SNS Drugs Anita Bolina 23rd March 2019

SNS Agonists

Learning Objectives List the clinical uses, principal pharmacological features, mechanism of action and unwanted effects of selective and non- selective α and β adrenoceptor agonists.

Physiological SNS transmitters Noradrenaline and adrenaline are the endogenous transmitters of the SNS Fight or flight response – what do you need to get away from predators? NA favours α>>>β Adrenaline favours β>>>α Metabolism of NA: - Thoraco-lumbar – ACh secreted acts on adrenal gland Made in ADRENAL MEDULLA (after synapse 1) One extra step to produce it from dopamine Acts on alpha and beta adrenoceptors (differing affinities) Fight or flight- these actions are what occurs when the SNS is stimulated. Either stimulated normally using NA or A , or via drugs Pupil dilation – to see your predator Skeletal muscles contraction – to run away Bronchodilation – increased airflow Increased HR and contraction – supply oxygen and increased circulation in order to run away (or fight I guess)

MOST IMPORTANT: Bronchioles – airway dilation – β2 When you stimulate: Bronchioles – airway dilation – β2 Liver- gluconeogenesis (increased blood sugar) – β2 Kidney – renin production – increased blood pressure – β1 Blood vessels: Β2 causes dilation – decrease BP Α1 causes constriction – increase BP Heart – β1 – increases HR, contractility and increased heart workload (NOT good in HF/ blood pressure)

Pharmacology of the SNS drugs Gq Target – the receptors of the post ganglionic synapse on the effector organ Alpha and beta adrenoceptors – these are all G-protein coupled!!! Agonists- bind to receptor and cause the physiological response Antagonists – bind to receptor and block the normal response Gi Gs Gs Constriction – a1- due to IP3 acting on ryanodine – Ca influx causes contraction Dilation – B2 – CAMP is a vasodilator

Non selective agonist- adrenaline Anaphylactic shock A severe allergic reaction in response to IGE and mast cell degranulation. Difficulty breathing, major vasodilation leading to plasma leakage >> decreased blood volume >> decreased BP b2 – broncho dilation b1 – tachycardia a1 – vasoconstriction Suppression of mediator release (histamine etc from mast cell)

Adrenaline continued UNWANTED EFFECTS Every SNS receptor is being stimulated – what extra SNS effects would be a problem? Thick and viscous secretions B2 overstimulate – skeletal muscle tremor due to contractions CVS: Tachycardia Arrythmia Hypertension – increased renin production and increased a1 vasoconstriction Cold extremities – a1 vasoconstriction No GIT effects – controlled by parasympathetic mainly

Alpha selective agonists Phenylephrine – a1 Similar to adrenaline (aka epinephrine) More resistant to COMT but not MAO Vasoconstriction Mydriasis (pupil dilation) Nasal decongestant Clonidine – a2 Hypertension (although not used anymore for this) Migraine – Gi receptor ↓ CAMP therefore ↓ vasodilation (stops blood pulsating round head) Acts on presynaptic a2, -VE feedback to decrease NA/A release

Beta selective agonists Dobutamine β1 Cardiogenic shock No reflex tachycardia Metabolised by COMT Salbutamol – β2 Resistant to COMT and MOA breakdown Clinical Uses Asthma - b2 relaxation of bronchial smooth muscle inhibition of release of brochoconstrictor substances from mast cells. Threatened premature labour - b2-relaxation of uterine smooth muscle Side effects- Reflex tachycardia, Tremor, blood sugar dysregulation Isoprenaline – β1 and β2 Uses: - cardiogenic shock -MI - Acute HF B2 stimulation – vasodilation – reduced BP – reflex tachycardia

SNS Antagonists

Learning Objectives Adrenoceptor antagonists: List the clinical uses, principal pharmacological features, mechanism of action and unwanted effects of selective and non-selective α and β adrenoceptor antagonists and compare the pharmacology of selective and non- selective adrenoceptor antagonists. Methyldopa: Identify the actions of the false transmitter methyldopa and identify its clinical uses and side effects.

UNWANTED EFFECTS: Bronchoconstriction – Asthma/COPD Cardiac Failure – Need some sympathetic drive to the heart Hypoglycemia - inhibit glycogen breakdown Fatigue - ↓ cardiac output and ↓ muscle perfusion. Cold Extremities - Loss of b-receptor mediated vasodilatation in cutaneous vessels. Bad Dreams 1- propranolol will act on b2 receptors and therefore is CI in asthmatics 2- alpha 1 properties of carvedilol means that it can reduce vasoconstriction Questions: 1- What is the advantage of atenolol over propranolol? 2- What is the advantage of carvedilol?

Alpha antagonists 1-receptors Gq-linked Postsynaptic on vascular smooth muscle 2-receptors Gi-linked Presynaptic autoreceptors inhibiting NE release NOTE – BLOCKING THIS WILL RESULT IN AN INCREASE IN NA RELEASE (DUE TO DECREASED NEGATIVE FEEDBACK) phentolamine - used to treat phaechromocytoma-induced hypertension Reflex tachycardia GI and diarrhoea S/Es 1 specific blocker: prazosin inhibit the vasoconstrictor activity of NE Reduced tachycardia Dramatic decrease in BP

False transmitter- methyldopa NOTE – this has nothing to do with Parkinson’s disease Used in hypertension Taken up by nerve terminal and converted to methyl-NA A2 receptor on presynaptic terminal remains unblocked – causes –VE feedback USES: Hypertension Renal disease Cerebrovascular disease Adverse effects – dry mouth, sedation, Orthostatic hypotension, Male sexual dysfunction – rarely used! QUESTION – Side effects of methyldopa?

Other uses of beta blockers- arrhythmia Main cause: myocardial ischaemia SNS antagonists - class II antiarrhythmics - Propranolol - Non - selective b- antagonist Class II drug, effects mainly attributed to b1 -antagonism

Angina

SNS treatments of glaucoma Agonist Vasoconstriction – reduced blood flow A1 Decreased vitreous humour formation Clonidine A2 Antagonist Timolol S/Es – bradycardia, bronchoconstriction (uncommon) B1

Exemplar question Name a Beta-Adrenorecptor antagonist (1) Describe 2 ways in which Beta antagonists help treat hypertension (2) Give 2 reasons why Beta Blockers should not be given to diabetics (2) Name an alternate anti-hypertensive that could be used safely in diabetics and explain its method of action? (2)

Of course, I had to end on a meme DISCLAIMER – Please do not listen to Ryan Gosling or you may fail LCRS

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