receptor blocker. Inhibits reuptake of NA and inhibits interaction of NA which adrenoceptor - inhibit vascosontriction

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What is the effect of prazosin on the sympathetic NS on the CVS?

Selective blocker of a1 receptors. Inhibit postsynaptic adrenoceptor (inactivation), vasoconstriction is inhibited

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What is the effect of labetalol on the sympathetic NS on the CVS?

Non-selective blocker of a1/b receptors. Inhibits a/b adrenoceptors on postsynaptic terminal. Leads to inhibition of vasoconstriction and inhibition of increased heart rate (side effect - bronchoconstriction)

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What is the effect of metaprolol on the sympathetic NS on the CVS?

Selective agonist of b2 receptor - inhibits postsynaptic receptor, inhibits increased heart rate

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What is the effect of salbutamol on the sympathetic NS on the CVS?

Selective agonist of b2 receptor - promotion of bronchodilation

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Summarise the selectively of the following drugs: salbutamol, atenolol, prazosin, labetalol

Salbutamol (b2 agonist, asthma, premature labour). Atenolol (b1 antagonist, hypertension, angina). Prazosin (a1 antagonist, hypertension). Labetalol (a1/b antagonist, hypertension)

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Noradrenaline

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