ADRENERGIC DRUGS & ANTI-ADRENERGIC

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ADRENERGIC & ANTI-ADRENERGIC DRUGS:

ADRENERGIC & ANTI-ADRENERGIC DRUGS ZEENATH BANU ASSISTANT PROFESSOR DEPARTMENT OF PHARMACOLOGY

ADRENERGIC DRUGS (Sympathomimetics/Adrenergic agonist/adrenoceptor activating drugs/adrenomimetic drugs/sympathetic drugs):

ADRENERGIC DRUGS ( Sympathomimetics /Adrenergic agonist/ adrenoceptor activating drugs/ adrenomimetic drugs/sympathetic drugs) These are drugs with actions similar to that of Adr or of sympathetic stimulation . CLASSIFICATION 1. Direct sympathomimetics : act directly as agonists on α and/or β adrenoceptors Ex: Adr , NA, isoprenaline ( Iso ), phenylephrine, methoxamine, xylometazoline , salbutamol and many others. 2 . Indirect sympathomimetics : act on adrenergic neurone to release NA, which then acts on the adrenoceptors Ex: tyramine , amphetamine. 3. Mixed action sympathomimetics They act directly as well as indirectly Ex: ephedrine , dopamine, mephentermine . THERAPEUTIC CLASSIFICATION OF ADRENERGIC DRUG:

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ADRENALINE: They act directly as agonists on α and/or β adrenoceptors MECHANISM OF ACTION (M.O.A): It act directly on α1, α2, β1, β2 receptors located on the cell membrane and have weak β3 ction . 1.At β receptor: 2. α1 receptor 3. α2 receptor

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PHARMACOLOGICAL ACTIONS: 1.HEART: Adr by stimulating β1 receptor in the heart, increase force of contraction, heart rate, conduction velocity----  increase in cardiac output , myocardial oxygen demand. 2.BLOOD VESSEL: Both vasoconstriction (α) and vasodilatation (β2) can occur depending on the drug, its dose and vascular bed . 3.BP: The effect depends on the amine, its dose and rate of administration. NA causes rise in systolic, diastolic and mean BP; it does not cause vasodilatation. Isoprenaline causes rise in systolic but marked fall in diastolic BP. Adr given by slow i.v. infusion or s.c. injection causes rise in systolic but fall in diastolic BP. Rapid i.v. injection of Adr produces a marked increase in both systolic as well as diastolic BP The BP returns to normal within a few minutes and a secondary fall in mean BP follows. This is called BIPHASIC RESPONSE. The mechanism is—rapid uptake and dissipation of Adr → concentration around the receptor is reduced → low concentrations are not able to act on α receptors but continue to act on β2 receptors. SIR HENRY DALE observed that when an α blocker has been given prior to Adr administration , only fall in BP is seen— VASOMOTOR REVERSAL OF DALE.

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4. RESPIRATION: Adr and isoprenaline ----  potent bronchodilators (β2). 5. GIT: In isolated preparations of gut-  relaxation (α and β receptors) In intact animals and man peristalsis is reduced and sphincters are constricted, but the effects are brief and of no clinical import 6 . BLADDER : Detrusor is relaxed (β) and trigone is constricted (α): both actions tend to hinder micturition . 7. UTERUS: Adr can both contract and relax uterine muscle, respectively through α and β receptors. 8. SPLENIC CAPSULE: Contracts (α) and more RBCs are poured in circulation . 9. CNS: Adr , in clinically used doses, does not produce any marked CNS effects because of poor penetration in brain, but restlessness, apprehension and tremor may occur. 10. METABOLIC Adr causes glycogenolysis → hyperglycaemia , hyperlactacidaemia ( β2); lipolysis → rise in plasma free fatty acid (FFA) and calorigenesis ( β2 + β3). These are due to direct action on liver, muscle and adipose tissue cells. PHARMAKOKINETIC: All catecholamines are ineffective orally • Slow s.c absorption (local vasoconstriction) • Rapid absorption after i.m injection • Inhalation is locally effective • Not usually given IV • Rapidly inactivated in Liver by MAO and COMT

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ADVERSE EFFECTS AND CONTRAINDICATIONS Transient restlessness, headache, palpitation, anxiety, tremor and pallor may occur after s.c. / i.m . injection of Adr . Marked rise in BP leading to cerebral haemorrhage, ventricular tachycardia/fibrillation, angina, myocardial infarction are the hazards of large doses or inadvertant i.v. injection of Adr . Adr is contraindicated in hypertensive, hyperthyroid and angina patients. THERAPEUTIC USES 1.Vascular uses ( i ) Hypotensive states: (shock, spinal anaesthesia , hypotensive drugs) One of the pressor agents can be used along with volume replacement for neurogenic and haemorrhagic shock ( ii) Along with local anaesthetics:Adr 1 in 200,000 to 1 in 100,000 for infiltration, nerve block and spinal anaesthesia (iii) Control of local bleeding From skin and mucous membranes, e.g. epistaxis : compresses of Adr 1 in 10,000, phenylephrine/ephedrine 1% soaked in cotton can control arteriolar and capillary bleeding. (iv) Nasal decongestant In colds, rhinitis, sinusitis, blocked nose or eustachian tube—one of the α-agonists is used as nasal drops

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2. Cardiac uses ( i ) Cardiac arrest (drowning, electrocution, Stokes-Adams syndrome and other causes) Adr may be used to stimulate the heart. (ii) Partial or complete A-V block Isoprenaline may be used as temporary measure to maintain sufficient ventricular rate. 3. Bronchial asthma and COPD Adrenergic drugs, especially β2 stimulants are the primary drugs for relief of reversible airway obstruction. 4. Allergic disorders. 5. Mydriatic 6. Uterine relaxant 7. Insulin hypoglycaemia 8. CENTRAL USES: ( i ) Narcolepsy (ii) Epilepsy (iii)Parkinsonism (iv)Obesity

ANTI-ADRENERGIC DRUGS:

ANTI-ADRENERGIC DRUGS ZEENATH BANU ASSISTANT PROFESSOR DEPARTMENT OF PHARMACOLOGY

Antiadrenergic Drugs (Adrenergic Receptor Antagonists/ Sympatholytics) :

Antiadrenergic Drugs (Adrenergic Receptor Antagonists/ Sympatholytics ) These are drugs which antagonize the receptor action of adrenaline and related drugs. They are competitive antagonists at α or β or both α and β adrenergic receptors. α ADRENERGIC BLOCKING DRUGS These drugs inhibit adrenergic responses mediated through the α adrenergic receptors without affecting those mediated through β receptor CLASSIFICATION:

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GENERAL EFFECTS OF α BLOCKERS 1 . Blockade of vasoconstrictor α1 (also α2) receptors reduces peripheral resistance and causes pooling of blood in capacitance vessels → venous return and cardiac output are reduced → fall in BP. The α blockers abolish the pressor action of Adr (injected i.v. in animals), which then produces only fall in BP due to β2 mediated vasodilatation. This was first demonstrated by Sir HH Dale (1913) and is called vasomotor reversal of Dale. 2 . Reflex tachycardia occurs due to fall in BP and increased release of NA due to blockade of presynaptic α2 receptors. 3 . Nasal stuffiness and miosis . 4 . Intestinal motility is increased— loose motion may occur. 5 . Reduced GFR :Na + retention and expansion of blood volume 6 . Tone of smooth muscle in bladder trigone, sphincter and prostate is reduced by blockade of α1 receptors 7 . Inhibition of Ejaculation: due to inhibition of Contractions of vas deferens and related organs

INDIVIDUAL DRUGS: 1. Phenoxybenzamine:

INDIVIDUAL DRUGS: 1. Phenoxybenzamine Non specific, long acting irreversible alpha antagonist. M.O.A: Spontaneously cyclizes in the body giving rise to a highly reactive ethyleniminium intermediate which reacts with α adrenoceptors and other biomolecules by forming strong covalent bonds. The α blockade is of nonequilibrium (irreversible) type and develops gradually and lasts for 3–4 days. Also Partial blockade of 5-HT, histaminergic and cholinergic receptors. Phenoxybenzamine is lipid soluble, penetrates brain and can produce CNS stimulation, nausea and vomiting on rapid i.v. injection. ADR: postural hypotension, palpitation, nasal blockage, miosis , inhibition of ejaculation . USES OF α BLOCKERS 1. Pheochromocytoma : Tumor of medullary cells of Adrenal gland. 2. Hypertension: Prazosin 3. Benign hypertrophy of prostate (BHP) 4. Secondary shock: Phenoxybenzamine . 5. Peripheral vascular diseases beneficial in Raynaud’s disease 6. Congestive heart failure (CHF )- short term 7. Phentolamine Induced Penile Erection (PIPE) therapy for impotence

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2. Prazosin M.O.A: Highly selective α1 blockers having α1 : α2 selectivity ratio 1000:1. All subtypes of α1 receptor (α1A, α1B, α1D) are blocked equally. It blocks sympathetically mediated vasoconstriction ----  fall in BP NA release is not increased due to absence of α2 blockade. Prazosin dilates arterioles more than veins. Postural hypotension is less marked, dizziness and fainting as ‘first dose effect. Also Inhibits phosphodiesterase which degrades cAMP . Rise in smooth muscle cAMP could contribute to its vasodilator action. THERAPEUTIC USES : A ntihypertensive drug Raynaud’s disease and benign hypertrophy of prostate ( BHP 3. Phentolamine M.O.A: This is a rapidly acting α blocker with short duration of action (in minutes). It equally blocks α1 and α2 receptors—NA release is increased and venodilatation predominates over arteriolar dilatation. USES: P heochromocytoma , for control of hypertension due to clonidine withdrawal, cheese reaction, etc.

β ADRENERGIC BLOCKING DRUGS :

β ADRENERGIC BLOCKING DRUGS These drugs inhibit adrenergic responses mediated through the β receptors. CLASSIFICATION:

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PROPRANOLOL: It is a pure, non selective antagonist at the β adrenergic receptors.It blocks both β1 & β2 receptors with similar efficacy. M.O.A:

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PHARMACOLOGICAL ACTIONS: 1.HEART: Decreases heart rate, force of contraction and cardiac output. Prolongs systole - synergy of contraction of ventricular fibres is disturbed. Cardiac work and oxygen consumption are reduced 2.BLOOD VESSELS: No direct effect on blood vessels Blocks vasodilatation and fall in BP evoked by isoprenaline and enhances the rise in BP caused by Adr . There is re-reversal of vasomotor reversal. On prolonged administration BP gradually falls in hypertensive subjects 3. RESPIRATORY TRACT: increases bronchial resistance by blocking dilator β2 receptors. 4.CNS: No overt central effects are produced. subtle behavioural changes, forgetfulness, increased dreaming and nightmares have been reported with long-term use. 5. LOCAL ANAESTHETIC potent a local anaesthetic as lidocaine, but is not clinically used for this purpose because it causes irritation at the injected site.

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6.EYE: reduces secretion of aqueous humor, i.o.t. is lowered. 7. SKELETAL MUSCLE Reduction of tremor Reduction of exercise capacity, reduction in blood flow, glycogenolysis and lipolysis. PHARMACOKINETICS: well absorbed after oral administration, but has low bioavailability due to high first pass metabolism in liver. lipophilic and penetrates into brain easily. It is metabolized in liver by hydroxylation and conjugation and excreted in urine as glucuronide. ADVERSE EFFECT: Precipitation of CCF/ Odema Bradycardia Respiratory: COAD & Bronchial asthma. Variant Angina Exacerbation Tiredness and reduced exercise capacity Cold hands and feet, worsening of peripheral vascular disease

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THERAPEUTIC USES: 1.Hypertension : 2. Angina pectoris 3. Cardiac arrhythmias 4. Myocardial infarction (MI ) 5. Congestive heart failure 6. Dissecting aortic aneurysm 7. Pheochromocytoma 8. Thyrotoxicosis 9. Migraine 10. Anxiety 11. Essential tremor 12. Glaucoma 13. Hypertrophic obstructive cardiomyopathy

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α + β ADRENERGIC BLOCKERS: Labetalol It is the first adrenergic antagonist capable of blocking both α and β receptors. There are 4 diastereomers of labetalol, each of which has a distinct profile of action on subtypes of α and β receptors . The commercial preparation has equal parts of each diastereomer and displays β1 + β2 + α1 blocking as well as weak β2 agonistic activity. The β blocking potency is about 1/3 that of propranolol, while α blocking potency is about 1/10 of phentolamine . ADRS: Postural hypotension,failure of ejaculation and others but no change in lipid profile. USES: pheochromocytoma and clonidine withdrawal essential hypertension .

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