SYMPATHOTROPIC DRUGS NEUROTRANSMITTER OF SYMPATHETIC NERVOUS SYSTEM NORADRENALINE (NOREPINEPHRINE) Substances affecting the sympathetic nervous system in the meaning of + SYMPATHOMIMETICS (adrenergics, adrenomimetics) - DIRECT - SELECTIVE - INDIRECT - NONSELECTIVE Substances affecting the sympathetic nervous system in the meaning of - SYMPATHOLYTICS (antiadrenergics, blockers, adrenolytics) - DIRECT - SELECTIVE - INDIRECT - NONSELECTIVE •Sympathomimetics (direct and indirect) • •Effects • •vasoconstriction, mydriasis (α1) •¯ BP (α2) •cardiostimulation (β1) •bronchodilatation, tocolysis, antialergic effect (β2) •psychostimulation •¯ appetite - anorectic effect (nondirect mechanism of action) • Endogenous catecholamines and their derivatives Overview of drugs, use: •adrenaline (epinephrine), noradrenaline (norepinephrine), dopamine, isoprenaline (obsol.) •non-selective against adrenergic receptors Use, indications: - peripheral analeptics - topical vasoconstriction - cardiostimulation Direct sympathomimetics Endogenous catecholamines •adrenaline (epinephrine) •a natural substance (hormone of the adrenal medulla, NT in the CNS, NT in the sympathetic system), stimulates α and β receptors •higher affinity to β receptors, in low concentrations stimulates mainly β-receptors •ineffective in oral administration •metabolized like other catecholamines by MAO and COMT, final products – normetanephrine, acid vanilmandelic Direct sympathomimetics Endogenous catecholamines •adrenaline (epinephrine) Effects: • heart, blood vessels (vasoconstriction) • changes of BP (according to the amount of dose – lower doses – β effect, higher doses – β and α-effect, high doses - α effect) • bronchodilatation • mast cells – inhibition of release of the allergic reaction mediators (histamine) • hyperglycemia – glycogenolysis, glucagone secretion • insulin secretion • lipolysis Direct sympathomimetics Endogenous catecholamines • adrenaline (epinephrine) Use, indications: • resuscitation during cardiac arrest, tonisation of myocard (1mg repeatedly in the 3 to 5min intervals – intravenously or intraosseously (= very rapid onset of action, intracardial application (very rarely)) • anaphylactic shock (1mg in 10ml saline sol.) - bronchodilatatory effect - the mucous membrane decongestion - positive inotropic - vasoconstriction in higher doses - blockade of mast cells degranulation • additive to local anaesthetic agents ➙ by vasoconstriction prolongs anaesthesia, reduces toxicity of LA • antiasthmatic agent: today usually replaced selective β2-mimetics (used in status asthmaticus) Direct sympathomimetics Endogenous catecholamines • noradrenaline (norepinephrine) •a natural substance (NT in CNS, NT of sympathetic system) •stimulates α and β receptors •ineffective in oral administration •Effects: - mainly on the cardiovascular system - increase of systolic (β effect) and diastolic BP (α effect) - reflexively by stimulation of n. vagus ➙ bradycardia •Use, indications: - therapy of hypotension - therapy of shocks (peripheral analeptics), today drug of the first choice in patients with failing blood circulation - (vasoconstrictor additive to LA) Direct sympathomimetics Endogenous catecholamines • dopamine (today not common use) •a natural substance (NT in CNS, in peripheria, precursor in NA synthesis) •stimulates dopaminergic receptors (kidney and intestinal arterioles), β receptors, in higher doses α receptors •effective only parenteral application •Use, indications: - Therapy of shock –stimulation of β1 receptors = positive inotropic and chronotropic effect –higher doses ➙ stimulation of α receptors = constriction of blood vessels (BP increase) –stimulation of D receptors = vasodilatation in the area of splanchnic system and kidneys ➙ increased perfusion (different from noradrenaline! ➙ today renoprotective properties of dopamine are being called into question, respectively they are expressed only in high doses of dopamine) Direct sympathomimetics Side effects of catecholamines - low distribution across HEB → low CNS toxicity - toxic peripheral effects result from increased from α or β receptor stimulation Side effects (mainly on the cardiovascular system): •significant vasoconstriction ➙ BP increase •tachycardia •heart arrhythmia •increased demands of the myocardium for oxygen α1 sympathomimetics Overview of drugs, use: •imidazolines – naphazoline, oxymetazoline, xylometazoline, tetryzoline, tramazoline •phenylephrine, midodrine •methoxamine •Use: - local vasoconstriction - system vasoconstriction (today not too frequent use) Direct sympathomimetics •imidazolines - naphazoline, oxymetazoline, xylometazoline, tetryzoline, tramazoline •stimulation of α1 receptors ➙ the mucous membrane decongestion Use, indications: - substances used primarily to decongest hyperemic mucous membranes (they are contained in the nasal and eye drops, sprays, gels, etc.) Direct sympathomimetics α1 selective sympathomimetics •phenylephrine • stimulation of α1 receptors ➙ mydriasis, the mucous membrane decongestion (nasal, conjuctivas), BP increase •Use, indication: - the mucous membrane decongestion - to induce mydriasis (in conjunctivitis, uveitis, during cataract surgery) - peripheral analeptics (in hypotensive conditions) – obsol. Direct sympathomimetics α1 selective sympathomimetics •midodrine •drug with prolonged effect (vasoconstrictor action possesses its metabolite) •can be administered orally or parenterally • •Use, indications: - hypotensive status - incontinentia urinaria (stimulation of α1 receptors in the area of urinary bladder sphincter ➙ sphincter contraction) Direct sympathomimetics α1 selective sympathomimetics •methoxamine (in Czech Rep. non registered) stimulates α1 receptors in blood vessels ➙ generalized vasoconstriction ➙ increase of BP = PERIPHERAL ANALEPTICS Use, indications: - therapy of hypotensive states (during spinal anaesthesia, therapy of shock; today, however, preferred NA) Direct sympathomimetics α1 selective sympathomimetics α2 sympathomimetics Overview of drugs, use: •clonidine, α-metyldopa •Use, indications: - for the treatment of hypertension (central and peripheral mechanism of action - α-metyldopa ) - rehab for addiction (clonidine – in Czech Rep. non registered) - glaucoma (clonidine – in Czech Rep. non registered) Direct sympathomimetics α– metyldopa → α – metyldopamin → α – metylNA (= corbadrine) activation of presynaptic 2 receptors → inhibition of sympathetic system activity (+ ligand of I1 receptors) clonidine Direct sympathomimetics α2 selective sympatomimetics = false precursor → NA depletion NA in vesicules Side effects: •confusion, sedation, zmatenost, sedace, decrease of psychomotoric functions • increase in body weight • postural hypotension • abrupt discontinuation of the treatment –hypertensive reaction = „rebound phenomenon“ Direct sympathomimetics α2 selective sympathomimetics β1 sympathomimetics Overview of drugs, use: •dobutamine •ibopamine (dopamine derivative for oral administration; in Czech Rep. non registered) • •Use, indications: - heart failure, stimulation of conductive heart system - cardiogenic shock (today combination NA + dobutamine preferred) - severe forms of heart failure Direct sympathomimetics •dobutamine •Use, effects: •syntetic substance similar to dopamine •stimulation of β1 receptors in heart ➙ strong inotropic effect, relatively poor chronotropic effect •oxygen consumption increases less than catecholamines •t1/2 =2.5 min ➙ should be administered in a continuous infusion •indicated for cardiogenic shock in combination with NA Direct sympathomimetics β1 selective sympathomimetics Overview of drugs, use: •salbutamol, fenoterol, hexoprenaline, terbutaline, orciprenaline,… •Use, indications: - bronchodilatators (asthma bronchiale, status associated with obstruction of the respirátory tract (COPD)) - tocolytics Direct sympathomimetics β2 selective sympathomimetics Effects: • stimulation of β2 receptors in bronchial smooth muscles of ➙ relaxation of smooth muscles and bronchodilatation • inhibition of inflammation mediators (leucotriens) release and allergic reaction mediators (histamine) release from mast cells • stimulation of mucociliar functions • relaxation of the uterine muscles Direct sympathomimetics β2 selective sympathomimetics Use of β2 sympatomimetics for bronchodilatation Short-term effect (4 – 6 h) orciprenaline (less selective than others) fenoterol, salbutamol, terbutaline, hexoprenaline… Long-term effect (8 – 15 h) clenbuterol, procaterol, formoterol, salmeterol Routes of administration: orally, by inhalation, by injection (intravenous infusion) Side effects: • tremor • palpitation, nervousness • ↓potassium (enhanced by theophyline and corticosteroids) Direct sympathomimetics β2 selective sympathomimetics Use of β2 sympatomimetics in gynekology and obstetrics • hexoprenaline → TOCOLYTICS → → relaxation of the uterine muscles • prevention of pre-term birth or risk of abortion during premature uterine aktivity • calming the uterus before, during and after the cerclage and in operations in the abdominal cavity • calming the uterus at the time between the decision on the implementation of the sectio caesarea (see point 1) Direct sympathomimetics β2 selective sympathomimetics •mirabegron •agonism of β3 receptors, relaxes the urinary bladder wall, increases the volume of urine during the storage phase of the micturition cycle •orally registered in 2012 •Substrate of CYP2D6, PgP Side effects: •infection of urinary tract Direct sympathomimetics β3 selective sympathomimetics Indirect sympathomimetics MECHANISM OF ACTION increase concentration of catecholamines in synaptic cleft by: • releasing from the storage vesicles • inhibition of neurotransmitter re-uptake presynaptically • inhibition of catecholamine metabolism (inhib. MAO) • increasing of neurotransmitter synthesis Overview of drugs, use: •amphetamine psychostimulants, substances related and other psychostimulants •ephedrine, pseudoephedrine •tyramine •MAO inhibitors (MAOI) •substances inhibiting re-uptake (TCA, cocaine) •Use: - antidepressants - for ADHD treatment - for narcolepsia treatment - anorectics (antiobesics) - mucous membrane decongestion Indirect sympathomimetics MofA: amphetamines possess wide scale of effects on NA, DA, 5-HT neurons: activity NT in brain > MAO postsynaptic neuron presynaptic neuron postsynapt. receptors Synaptic Cleft 2) blockade of the binding sites for re-uptake transporter, re-uptake inhibition 1) stimulation of NT release 3) MAO inhibition Indirect sympathomimetics amphetamine psychostimulants and substances related Effects on the sympathetic system - stimulation: •↑ HR •↑ BP •↑ body temperature •mydriasis •effects on CNS ➙ psychostimulation Indirect sympathomimetics amphetamine psychostimulants and substances related AFFECTING THE CNS Acute effects improvement in mood, sense of self-confidence, increased psychomotor activity (doping), dynamogenic effect (an increase in determination to take action), anorexic effect Chronic effects exogenous psychosis – halucinations, delirium, delusions, aggression, severe major depressive disorder with suicidal behaviour, paranoid states with anxiety symptomatology and agitation, insomnia, risk of „serotonin syndrome“ development   psychic addiction and tolerance Indirect sympathomimetics amphetamine psychostimulants and substances related • amphetamine, methamphetamine MDMA (ecstasy) •  psychic addiction and tolerance • no medical use (in the past yes) • among abused substances Indirect sympathomimetics amphetamine psychostimulants and substances related Indications •modafinil - narcolepsy •methylphenidate - ADHD •phentermine - supportive treatment in diet in patients with BMI > 30 obesity, in which reduction diet is not sufficient to reduce body weight •not among the classical stimulants  central SM ® selectively inhibits NA re-uptake   NA concentration and indirectly  DA in prefrontal cortex •atomoxetine – ADHD Indirect sympathomimetics amphetamine psychostimulants and substances related and other psychostimulants SIDE EFFECTS – summary: •tachycardia •↑ BP •sweating •insomnia •psychotic attacks •depressive disorders •anxiety, panic attacks •serotonin syndrome •drug addiction Indirect sympathomimetics amphetamine psychostimulants and substances related and other psychostimulants • ephedrine • • indirect (+ direct) sympathomimetic effects • slightly prevalent is β-sympathomimetic effect • nasal mucosa decongestion (α-SM effect) • risk of developing an addiction (psychostimulant) • methamphetamine production • obsol. Other indirect sympathomimetics • pseudoephedrine (ephedrine stereoisomer) •lower risk of addiction in comparison with ephedrine •abused for the production of methamphetamine •among OTC with restrictions •included in preparations for colds •in combination with H1-antihistamine loratadine for decongestion Other indirect sympathomimetics •tyramine • metabolit of thyrosine • product in the synthesis of catecholamines • tyramine-containing foods → dangerous in patients receiving MAOI → risk of hypertension reaction Other indirect sympathomimetics