Catecholamines and Sympathomimetic agents

Sympathomimetic agents drugs that mimic the actions of adrenaline or noradrenaline can be grouped by mode of action the spectrum of receptors that they effect chemical structure Classification by modes of action direct action agents directly interact with and activate adrenoceptors indirect action actions depend upon displacement of stored catecholamines from the adrenergic nerve endings (amphetamine, tyramine) inhibition of reuptake of released catecholamines (cocaine, tricyclic antidepressants) Classification by receptor types alpha beta dopamine alpha adrenoceptor agonists potency series adrenaline noradrenaline >> isoprenaline (Ahlquist, 1948) 2 major groups alpha1 (prazosin), alpha2 (yohimbine), both receptor types (dihydroergocryptine) subtypes 1A, 1B, 1D, 1L, 2A, 2B, 2C subtypes distinguished based on their affinities for a variety of a variety of drugs and experimental compounds dopamine adrenoceptor agonists distinct from and receptor agonists of particular importance in the brain, and in the splanchnic and renal vasculature subtypes D1-5 effects of dopamine adrenoceptor activation D1, D5: increase cAMP D2: decrease cAMP, opening of K+ channel and decrease calcium influx D3, D4: decrease cAMP Classification by chemical structure catecholamines naturally occurring: adrenaline, noradrenaline, dopamine synthetic: isoprenaline, dobutamine, dopexamine non-catecholamines: ephedrine, methoxamine, metaraminol -CH2-CH2-NH2 Chemistry and pharmacokinetics phenylethylamine benzene ring with ethylamine side chain 2 carbon atoms separate the aromatic ring & the amino group considered the parent compound from which sympathomimetic drugs are derived modification of phenylethylamine changes the affinity of the agent for and receptors influences the intrinsic activity to activate the receptors structural activity C3, C4 OH substitution at both C3, C4 yields catecholamines inactivated by catechol-O-methyltransferase no OH substitution for non-catecholamine sympathomimetic agents with absence of one or both -OH groups bioavailability after oral administration is increased duration of action is prolonged distribution of the molecule to the central nervous system is increased OH at C3 but absence of OH at C4 promotes 1 selectivity C3, C4 substitution by OH groups yields sympathomimetic agents collectively known as catecholamines

beta adrenoceptor agonists potency series isoprenaline > adrenaline noradrenaline subtypes 1 (affinity: adrenaline = noradrenaline) 2 (affinity: adrenaline > noradrenaline) 3 (affinity: noradrenaline > adrenaline), selective agonist BRL37344, antagonist bupranolol effect of adrenoceptor activation increase cAMP, common to all subtypes lipolysis with 3

noncatecholamines sympathomimetic agents are agents without -OH groups at C3 and C4

structural activity - benzene ring catecholamines have maximal and activity absence of one of the -OH groups without other substitution on the ring may dramatically reduce the potency of the agent absence of -OH at C4 promotes 1 selectivity, e.g. phenylephrine activity decreased by 100-fold and activity almost negligible at very high concentrations, therefore phenylephine considered a pure agonist

structural activity - alpha carbon catecholamines do not have methyl compounds at carbon methyl compounds aka phenylisopropylamines by resisting oxidation by monoamine oxidase, the action of these agents (ephedrine and amphetamine) is prolonged, enhancing the ability of these indirectly acting sympathomimetics to displace catecholamines from storage sites in noradrenergic nerves a portion of their action depends upon the presence of normal noradrenaline stores in the body

catecholamines are inactivated by catechol-Omethyltransferase (in the gut and liver) with absence of one or both -OH groups bioavailability after oral administration is increased duration of action is prolonged distribution of the molecule to the central nervous system is increased e.g. ephedrine and amphetamine, both have absence of OH groups at C3 and C4 position

structural activity - beta carbon direct-acting agonists typically have a -hydroxyl group (except dopamine) hydroxyl group may be important for storage of sympathomimetic amines in the neural vesicles

structural activity - amino group bulky amine substitution reduces -receptor activity increases -receptor activity too bulky for amine reuptake MAO unable to oxidise agent 2 selective agonists generally require a large amino substituent group N-methylation increases the potency of the primary amines increasing the size of alkyl substituents increases receptor activity, the larger the substituent group, the lower the activity at receptors methyl (adrenaline) and isopropyl substitution (isoprenaline) 2 selective agonists generally require a large amino substituent group e.g. salbutamol (tertiary butyl group)

isomerism conferred by substitution on either of the ethyl C atoms levorotatory substitution at the -C atom produces naturally occurring noradrenaline and adrenaline both are > 10 times as potent as their d-isomers dextrorotatory substitution at the -C atom generally confers greater potency in stimulation of the central nervous system e.g. d-amphetamine Mechanism of action G proteins G (guanine nucleotide regulatory) proteins couple adrenoceptors to various effector proteins whose activities are regulated by the receptors each G protein is a heterotrimer consisting of , and subunits classified on the basis of the subunit Gs: activates adenylyl cyclase Gi: inhibits adenylyl cyclase Gq: activates phospholipase C

N-methylation increases the potency of the primary amines activity of adrenaline > isoprenaline

activation of G protein coupled receptors upon activation by an extracellular ligand, the receptor triggers the activation of a G protein located on the cytoplasmic face of the plasma membrane GDP dissociates from the subunit, followed by binding of GTP to G protein GTP-bound subunit then dissociates from the - unit and regulate the activity of its effector (adenylyl cyclase, cGMP phosphodiesterase, phospholipase C, and ion channels), which then changes the concentration of the intracellular second messenger (cyclic adenosine-3,5monophosphate (cAMP), Ca++, or phosphoinositides) subunit is inactivated by hydrolysis of the bound GTP to GDP and Pi, and the subsequent reassociation of the subunit with the subunit subunit may act directly on ion channels and other enzymes activation of alpha1 receptor

activation of beta receptor

in the liver activation of glycogen phosphorylase, with increased glycogenolysis release of K+ from liver in the heart increase in cAMP results in increase Ca++ influx across the cell membrane and its sequestration inside the cell adrenoceptor may activate voltage-sensitive calcium channels independent of changes in cAMP concentration via Gs-mediated enhancement in smooth muscle phosphorylation of myosin light chain kinase to an inactive form promotes relaxation of smooth muscle promotes entry of K+ into cells via Na+/K+ ATPase pump modifies gene expression by phosphorylating cAMP response element binding protein Receptor regulation - desensitization aka tachyphylaxis, refractoriness, tolerance occurs after long-term usage of -adrenergic agonist and is reversible with removal of agonist 3 mechanisms receptor sequestration, a rapid and transient event wherein the receptors are made temporarily unavailable for activation by agonists down-regulation, disappearance of the receptors from the cell, may take place by the action of enzymes on the receptor or decreased synthesis phosphorylation of the receptor on the cytoplasmic side by protein kinase A or adrenergic receptor kinase ARK may impair coupling of -adrenoceptors with Gs

1 receptors also activate mitogen-activated kinase (MAP kinases) and polyphosphoinositol-3-kinase (PI-3-kinase) these pathways may have importance for the 1receptor mediated stimulation of cell growth activation of alpha2 receptor

Synthesis of noradrenaline and adrenaline

Termination of action actions of adrenaline and noradrenaline are terminated by three processes presynaptic re-uptake into the nerve terminal dilution by diffusion from the junctional cleft and uptake at non-neuronal sites, and metabolic transformation COMT for methylation MAO for oxidative deamination Metabolism COMT & MAO distributed widely throughout the body, including the brain highest concentrations in liver and kidney different cytosolic locations, MAO located on the outer surface of mitochondria, especially in adrenergic neurones COMT located in cytoplasm, and some in membranes no selective association with adrenergic nerves

Noncatecholamine sympathomimetics with few exceptions the actions of the noncatecholamines fit within the framework of and receptors mechanisms of action direct agonist activity (phenylephrine (), ephedrine (2) uptake into the adrenergic nerve terminal, with subsequent stoichiometric displacement of noradrenaline from storage sites (uptake & displacement hypothesis of Burn & Rand, 1958) agents that release noradrenaline have predominantly actions elimination of non-catecholamines pathways for metabolism include p-hydroxylation N-demethylation deamination conjugation in the liver substantial fractions of these drugs are eliminated unchanged in the urine renal excretion of amphetamine (pKa = 9.9), and many other non-catecholamine's is profoundly influenced by urinary pH large number of noncatecholamines have pKa between 9.0 to 10.3 therefore excretion is enhanced by acidification of the urine although these agents are resistant to the actions of the MAO inhibitors, they provoke the release of noradrenaline and may cause hypertensive crises if administered concurrently Beta adrenergic agonists

Pharmacodynamics effect on blood vessels receptor agonists increase arterial resistance 2 receptor agonists promote smooth muscle relaxation overall effects of a sympathomimetic agent depend on the relative activities of that drug at and receptors and the anatomic sites of the vessels affected e.g. skin vessels have predominant receptors, constrict with adrenaline and noradrenaline D1 receptor agonists promote vasodilatation of renal, splanchnic, coronary, and cerebral arteries effects on the heart direct effects are determined largely by 1 receptors, though 2 and to a less extent receptors are also involved receptor activation results in increased calcium influx in cardiac cells chronotropy - pacemaker activity (sinoatrial node and Purkinje fibres) is increased dromotropy - conduction velocity in atrioventricular node is increased inotropy - intrinsic contractility is increased lusitropy - accelerated relaxation effects on blood pressure explained on the basis of the action on the heart, peripheral vascular resistance and venous return pure agonist, (phenylephrine) increases peripheral vascular resistance and decreases venous capacitance, leading to a marked rise in blood pressure with intact baroreceptor-mediated response, vagal tone increases resulting in bradycardia cardiac output may not decrease with increased venous return, and modest positive inotropic effect pure agonist, (isoprenaline) decreases peripheral vascular resistance net effect is increased cardiac output with maintained or slightly increased systolic pressure, and a decrease in diastolic pressure

effects on the eye mydriasis radial pupillary dilator muscles of the iris contains receptors, activation (by phenylephrine) causes mydriasis aqueous humour outflow increased by agonists production decreased by agonists, (treatment of glaucoma) decrease in accommodation receptor activation relaxes the ciliary muscle to a minor degree causing insignificant decrease in accommodation effects on the respiratory tract bronchodilation mediated by 2 receptors on smooth muscle cells decongestion of upper respiratory tract mucosa blood vessels of the upper respiratory tract mucosa contains 1 receptors, activation results in decongestion effects on the gastrointestinal tract relaxation of the gastrointestinal smooth muscle receptors located on smooth muscle cells and mediate relaxation via hyperpolarisation and decreased spike activity in these cells agonists, especially 2 selective agonists decrease muscle activity indirectly by presynaptically reducing the release of acetylcholine and possibly other stimulants within the enteric nervous system response probably of greater pharmacologic significance than response 2 receptors may also decrease salt and water flux into the lumen of the intestine effects on the genitourinary tract relaxation of uterus uterus contains both and 2 receptors, receptors mediate relaxation urinary incontinence bladder base, urethral sphincter, and prostate contain receptors that mediate contraction relaxation of bladder wall mediated by 2 receptors of bladder wall effects on the exocrine glands dry mouth central 2 activity increased sweat production by apocrine sweat glands (palm of hands) these are nonthermoregulatory apocrine glands usually associated with psychologic stress in contrast with diffusely distributed thermoregulatory eccrine sweat glands which are regulated by sympathetic cholinergic postganglionic nerves that activate muscarinic cholinoceptors

metabolic effects lipolysis increased by 3 receptor activation inhibited by 2 receptor activation, via decreased intracellular cAMP glycogenolysis in the liver enhanced by sympathomimetic drugs (>1), leading to increased glucose release into the circulation and hyperglycaemia hypokalaemia by promoting uptake of potassium into skeletal muscle cells via Na+/K+ ATPase pump metabolic acidosis effects on endocrine and other functions insulin secretion stimulated by 2 receptor activation decreased by 2 receptor activation renin secretion stimulated by 1 receptors inhibited by 2 receptors modulate secretion of parathyroid hormone, calcitonin, thyroxine, and gastrin but physiologic significance unclear leukocytosis, with high concentrations of adrenaline in part, by promoting demargination of white blood cells sequestrated away from the general circulation effects on the central nervous system depend on the ability to cross the blood-brain barrier phenylisopropylamines, the most commonly used noncatecholamines are widely distributed in tissues and readily cross the blood brain barrier, therefore have pronounced effects on the central nervous system catecholamines nervousness feeling of impending disaster noncatecholamines alerting, with improved attention to boring tasks elevation of mood, insomnia, euphoria, and anorexia psychotic behaviour probably represent enhancement of dopaminemediated processes in the central nervous system summary of effects peripheral excitatory action on certain types of smooth muscle blood vessels supplying the skin and mucous membranes gland cells, including the salivary & sweat peripheral inhibitory action on certain types of smooth muscle the wall of the gut and bronchial tree the blood vessels supplying skeletal muscle a cardiac excitatory effect, increase in rate and force of contraction metabolic actions, including, increased rate of glycolysis in muscle & liver, and the liberation of free fatty acids from adipose tissue

endocrine actions modulation of renin, insulin & pituitary hormones CNS actions stimulation of respiration some agents increase psychomotor activity & wakefulness, and decreased appetite Specific sympathomimetic agents Adrenaline rise in blood pressure due to positive inotropic and chronotropic actions on the heart (1) vasoconstriction induced in many vascular beds () vasodilatation in skeletal muscle blood vessels (2) total peripheral resistance may actually fall due to fall in diastolic blood pressure vascular effects of adrenaline

smooth muscle effects of adrenaline

Noradrenaline similar effects with adrenaline on 1 and receptors positive inotropic and chronotropic actions on the heart (1) vasoconstriction induced in many vascular beds () relatively little effect on 2 receptors actions lead to increase in total peripheral resistance, diastolic and systolic blood pressure compensatory vagal reflexes tend to overcome direct positive chronotropic effects, but positive inotropic effect is maintained

Isoprenaline extremely potent receptor agonist, little effect on receptor positive chronotropic and inotropic action potent vasodilator actions lead to marked increase in cardiac output associated with a fall in diastolic and mean arterial pressure a lesser decrease or slight increase in systolic pressure Dopamine 0.1-2 g/kg/min D1 activation, increasing renal and splanchnic blood flow, urine output and sodium excretion D2 activation, inhibiting noradrenaline release and resulting in vasodilatation 1-5 g/kg/min activation of 1 receptors, increasing myocardial contractility tachycardia, arrhythmias and increased cardiac work with higher dose ranges >6 g/kg/min activation of receptors, causing peripheral vasoconstriction, reducing splanchnic and renal blood flows Dobutamine relatively 1-selective synthetic catecholamine 2 isomers, administered as racemic mixtures (+) isomer is potent 1 agonist and an 1 receptor antagonist (-) isomer is a potent 1 agonist, capable of causing vasoconstriction when administered alone effects increase in stroke volume and left ventricular dP/dt reduction in LVEDP, PAWP, and SVR dose range: 2-15 g/kg/min, but tolerance develops after 6-8 hours of infusion, probably due to downregulation pharmacokinetics Vd 0.2 L/kg clearance 60 ml/min/kg t 2.5 minutes Dopexamine synthetic catecholamine, structurally related to dopamine and dobutamine produces a combination of D1 and 2and 1 receptor agonist activity compared with dopamine, one-third potency at D1 receptors but 60x more at 2 adrenoceptors relative selectivity for 2:1-receptors about 9.8:1 inhibitory action in neuronal catecholamine uptake more potent than dopamine this likely accounts for the positive inotropic action of the agent dose range 0.5-4 g/kg/min: preferential systemic, mesenteric and renal vasodilatation; t about 7 minutes dose range >4 g/kg/min: tachycardia and hypotension in patients with severe congestive cardiac failure profound reduction in afterload with increased cardiac output (mainly rate) mild positive inotropy (5-10%) increased renal blood flow tachyphylaxis may occur

Phenylephrine relatively pure agonist acts directly on receptors noncatecholamine, therefore not metabolised by COMT longer duration of action than catecholamines applications mydriasis nasal decongestant pressor agent side effects rebound hyperaemia mucosal ischaemia Ephedrine noncatecholamine phenylisopropylamine mixed-action mechanism of action stimulates both alpha and beta receptors and its peripheral actions are due partly to release of stored noradrenaline and partly to direct effect on receptors has 1, 2, 1, 2 adrenergic receptor-agonist properties. 40% of the thermogenic activity of ephedrine is reported to be due to the activation of the 3 adrenoreceptors in the adipose tissues also stimulates thyroid function absorption active by oral route, with high bioavailability rapidly and completely absorbed following parenteral injection distribution access into brain, is a mild stimulant central effects of ephedrine are overshadowed to a large extent by its peripheral actions increases oxygen consumption and metabolic rate as a probable result of central stimulation long duration of action pressor and cardiac responses to ephedrine persist for one hour following intramuscular or subcutaneous administration of 25 to 50 mg may deplete norepinephrine stores in sympathetic nerve endings, so that tachyphylaxis to cardiac and pressor effects of the drug may develop metabolism small amounts of ephedrine are slowly metabolized in the liver p-OHephedrine, p-OHnorephedrine, norephedrine, and conjugates of these compounds elimination the drug and its metabolites are excreted in the urine, mostly as unchanged ephedrine rate of urinary excretion is dependent on urinary pH as a weak base, excretion is accelerated by acidification of urine elimination half-life of the drug has been reported to be about 3 hours when the urine is acidified to pH 5 and about 6 hours when urinary pH is 6.3 applications nasal decongestant pressor agent

pseudoephedrine one of the 4 enantiomers of ephedrine use as nasal decongestant treatment of stress incontinence in women side effects hypertension dysrhythmias angina hyperglycaemia contraindications people prone to hypertension, heart disease, hyperglycemia, hyper-thyroidism, prostate disease Amphetamine noncatecholamine phenylisopropylamine enters central nervous system even more readily than ephedrine has a more marked stimulant effect on mood and alertness and a depressant effect on appetite peripheral actions mediated through release of catecholamine Cocaine local anaesthetic with peripheral sympathomimetic action inhibition of dopamine and noradrenaline reuptake at the noradrenergic synapses, enhances the effects of the catecholamines readily enters the central nervous system produces amphetamine-like effect but shorter lasting and more intense heavily abused drug as it can be inhaled as well as injected by inhibiting neuronal uptake of amine, also inhibits the effects of the noncatecholamines

Clinical applications of sympathomimetic agents correction of hypotension correction of hypertension (clonidine, methyldopa) aid haemostasis mucous membrane decongestion emergency management of complete heart block (isoprenaline), cardiac arrest (adrenaline) acute right heart failure (isoprenaline) management of congestive heart failure (adrenaline, dobutamine, prenalterol) treatment of bronchial asthma management of anaphylaxis, anaphylactic shock and related immediate (type I) IgE-mediated reactions syndrome of bronchospasm, mucous membrane congestion, angioedema, cardiovascular collapse responds rapidly to subcutaneous administration of adrenaline 0.3-0.5 mg (stimulation of , 1, and 2 receptors) ophthalmic applications mydriasis to facilitate examination of retina conjunctival decongestant treatment of glaucoma (alpha effects increase outflow and beta effects decrease production of aqueous humour) genitourinary applications relaxation of uterus to suppress premature labour treatment of stress incontinence central nervous system applications treatment of narcolepsy appetite suppressant treatment of attention-deficit hyperkinetic syndrome Toxicity of sympathomimetics severe hypertension angina myocardial infarction arrhythmias (sinus tachycardia, ventricular arrhythmias) tissue ischaemia if extravasation has occurred (treat with alpha antagonist) restlessness, tremor, anxiety, insomnia, convulsions, cerebra haemorrhage with agents that access the brain