Treatment of Shock & Vasopressor Agents the inability of the ventricle of fill during diastole markedly limiting the stroke volume and cardiac output Another cause is massive pulmonary embolism In pericardial temponade, administration of sympathomimetic amines e.g norepinephrine and/or dopamine may improve haemodynamics temporarily and surgical pericardial drainage is the only effective treatment DISTRIBUTIVE SHOCK Anaphylactic, septic and neurogenic shock are the examples of distributive shock and all of which usually cause profound decrease in periperal vascular resistance In anaphylactic shock, when a sensitized person is re-exposed to the specific antigen and due to antigen-antibody reaction there is large amount of histamine release along with other mediators of anaphylaxis, resulting in fall in blood pressure with savere allergic reaction and bronchospasm Penicillin is the common example of anaphylactic shock in sensitized individuals Epinephrine is a life saving drug of choice in this type of case Dopamine may be given 143 in severe vasomotor collapse Septic shock is characterized by a low systemic vascular resistance and an elevated cardiac output and it usually begins with a nidus of infection that releases microbes and/or one or more mediators e.g histamine, kinine, prostaglandins, endorphins, TNF, interlukin & etc into the blood stream which produce vascular dilatation and vasoconstriction (some PG’s & leukotrienes) The peripheral vasodilatation result in a reduced systemic vascular resistance and high cardric output Management of septic shock may be carried out in three simultaneous ways, firstly, the nidus of infection must be identified and eliminated, using surgical drainage and antimicrobial therapy Sacondly, using cardiovascular monitoring and support, adequate organ system perfusion and function must be maintained Thirdly, to interrupt the pathogenic sequence leading to septic shock Neurogenic shock is generally occur in abdominal trauma, spinal anasthesia, spinal cord injury and is managed by vasopressor agents e.g dopamine This page intentionally left blank tterer p p a h CCh 3.3 1.4 Pharmacodynamics Sympatholytics (Antiadrenergic Agents) These are the agents, which block the action of adrenaline and noradrenaline They block either alpha or beta or both adrenergic receptors They are classified as in table 3.3.1 and 3.3.2 GENERAL CHARACTERISTICS OF ALPHA BLOCKERS Alpha blockers are the drugs which block the pressor response to noradrenaline and Table 3.3.1: Classification for alpha adrenergic blocking agents A Non-equilibrium Phenoxybenzamine (FENOXENE) B Equilibrium I Nonselective (α1+α2 blockers) i Ergot alkaloids Ergotamine (GYNERGEN) Dihydroergotamine Dihydroergotoxine (HYDERGINE) ii Imidazolines Phentolamine mesylate (FENTANOR) Tolazoline (PRISCOL) iii Phenothiazines Chlorpromazine (LARGECTIL) II α1 Selective Prazosin (MINIPRESS) Terazosin (OLYSTER) Triamazosin Doxazosin (DOXACARD) Tamsulosin (DYNAPRES) III α2 Selective Yohimbine 20-60 mg orally, mg/kg IV infusion 1-3 mg oral, 0.25-0.5 mg IM/SC 2-6 mg oral, 0.5-1 mg IM 1.5 mg oral TDS, 0.15-0.6 mg IM 50 mg QID 25-50 mg TDS 25-50 mg oral/IM 0.5-1.0 mg TDS 2-10 mg/day, mg HS 25-200 mg TDS 1-4 mg/day 0.4-0.8 mg OD 2-4 mg TDS 146 convert adrenaline induced stimulation response to depressor response Blockage of vasoconstrictor receptors reduces peripheral resistance, venous return and cardiac output leading to fall in blood pressure The decrease in blood pressure by alpha blockers can reduce renal blood flow, which can lead to reduction of glomerular filtration rate and more reabsorption of sodium and water in the tubules and ultimately sodium retention and increase in blood volume Positive inotropic and chronotropic effects of catecholamines are not blocked by alpha blockers, but these drugs can block catecholamine induced cardiac arrhythmias Certain stimulant actions of catecholamines on various smooth muscles are blocked by alpha blockers such as uterine contraction of certain species, contraction of vas deferens and retractor penis, stimulation of seminal vesicles and vas deferens Alpha blockers can inhibit ejaculation and produce impotence Salivary secretion and sweat formation induced by catecholamines is blocked by alpha blockers Alpha blockers also produce certain metabolic effects such as inhibitory action of adrenaline on insulin secretion is blocked and adrenaline induced rise in blood potassium level is also blocked Miosis and nasal stuffiness can occur with alpha blockers by acting on radial muscles of iris and nasal blood vessels Diarrhoea may occur due to increase in intestinal motility The common adverse effects with alpha blockers are palpitation, nasal stuffiness, postural hypotension, retention of fluid, diarrhoea, inhibition of ejaculation and impotence Section 3/ Drugs Acting on ANS PHENOXYBENZAMINE It is a potent alpha-adrenergic blocking agent and only haloalkylamine used clinically It effectively prevents the responses mediated by alpha receptors and diastolic blood pressure tends to decrease It interferes with the reflex adjustment of blood pressure and produces postural hypotension It increases the cardiac output and decreases the total peripheral resistance It also antagonizes cardiac arrhythmias provoked by catecholamines Apart from these effects, phenoxybenzamine has other actions also e.g antagonism of acetylcholine, histamine, 5-hydroxytryptamine (serotonin) However, the vasodilatation produced by phenoxybenzamine is because of alpha blockage Adverse reactions are miosis, dryness of mouth, inhibition of ejaculation, palpitation, nasal stuffiness and in higher doses, postural hypotension and reflex bradycardia It is used in the management of pheochromocytoma and also to treat peripheral vasospastic conditions e.g Raynaud’s disease and shock syndrome Phentolamine, another alpha blocker is exclusively used for the diagnosis of pheochromocytoma and for the prevention of abrupt rise in blood pressure during surgical removal of adrenal medulla tumors ERGOT ALKALOIDS Ergot is a parasitic fungus (Claviceps purpurea) It contains different alkaloids of complex chemical structure The amino acid ergot alkaloids are ergotamine, ergocristine, ergocornine, ergosine, ergocryptine and their dehydrogenated derivatives can block the Sympatholytics (Antiadrenergic Agents) alpha receptors Ergotamine is an important alkaloid that possesses both vasoconstrictor and alpha-receptor blocking activity Both ergotamine and dihydroergotamine are used in the treatment of migraine MIGRAINE Migraine is a severe episodic throbbing or dull pain in head, may be lateralized or generalised associated with anorexia, nausea, vomiting, photophobia and blurring of vision The pain of migraine and vascular headaches are associated with vasodilatation, edema and visible pulsations of the extracranial blood vessels The 5-HT plays a pivotal role in pathophysiology of migraine 147 subtype of 5-HT receptor at very high concentration Oral bioavailability is only 15% but after SC injection absorption is rapid and complete It is metabolized by MAO-A isoenzyme and metabolites are excreted in urine Adverse effects include tightness in head and chest, paresthesia in limb, dizziness, rise in BP and bradycardia Rarely seizures and hypersensitivity reactions occur Dose: SUMINAT; 25-100 mg/day, mg SC Drugs useful in prophylaxis of migraine are β-adrenergic blockers (usually propranolol), methysergide, calcium channel blockers OTHER α-INHIBITORS DRUG THERAPY OF MIGRAINE PRAZOSIN a Simple analgesics (aspirin or paracetamol), NSAIDs and antiemetics are useful in mild attacks of migraine It is an piperazinyl quinazoline effective in the management of hypertension It is highly selective for α1 receptors It also reduces the venous return and cardiac output It is used in essential hypertension, benign prostatic hypertrophy and in Raynaud’s syndrome Prazosin lowers blood pressure in human beings by relaxing both veins and resistance vessels but it dilates arterioles more than veins b Moderate and severe attacks of migraine besides NSAIDs need specific drugs like ergot alkaloids, sumatriptan and methysergide along with antiemetics METHYSERGIDE It is a 5-hydroxytryptamine antagonist (5HT2A/2C) It is effective in preventing an attack of migraine Adverse effects include nausea, abdominal pain, diarrhoea and nervousness SUMATRIPTAN It is a potent selective 5-HT1D receptor agonist used in the treatment of migraine The 5HT1D receptor is found dominantly in cranial blood vessel It activates other It has variable absorption from GIT and has about 50% hepatic first pass metabolism It is highly bound to plasma proteins Adverse effects include orthostatic hypotension, dizziness, headache, drowsiness, weakness, palpitation and impotence TERAZOSIN It is similar to prazosin but has higher bioavailability and longer plasma t½ ... and shock syndrome Phentolamine, another alpha blocker is exclusively used for the diagnosis of pheochromocytoma and for the prevention of abrupt rise in blood pressure during surgical removal... deferens Alpha blockers can inhibit ejaculation and produce impotence Salivary secretion and sweat formation induced by catecholamines is blocked by alpha blockers Alpha blockers also produce certain... are the drugs which block the pressor response to noradrenaline and Table 3.3.1: Classification for alpha adrenergic blocking agents A Non-equilibrium Phenoxybenzamine (FENOXENE) B Equilibrium