Other Adrenergic Drugs

BY: Joseph Anthony G. Martinez

Noradrenaline

• Neurotransmitter released from postganglionic adrenergic nerve endings (80%)

• Orally ineffective and poor SC absorption

• IV administered

• Metabolized by MAO, COMT

• Short duration of action

Actions and uses• Agonist at α1(predominant), α2 and β1 Adrenergic receptors

– Equipotent with Adr on β1, but No effect on β2• Increases systolic, diastolic B.P, mean pressure, pulse pressure

and stroke volume– Total peripheral resistance (TPR) increases due to vasoconstriction -

Pressor agent• Increases coronary blood flow• Decreases blood flow to kidney, liver and skeletal muscles• Uses: Injection Noradrenal bitartrate slow IV infusion at the rate

of 2-4mg/ minute used as a vasopressor agent in treatment of hypovolemic shock and other hypotensive states in order to raise B.P– Problems: Down regulation of receptors, Renal Vasoconstriction– Septic and neurogenic shock

Noradrenaline - ADRs

• Anxiety, palpitation, respiratory difficulty

• Acute Rise of BP, headache

• Extravasations causes necrosis, gangrene

• Contracts gravid uterus

• Severe hypertension, violent headache, photophobia, anginal pain, pallor and sweating in hyperthyroid and hypertensive patients

Isoprenaline• Catecholamine acting on beta-1 and beta-2 receptors – negligible

action on alpha receptor

– Therefore main action on Heart and muscle vasculature

• Main Actions: Fall in Diastolic pressure, Bronchodilatation and relaxation of Gut

• ADME: Not effective orally, sublingual and inhalation (10mg tab. SL)• Overall effect is Cardiac stimulant (beta-1)

– Increase in SBP but decrease in DBP (beta-2)

– Decrease in mean BP

• Used as Bronchodilator and for treatment of AV block, Stokes-Adam Syndrome etc. – but not preferred anymore

Adrenaline, NA and Isoprenaline - Summary

Dopamine

• Immediate metabolic precursor of Noradrenalin

• High concentration in CNS - basal ganglia, limbic system and hypothalamus and also in Adrenal medulla

• Central neurotransmitter, regulates body movements ineffective orally, IV use only,

• Short T 1/2 (3-5minutes)

Dopamine

• MECHANISM:

– Agonists at dopaminergic D1, D2 receptors– Agonist at adrenergic α1 and β1

Dopamine

• In small doses 2-5 μg/kg/minute, it stimulates D1-receptors in renal, mesenteric and coronary vessels leading to vasodilatation (Increase in cAMP)– Recall: Renal vasoconstriction

occurs in CVS shock due to sympathetic over activity

– Increases renal blood flow, GFR an causes natriuresis

– Interaction with D2 receptors (present in presynaptic adrenergic neurones) – suppression of NA release (no alpha effect)

Dopamine – cond.

• Moderate dose (5-10 μg/kg/minute), stimulates β1-receptors in heart producing positive inotropic and chronotropic actions actions

• Releases Noradrenaline from nerves by β1-stimulation

• Does not change TPR and HR• Great Clinical benefit in CVS shock and CCF• High dose (10-30 μg/kg/minute), stimulates

vascular adrenergic α1-receptors (NA release) – vasoconstriction and decreased renal blood flow

Why renal and mesenteric vasodilatation is useful in Shock?– Increases renal blood flow, GFR an

causes natriuresis

• In CVS shock – excessive sympathetic activity leading to ischemia of gut, sloughening and entry of Bacteria to systemic circulation - septicemia

Dobutamine - Derivative of Dopamine

• MOA:– Acts on both alpha and beta receptors but more prominently in beta-1

receptor – increase in contractility and CO– Does not act on D1 or D2 receptors – No release of NA and thereby

hypertension– Predominantly a beta-1 agonist with weak beta-2 and selective alpha-1

activity– Racemic mixture consisting of both (+) and (−) isomers - the (+) isomer

is a potent β1 agonist and α1 antagonist, while the (−) isomer is an α1 agonist

– Overall beta-1 activity and weak beta-2 activity– Increase in force of contraction and cardiac output but no change in

heart rate• Uses: Clinically give in dose of 2-8 mcg/kg/min IV infusion in Heart

failure in cardiac surgery, Septic and cardiogenic shock, Congestive Heart failure

• ADRs: Tachycardia, hyperension, angina and fatal arrhythmia

Adrenergic agonists

• Selective Alpha-1 Agonists:– Phenylepherine, Ephederine, Methoxamine,

Metaraminol, Mephentermine• Selective Alpha-2 Agonists:

– Clonidine, α-methyldopa, Guanfacine and Guanabenz

• Β-2 Adrenergic agonists:– Salbutamol, Terbutaline, Salmeterol,

Reproterol, Oxiprenaline, Fenoterol, Isoxsuprine, Rimiterol, Ritodrine, Bitolterol and Isoetharine

Adrenergic Drugs – Therapeutic Classification

• Pressor agents:– NA, Phenylephrine, ephedrine, Methoxamine, Dopamine

• Cardiac Stimulants:– Adr, Dobutamine and Isoprenaline, Dopexamine

• Nasal Decongestants:– Phenylepherine, Xylometazoline, Oxymetazoline, Naphazoline and

Tetrahydrazoline and Phenylpropanolamine and Pseudoephidrine• Bronchodilators:

– Isoprenaline, Salbutamol, Salmeterol, Terbutaline, Formeterol• Uterine Relaxants:

– Ritodrine, Salbutamol, Isoxsuprine• Anorectics

– Fenfluramine, Dexfenfluramine and Sibutramine• CNS Stimulants:

– Amphetamine, Methamphetamine

Ephedrine• Plant alkaloid obtained from Ephedra vulgaris – Mixed acting drug

(also metaraminol) – effective orally• Crosses BBB and Centrally – Increased alertness, anxiety,

insomnia, tremor and nausea in adults. Sleepiness in children• Effects appear slowly but lasts longer (t1/2-4h) – 100 times less

potent• Tachyphylaxis on repeated dosing (low neuronal pool)• Used as bronchodilator, mydriatic, in heart block, mucosal

vasoconstriction & in myasthenia gravis• Not used commonly due to non-specific action• Uses: Mild Bronchial asthma, hypotension due to spinal anaesthesia• Available as tablets, nasal drop and injection

Phenylepherine - Selective, synthetic and direct α1 agonist

• Actions qualitatively similar to noradrenaline• Long duration of action• Resistant to MAO and COMT• Does not cross BBB, so no CNS effects• Peripheral vasoconstriction leads to rise in BP but Reflex

bradycardia• Produces mydriasis and nasal decongestion• Use:

– hypovolaemic shock as pressor agent– Sinusitis & Rhinitis as nasal decongestant (common in oral preparations)– Mydriatic in the form of eye drops and lowers intraocular pressure

• ADRs: Photosensitivity, conjunctival hyperemia and hypersensitivity• Administered parenteraly & topically (eye, nose)

What are Mucosal Decongestants?• Nasal and bronchial decongestants are the drugs used in allergic rhinitis, colds, coughs

and sinusitis as nasal drops - Sympathomimetic vasoconstrictors with α- effects are used

• Drugs: Phenylepherine, xylometazoline, Oxymetazoline, PPA, Pseudoephidrine etc. • Drawbacks:

– Rebound congestion due to overuse– However, mucosal ischaemic damage occurs if used excessively (more often than 3 hrly) or for

prolonged periods (>3weeks)– CNS Toxicity– Failure of antihypertensive therapy– Fatal hypertensive crisis in patients on MAOIs

• Use only a few days since longer application reduces ciliary action• Nasal and bronchial decongestants are the drugs used in allergic rhinitis, colds, coughs

and sinusitis as nasal drops - Sympathomimetic vasoconstrictors with α- effects are used

• Drugs: Phenylepherine, xylometazoline, Oxymetazoline, PPA, Pseudoephidrine etc. • Drawbacks:

– Rebound congestion due to overuse– However, mucosal ischaemic damage occurs if used excessively (more often than 3 hrly) or for

prolonged periods (>3weeks)– CNS Toxicity– Failure of antihypertensive therapy– Fatal hypertensive crisis in patients on MAOIs

• Use only a few days since longer application reduces ciliary action

Nasal Decongestants• Pseudoephedrine to Ephedrine but less CNS and Cardiac

effects– Poor Bronchodilator

– Given in combination with antihistaminics, antitussives and NSAIDs in common cold and, allergic rhinitis, blocked Eustachian tube etc.

– Rise in BP inhypertensives

• Phenylpropanolamine (PPA) is similar to ephedrine and used as decongestants in many cold and cough preparations– Also as weight loosing agent

• Xylometazoline, Oxymetazoline etc.

Amphetamine• Synthetic compound similar to Ephedrine Pharmacologically• Known because of its CNS stimulant action – psychoactive drug and

also performance enhancing drug• Actions:

– alertness, euphoria, talkativeness and increased work capacity – fatigue is allayed (acts on DA and NA neurotransmitters etc. –reward pathway)

– increased physical performance without fatigue – short lasting (Banned drug and included in the list of drugs of “Dope Test)” – deterioration occurs

– RAS Stimulation – wakefulness, sleep deprivation (then physical disability)

• However, anxiety, restlessness, tremor and dysphoria occurs

– Other actions: Stimulation of respiratory centre, Hunger suppression, also anticonvulsant, analgesic and antiemetic actions

Amphetamine

• Drug of abuse – marked psychological effect but little physical dependence

• Generally, Teenage abusers - thrill or kick• High Dose – Euphoria, excitement and may progress to

delirium, hallucination and acute psychotic state– Also peripheral effects like arrhythmia, palpitation, vascular

collapse etc.

• Repeated Dose – Long term behavioural abnormalities• Starvation – acidic urine• Uses: Hyperkinetic Children (ADHD), Narcolepsy,

Epilepsy and Parkinsonism

Anorectics

• Drugs used for suppression of appetite

• MOA: Inhibition of NA/DA or 5-HT uptake – enhancement of monoaminergic transmission– NA agents affect the appetite centre and

Serotonergics act on satiety centre– Fenfluramine, dexfenfluramine and

sibutramine – ALL ARE BANNED NOW– Reasons: Heart valve defects, fibrosis and

pulmonary hypertension etc.

Clonidine• Centrally acting: Agonist to postsynaptic α2A

adrenoceptors in brain – vasomotor centre in brainstem (presynaptic Ca++ level – increased NA release)– Decrease in BP and cardiac output

• Peripherally action: High dose activates peripheral presynaptic autoreceptors on adrenergic nerve ending mediating negative feedback suppression of noradrenaline release

• Overdose stimulates peripheral postsynaptic α1 adrenoceptors & cause hypertension by vasoconstriction

Clonidine• Uses: ADHD in children, opioid withdrawal (restless legs, jitters and

hypertension), alcohol withdrawal (0.3 to 0.6 mg)• Abrupt or gradual withdrawal causes rebound hypertension

– Onset may be rapid (a few hours) or delayed for as long as 2 days and subsides over 2-3 days

– Never use beta-blockers to treat

• Available as tablets, injections and patches• Sedation, dry mouth, dizziness and constipation etc.• TCAs antagonize antihypertensive action & increase rebound

hypertension of abrupt withdrawal• Low dose Clonidine (50-100μg/dl) is used in migraine prophylaxis,

menopausal flushing and chorea• Moxonidine, Rilmenidine – Newer Imidazolines

β2 Adrenergic Agonists – discussed elsewhere!

• Short acting : Salbutamol, Metaproterenol, Terbutaline, pirbuterol

• Selective for β2 receptor subtype• Used for acute inhalational treatment of bronchospasm.• Onset of action within 1 to 5 minutes• Bronchodilatation lasts for 2 to 6 hours• Duration of action longer on oral administration• Directly relax airway smooth muscle• Relieve dyspnoea of asthmatic bronchoconstriction• Long acting: Salmeterol, Bitolterol, colterol

Uterine Relaxants• Antioxytocics or tocolytic agents• β2 agonists relax uterus• Used by i.v. infusion to inhibit premature labour• Isoxsuprine, Terbutaline, Ritodrine, Salbutamol• Tachycardia & hypotension occur• Use minimum fluid volume using 5% dextrose as

diluents• Ritodrine: 50 μg/min, increase by 50 μg/min

every 10 minutes until contractions stop or maternal heart rate is 140 beats/minute. Continue for 12-48 hours after contractions stop

THANK YOU!!