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Antihypertensives
- 1.
- 2. HYPERTENSION Hypertension canbe defined as the level of blood pressure at which there is risk to the organs or vasculature. Diagnosed on repeated & reproducible measurements of elevated blood pressure.
- 3. A sustained increasein blood pressure More than or equal to 140/90 mm Hg.
- 4. HYPERTENSION Category Systolic (mmHg)Diastolic (mm Hg) optimal <120 < 80 normal < 130 < 85 high-normal Hypertension stage 1 stage 2 stage 3 130-139 85-89 140-159 90-99 160-179 100-109 > 180_ >110_
- 5. PRIMARY HYPERTENSION The causeis unknown. Also referred to as Essential Hypertension Includes approximately 90% of cases.
- 6. SECONDARY HYPERTENSION The causeis known Renal Endocrine Anatomic disorders etc. Includes approximately 10% of cases
- 7.
- 8. BP= CO XTPR CO= SV X HR BP= SV X HR X TPR
- 11. BLOOD VESSELS CONTROLLINGBLOOD PRESSURE The major blood vessels controlling blood pressure are referred to as The Resistance vessels The Capacitance vessels
- 12. RESISTANCE VESSELS Arterioles arethe primary resistance vessels, Control mean arterial blood pressure & blood flow to specific tissues. Vascular smooth muscle tone in these vessels is controlled by the sympathetic nervous system and local factors (metabolic need)
- 13. CAPACITANCE VESSELS Systemicvenules and veins serve as a volume reservoir for the circulatory system (approx. 50% of total blood volume is contained in these vessels) Sympathetic and humoral regulation of these vessels can significantly alter venous return (preload) and fluid exchange in the associated capillary beds
- 14. Blood pressureis closely regulated on Short-term (seconds-to-minutes) Long-term (days-to-weeks) basis Mean arterial pressure is monitored by Baroreceptors primarily in the aortic arch and carotid artery
- 15. SHORT-TERM REGULATION Short-termchanges in blood pressure are mediated by the autonomic nervous system
- 16. Changes in meanarterial pressure are sensed by the baroreceptors and processed by the vasomotor centers in the medulla which differentially regulate sympathetic and parasympathetic nervous system output.
- 17. If a dropin blood pressure is seen by the baroreceptors, neuronal activity to the vasomotor centers is decreased, resulting in an increase in sympathetic tone and a decrease in parasympathetic (vagal) tone.
- 18. A rise inmean arterial pressure causes an increase in baroreceptor neuronal activity and gives rise to an increase in vagal tone (activity of the vagus nerve) and a decrease in sympathetic tone.
- 19. 1. Increases invagal tone lead to lowering of heart rate. 2. Increases in sympathetic tone result in increased peripheral vascular resistance, increased venous tone, increased heart rate, and increased contractility of the myocardium
- 20. LONG-TERM REGULATION Long-term changesin blood pressure (hours to days) are primarily mediated by humoral factors that control blood volume by regulating Na+ and water retention.
- 21. Changes inrenal blood flow and pressure, which are directly related to mean arterial pressure, result in changes in renin secretion. A drop in renal blood flow or pressure results in an increase in renin release from the kidney. High sympathetic outflow also causes an increase in renin secretion
- 22. 1. An increasein renin release leads to an increase in circulating angiotensin II. 2. The primary actions of angiotensin II are: a) To stimulate the synthesis and secretion of aldosterone. b) To raise blood pressure by direct vasoconstrictor effects (angiotensin II is one of the most potent vasoconstrictors known). c) Aldosterone acts on the kidney to retain Na+ (and therefore water), leading to an increase in blood volume
- 23.
- 24. In hypertensivepatients, the baroreceptors & renal blood volume-pressure control systems appear to be “set” at a higher level of blood pressure.
- 25. WHY TO TREATHYPERTENSION ?
- 28. Hypertension -Clinical Significance 1. Heart disease 2. Stroke 3. Kidney failure 4. Blindness Effects usually are not apparent until after 10 or more years of sustained high blood pressure.
- 29. TREATMENT STRATEGIES A.LifestyleModifications low fat diet rich in vegetables and fruit reduction of excess body weight limited alcohol consumption daily aerobic exercise smoking cessation reduction of sodium intake B. Drug Therapy
- 30. C. AdditionalRisk factors for cardiovascular disease smoking dyslipidemia diabetes mellitus age older than 60 sex (men and postmenopausal women) family history of cardiovascular disease
- 31. TREATMENT STRATEGIES RiskGroup A No risk factors No cardiovascular disease No Target organ damage Risk Group B At least one risk factor not including diabetes mellitus No cardiovascular disease No target organ damage Risk Group C Cardiovascular disease Target organ damage Diabetes mellitus
- 32. TREATMENT STRATEGY Blood PressureRisk group A Risk group B Risk group C High-normal Stage 1 Stage 2 lifestyle modification lifestyle modification lifestyle modification lifestyle modification lifestyle modification (up to 6 months) drug therapy drug therapy drug therapy drug therapy (140-159/90-99) (130-139/85-89) (160-179/100-109)
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- 34.
- 35. 1- ALPHA-ADRENERGIC BLOCKERS a-Selective Alpha-1 Blockers Prazocin Doxazocin Terazocin Tamsuluson b-Non-Selective Alpha Blockers Phentolamine Phenoxybenzamine
- 36. 2- BETA-ADRENERGIC BLOCKERS a-Cardio-selectiveBeta-Blockers Atenolol Acebutolol Metoprolol b-Cardio-Nonselective Beta-Blockers Propranolol Nadolol Timolol
- 37. 3- ALPHA &BETA -ADRENERGIC BLOCKERS Carvidilol Labetolol
- 38. 4- CENTRALLY ACTING SYMPATHOPLEGICSOR ALPHA-2 AGONISTS Alpha-methyldopa Clonidine Guanabenz Guanfacine
- 39. 5- ADRENERGIC NEURON BLOCKERS Guanethidine Guanadrel Reserpine
- 40. 6-GANGLION BLOCKERS Hexamethonium Trimetaphan Mecamylamine Pempidine
- 41. B- Diuretics 1-Thiazide diuretics1-Thiazidediuretics 2-Loop diuretics2-Loop diuretics 3-Potassium sparing3-Potassium sparing diureticsdiuretics
- 42. C- Angiotensin Antagonists 1-ACEinhibitors1-ACE inhibitors •CaptoprilCaptopril •LisinoprilLisinopril •AnalaprilAnalapril 2-Angiotensin receptor blockers2-Angiotensin receptor blockers •LosartanLosartan •ValsartanValsartan •saralasinsaralasin
- 43.
- 44. 1-DIRECT VASODILATORS a-Arteriolar dilators Hydralazine Minoxidil Diazoxide Fenoldopam b-venodilators Nitrates Nitrites c- Both Arteriolar & veno-dilators Sodium Nitroprusside
- 45. 2-CALCIM CHANNEL BLOCKERS Niedipine Amlodipine Verapamil Diltiazem
- 46. 3- MISCELLANEOUS 1-ACEinhibitors 2-Angiotensin receptor blockers 3-Alpha-Adrenergic Blockers 4-adrenergic neuron blockers 5-Ganglion blockers
- 48. 1. DECREASE BLOODVOLUME Diuretics
- 49. 2. DECREASE HEARTRATE & FORCE β-blockers
- 50. 3. DECREASE TPR a. Vasodilators Direct Vasodilators Minoxidil Hydralazine Indirect Vasodilators Calcium channel blockers ACEI AT Blockers
- 51. 3. DECREASE TPR b. Decrease sympathetic tone Central sympathoplegics Ganglion Blockers Adrenergic neuron blockers Receptor blockers Alpha blockers Beta blockers
- 52. BP = COX PVR CCB = calcium channel blockers CA Adrenergics = central-acting adrenergics ACEi’s = angiotensin-converting enzyme inhibitors cardiac factors circulating volume heart rate contractility 1. Beta Blockers 2. CCB’s 3. C.A. Adrenergics salt aldosterone ACEi’s Diuretics
- 53. BP = COx PVR Hormones 1. vasodilators 2. ACEI’s 3. CCB’s Central Nervous System 1. CA Adrenergics Peripheral Sympathetic Receptors alpha beta 1. alpha blockers 2. beta blockers Local Acting 1. Peripheral-Acting Adrenergics
- 54.
- 55. Drugs whichact at postganglionic adrenergic nerve endings & inhibit their function by interfering with synthesis,storage or release of Noradrenaline. Do not control supine blood pressure. Cause postural hypotension. Used rarely in resistant hypertension.
- 56.
- 57. DRUGS THAT PREVENTRELEASE OF NORADRENALINE Guanethidine Bethanidine Debrisoquine Guanoxan Guanadrel Bretylium
- 58. 2-DRUGS THAT INHIBITSTORAGE OF NORADRENALINE Reserpine Deserpidine Syrosingopine Methoserpidine
- 59. 3-DRUGS THAT INTERFEREWITH SYNTHESIS OF NORADRENALINE Methyldopa Metyrosine
- 60. GUANETHIDINE High doses----profound sympathoplegia Polar----------do not cross BBB Long half-life----5 days
- 61. MECHANISM OF ACTION It inhibits the release of noradrenaline(NE) from Sympathetic nerve endings. It is transported across the Sympathetic nerve membrane by the same mechanism that transports NE itself ( uptake 1),then it is stored in vesicles, replaces the NE & released itself by nerve stimulation. Hypotensive action, With early therapy----decrease CO,HR & relaxation of capacitance vessels. With long-term therapy---decrease PVR Compensatory sodium & water retention decrease
- 64. PHARMACOLOGICAL ACTIONS 1-CVS a-Bloodpressure Rapid I.V injection--- Triphasic response 1-rapid fall 2-Hypertention 3-progressive fall in B.P b- Decrease concentration of catecholamine in Heart & blood vessels. 2-CNS ,NO effect
- 65. 3-GIT, increasemotility 4- EYES, miosis 5-SUPERSENSITIVITY CLINICAL USES Rarely used 1-Moderate to severe HTN 2-Hyperreflexia of high spinal cord lesion 3-Glaucoma 4-Management of lid retraction in thyrotoxicosis
- 66. ADVERSE EFFECTS Posturalhypotension Bradycardia Diarrhea Failure of ejaculation Nasal congestion Fluid retention & oedema Heart failure Hypertensive crisis in patients with pheochromocytoma & taking cold remedies containing directly acting sympathomimetics
- 67. DRUG INTERACTIONS Drugsthat block catecholamine uptake- 1 or displaces amines from the nerve terminal block its effects e.g.cocaine, tricyclic antidepressants Hypertension ---------sympathomimetcs CONTRAINDICATIONS Pheochromocytoma Renal failure
- 68. BRETYLIUM Quaternary ammoniumcompound concentrated in adrenergic neurons. Prevent release of NE Now used as antiarrhythmic in resistant ventricular arrhythmias. Causes hypotension,nausea,parotid pain, Bradycardia.
- 69. RESERPINE Alkaloid innature. Obtained from Rauwolfia Serpentina Used in Indo-Pakistan to treat mental illness since ancient times. Pure alkaloid was isolated in 1955.it was popular antihypertensive in late 1950s & early 1960s but now used as pharmacological tool. Well absorbed orally Crosses BBB,placental barrier & excreted in milk.
- 70. MECHANISM OF ACTION It interferes with intracellular storage of catecholamines.It acts at the membrane of intraneuronal granules which stores monoamines ( NE,5-HT,DA) & irreversibly inhibits the active amine transport ( ATP-Mg++ dependent uptake mechanism). Monoamines are gradually depleted & degraded by MAO enzyme. Occurs throughout the body even in adrenal medulla. Action not reversed until new vesicles are synthesized The effects last long after the drug is eliminated ( hit & run drug) because tissue CA stores are restored only gradually.
- 71. PHARMACOLOGICAL ACTIONS 1-CARDIOVASCULAR SYSTEM B.P, Causes slowly developing fall in B.P & bradycardia,taking 2-3 weeks for full action. The hypotensive action is due to peripheral as well as central action. salt & water retention Decrease PR,CO & Cardiovascular reflexes are partially inhibited. Increase cutaneous blood flow. Decreae Renin secretion s
- 72. 2-CENTRAL NERVOUSSYSTEM It produces a characteristic sedation , tranquillizing effect & a state of indifference to environmental stimuli due to depletion of CA & 5-HT stores in brain. Extra-pyramidal effects on prolong use of high doses due to depletion of dopamine. 3-PARASYMPATHETIC OVERACTIVITY Effects are similar to Acetylcholine
- 73. CLINICAL USES HYPERTENSIONMILD TO MODERATE along with a thiazide diuretic & other antihypertensive drugs. Hypertensive emergencies Now Not used as antipsychotic
- 74. ADVERSE EFFECTS CVS Postural hypotension Bradycardia Oedema GIT Increase salivation,GIT motility Increase gastric acid secretion (peptic ulcer) diarrhoea
- 75. CNS Parkinsonism-likeextra-pyramidal syndrome Nightmares sedation Most serious ---------psychic depression lead to suicide OTHERS Weight gain Nasal stffiness Decreased libido (impotence)
- 76. CENTRALLY ACTING SYMPATHOPLEGICS Decrease sympatheticoutflow from vasopressor centers in brain
- 77. Patients withmoderate to severe hypertension,most effective drug regimens include an agent that inhibits function of sympathetic nervous system. These agents reduce sympathetic outflow from vasopressor centre in the brain stem but allow these centres to retain or even increase their sensitivity to baroreceptor control.
- 78. CLASSIFICATION L-Dopa analog Alpha-methyldopa Imidazolinederivatives Clonidine Apraclonidine Brimonidine Relmenidine Moxonidine Others Guanabenz guanfacine
- 79. ALPHA-METHYLDOPA (L- ALPHA-METHYL-3,4-DIHYDROXYPHENYLALANINE) It isan analog of L-Dopa (precursor of dopamine & NE) is converted to alpha- methyl dopamine then to alpha- methylnoradrenaline (selective alpha-2 agonist), stored in adrenergic nerve vesicles, where it replaces NE & is released by nerve stimulation to interact with postsynaptic adrenoreceptors. It probably acts as an agonist at presynaptic alpha-2 receptors in brainstem to decrease efferent sympathetic activity.
- 81. PHARMACOLOGICAL EFFECTS Bloodpressure In young patient------decrease PVR In older patient ------- decrease PVR & CO as a result of decrease HR & stroke volume. Fall in B.P is maximum 6-8 hours after an oral or I/V dose Postural hypotension is less common RBF is maintained Renin is reduced Salt & water retention blunt antihypertensive effect (pseudo tolerance)
- 82. PHARMACOKINETICS Prodrug Absorbedby active amino acid transporter on oral adminstration. Peak concentration in plasma occurs after 2-3 hrs Vd is small Half life is 2hrs ( 4-6hrs in renal failure) Transport in CNS is also a active process. Peak effect occurs in 6-8hrs Duration of action is 24hrs so given in once & twice daily dosing This discrepancy is related to time required for 1-transport into CNS 2-conversion into active metabolite 3-storage 4-release in vicinity of relevant alpha-2 receptors in CNS
- 83. Sedation, nightmares,movement disorders, hyperprolactinemia
- 84.
- 85. MECHANISM OF ACTION: Clonidine, when given I/V , causes an acute rise in B.P. probably due to activation of post- synaptic alpha2 receptors in vascular smooth muscle (arterioles).It is classified as Partial agonist at alpha receptors because it also inhibits pressor effects of other alpha agonists.
- 86. Clonidine isa partial agonist with high selective affinity and high intrinsic activity at alpha 2 receptors, especially alpha 2A subtype which are mainly present in hypothalamus and lower brain stem regions, especially nucleus tractus solitarius which regulates sympathetic activity. Activation of central pre-synaptic alpha 2 receptors inhibit the release of noradrenaline from adrenergic neurons, decreases sympathetic outflow and produces a fall in B.P. Alternatively, Clonidine may act on post- synaptic alpha 2A receptors in medulla (vasomotor centre)
- 87. Clonidine alsobinds to a non-adrenoceptor site, the imidazoline receptors which are present in brain as well as in periphery. Clonidine may first stimulate central imidazoline receptors which then trigger medullary alpha2A receptors to reduce sympathetic outflow. Clonidine increases parasympathetic tone and results in fall of B.P. and bradycardia. The reduction in B.P. is accompanied by a reduction in catecholamine levels. This suggests that Clonidine sensitizes brain stem pressor centres to inhibition by baroreflexes.
- 88. PHARMACOLOGIC EFFECTS CVS: DecreasesB.P. & H.R. High doses-Inc. B.P. Dec. renal vascular resistance Inc. renal blood flow Inc. GFR Relaxation of veins Dec. C.O.
- 89. Abrupt withdrawal-reboundhypertension Causes salt & water retention CNS ???
- 90. PHARMACOKINETICS Absorbed byoral route Bioavailability- 75-100% Lipid soluble-enters brain Peak plasma level: 1-3 hrs. T1/2 6-24hrs. Mean 24hrs. Excretes unchanged in urine
- 91. ADVERSE EFFECTS Drymouth, sedation Sexual dysfunction Marked bradycardia Contact dermatitis Withdrawal reaction
- 92.
- 93. Hypertension. Pre-anaestheticmedication: Stimulation of central alpha 2 adrenoceptors produces sedation and analgesia. Administered before surgery, clonidine reduces anaesthetic requirement and improves cardiovascular stability. Opioid withdrawal : Clonidine suppresses exaggerated transmitter release that occurs during withdrawal of opioids. Clonidine also facilitates alcohol withdrawal and smoking cessation.
- 94. Clonidine hasbeen used to substitute morphine for intrathecal and epidural analgesia. Clonidine attenuates vasomotor symptoms of menopausal syndrome such as hot flushes. Clonidine has been used to control diarrhea due to diabetic neuropathy. Prophylaxis of migraine.
- 95. DRUG INTERACTIONS Tricyclicanti-depressants DOSE: 0.2-0.8 mg/day Max. 2.4 mg