Pharmcol201 2005: Lecture 16

PHARMCOL201 2005: Lecture 16

Learning Objectives

Lecture 16

ANS Lecture 3 Noradrenergic Transmission Chapter 11, 5th Edition, Rang, Dale and Ritter.

Describe the classification of adrenoceptors, adrenoceptors, their effectors and second messengers Describe the synthesis, storage and release of NA and Adrenaline and points where drug action (with examples) can occur. Describe the mechanism by which NA’s actions are terminated and the key enzymes involved in its metabolism Describe the actions of adrenoceptor agonists on smooth muscle, the heart and metabolism. Describe, with examples, the key clinical uses of adrenoceptor agonists & antagonists. Differentiate direct and indirect acting sympathomimetics Describe and predict the effects of drugs that inhibit NA uptake transporters

Chemistry of the Peripheral Nervous System SMOOTH MUSCLE NA CARDIAC GLANDS

ACh N

SYMP.

Synthesis Tyrosine

-ve

Tyrosine hydroxylase

Methyl dopa -false substrate, decarboxylated

DOPA Dopa decarboxylase

SYMP.

SWEAT GLANDS

ACh N

ACh M PILOERECTOR

Dopamine Dopamine- -hydroxylase

depolarisation

Ca2+ NA ATP

cAMP AC

Gi α2 NA

ATP

Ca2+

and hydroxylated to form -methyl NA a false trasmitter, which is not a substrate for MAO, so accumulates and displaces NA from vesicles - less active on -1 receptors -more active on -2. USED AS AN ANTIHYPERTENSIVE

-ve

Noradrenaline

Storage and Release

Methyl tyrosine - used in the treatment of phaeochromocytoma

Carbidopa-used as an adjunct therapy in PD Does not enter the brain

Uptake and Degradation

Ca2+ in Vesicle exocytosis

No synaptically localised enzyme to degrade NA (or other catecholamines) catecholamines) Action is terminated by REUPTAKE

Release of NA and ATP (1:4)

UPTAKE I: I: High affinity system with a relatively low maxmium rate of uptake (neuronal)

Action at postand pre-synaptic receptors

UPTAKE 2: 2: Low affinity for NA, but high maximum rate: Smooth muscle, cardiac muscle, endothelium (non(non-neuronal)

PHARMCOL201 2005: Lecture 16

Metabolism

Adrenoceptor Agonists Subtype selective drugs exist: -α1-agonists – phenylephrine, phenylephrine, oxymetazoline - α2-agonists - clonidine – cause fall in blood pressure partly due to decreased NA release,major central actions. -β1-agonists – dobutamine – increased cardiac contractility, but cause dysrhythmias -β2-agonists – salbutamol – bronchodilater asthma

Agonists of α1 on Smooth Muscle NA α1 Gq/11 IP3 Ca2+ contraction Main effect is on vascular smooth muscle decreased vascular compliance increased central venous pressure increased peripheral resistance Increased systolic and diastolic arterial pressure, triggering baroreceptor reflexes reflex bradycardia and inhibition of respiration

Heart

Agonists of β-receptors on Smooth Muscle Produce relaxation of smooth muscle -β 2 cAMP PKA inhibits contraction

inhibition of MLCK

-β2 agonists e.g. salbutamol are used in the treatment of asthma (brochodilation ), or to cause (brochodilation), relaxation of uterine smooth muscle during premature labour Adrenaline is used in anaphylactic reaction to help breathing

Metabolism

β-receptor activation Heart rate (chronotropic (chronotropic)) Force of contaction (inotropic) inotropic) Cardiac output Oxygen consumption Clinically: adrenaline iv for cardiac arrest Dalbutomol (β1 agonist) IV in cardiogenic shock

Beta agonists encourage the conversion of energy into freely available fuels causing an increase in plasma concentration of glucose and free fatty acids.

PHARMCOL201 2005: Lecture 16

Alpha Adrenoceptor Antagonists NonNon-selective -antagonists – Haloalkylamines (eg phenoxybenzamine) phenoxybenzamine)

11-selective antagonists – Prazosin, Prazosin, 22-selective antagonists – Yohimbine – Ergot derivatives

α-1 Selective Antagonists PRAZOSIN Cause vasodilation and a fall in arterial pressure (hypotensive (hypotensive)) Used in the treatment of mild hypertension. Major side effects - postural hypotension, impotence

β-Adrenoceptor Antagonists Propranolol ( 1 and 2) Atenolol 11-selective antagonist Effects depend on the degree of sympathetic activity - very little effect at rest. Most important effects are on the cardiovascular system and on bronchial smooth muscle Propranolol - at rest, very little change in heart rate, cardiac output or blood pressure. But the effects of exercise on these variables is reduced.

NonNon-Selective -AR Antagonists Phenoxybenzamine (irreversible) – used to treat pheochromocytoma but nonnonspecific for alpha adrenoceptors (also 5HT, His & Ach) Phentolamine – binds to both alpha 1 and alpha 2. These drugs cause a fall in blood pressure but baroreceptor reflexive increase in cardiac output and heart rate.

α-2 Selective Antagonists. e.g. Yohimbine (naturally occurring alkal oid)) alkaloid Block presynaptic -2 receptors, therefore increase release of NA - sympathomimetic Also block postpost-synaptic -2 receptors so responses are complex – Dominant effects - vasodilation, vasodilation, drop in blood pressure.

No therapeutic use but useful pharmacological tool

Cardiac Effects Beta blocker use lowers blood pressure in patients with hypertension. complex mechanism involving: – Reduction in cardiac output – Reduced sympathetic activity – Reduction of renin release from the kidney – Central actions

Beta blockers do not cause hypotension in normotensive patients.

PHARMCOL201 2005: Lecture 16

Other Clinical Uses BetaBeta-antagonists reduce intraocular pressure due to decreased aqueous humor productionproduction- used in glaucoma – Delivered directly to eyeeye- timolol may have cardiovascular effects if absorbed

Also used to treat the peripheral symptoms of anxiety - racing heart, tremor etc

Other Effects Only minor metabolic changes in healthy patients – Inhibition of sympathetic stimulation of lipolysis. lipolysis. – May inhibit glucose response in diabetic patients in response to adrenaline -increased likelihood of exercise induced hypoglycemia because normal adrenaline induced release of glucose from liver is diminished – Decreased sympathetic reflexes so hypoglycemia is more likely to go unnoticed.

Drugs That Affect NA Release 1. Prevent exocytosis e.g. guanethidine 2. Evoke NA release in the absence of

nerve terminal depolarisation (indirectly acting sympathomimetics) sympathomimetics) 3. Interact with -2 presynaptic receptors to inhibit or enhance depolarisation evoked release 4. Increase or decrease available stores of NA, e.g. reserpine or MAO inhibitors.

Adverse Effects For propranolol, propranolol, 2 receptor blockade of bronchial smooth muscle relaxation leads to increased airway resistance. – Inconsequential in healthy individuals but very serious in asthmatics. Other adverse effects are bad dreams - probably centrally mediated

Cold extremities due to loss of beta receptor mediated vasodilatation in cutaneous vessels Fatigue - probably due to reduced muscle perfusion

Drugs That Affect Noradrenergic Storage - Reserpine From the shrub Rauwolfia At low concentrations blocks the transport of noradrenaline and other amines into vesicles NA accumulates in the cytoplasm where it is broken down by MAO Decreased NA levels in tissue - blockade of sympathetic transmission Also depletes 5HT and dopamine levels Has antianti-hypertensive effects - but not used due to side effects - what are the likely side effects?

Guanethidine Multiple sites of action to abolish response of tissue to sympathetic nerve stimulation Transported by uptake 1 into NA nerve terminals Stored in synaptic vesicles displacing NA Produces a slowly developing, but long lasting depletion of NA in nerve terminals Prevents fusion of vesicles with cell membrane

PHARMCOL201 2005: Lecture 16

Indirectly Acting Sympathomimetic Agents Tyramine, Tyramine, amphetamines and ephedrine Transported into nerve terminals by uptake I Displace NA from vesicles broken down by MAO So effects are caused by: 1. Activation of receptors 2. Inhibition of uptake 1

Diffuses out of nerve terminal to activate post-synaptic receptors

Indirectly Acting Sympathomimetic Agents The effects of these drugs are similar to NA, but longer lasting. – – – – –

Bronchodilation Increased arterial pressure Peripheral vasoconstriction Tachycardia Inhibition of gut motility.

Many central effects are due to effects on 5HT and DA terminals e.g. amphetamine - euphoria, excitement, wakefulness and increased attentiveness, loss of appetite.

Indirectly Acting Sympathomimetic Agents Effects abolished by reserpine (as terminals will be depleted of NA) Effects potentiated by MAO inhibitors (prevent breakdown of NA displaced from vesicles) Uptake 1 inhibitors e.g. imipramine prevent uptake of sympathomimetic amines so prevent their actions

Inhibitors of NA Uptake 1 What effect will this have on NA activity? Tricyclic antidepressants e.g. desipramine Cocaine - local anesthetic – Tachycardia, increased arterial pressure – CNS effects - euphoria, excitement.

Amphetamine, guanethidine. guanethidine.