Hypertension Lecture-5.pptx for pharmacy students

1. Mention three types of polymers used in preparation of sustained release tablets?
A. HPMC
B. Polyvenyl alcohol
C. polyethylene oxide
2. What are the objectives of Novel Drug Delivery System?
A. Keeping the drug in the therapeutic range
B. Maintaining drug levels overnight
C. Reducing side effects by reducing dose frequency
3. Which is the classes of drug will be an ideal candidate for prolonged-release dosage forms?
Drugs with high solubility and high permeability.
4. Define Delayed-release dosage forms?
These release the drug at a time later than immediately after administration.
5. Define release liner?
a protective liner that is removed and discharged immediately before the application of the patch to skin.
6. Define backing laminate?
a backing layer, used as support in Transdermal patches.
7. What is the release profile in osmotic pump drug delivery system?
Zero order
1. Mention three types of polymers used in preparation of sustained release tablets?
A. HPMC
B. Polyvenyl alcohol
C. polyethylene oxide
2. What are the objectives of Novel Drug Delivery System?
A. Keeping the drug in the therapeutic range
B. Maintaining drug levels overnight
C. Reducing side effects by reducing dose frequency
3. Which is the classes of drug will be an ideal candidate for prolonged-release dosage forms?
Drugs with high solubility and high permeability.
4. Define Delayed-release dosage forms?
These release the drug at a time later than immediately after administration.
5. Define release liner?
a protective liner that is removed and discharged immediately before the application of the patch to skin.
6. Define backing laminate?
a backing layer, used as support in Transdermal patches.
7. What is the release profile in osmotic pump drug delivery system?
Zero order
1. Mention three types of polymers used in preparation of sustained release tablets?
A. HPMC
B. Polyvenyl alcohol
C. polyethylene oxide
2. What are the objectives of Novel Drug Delivery System?
A. Keeping the drug in the therapeutic range
B. Maintaining drug levels overnight
C. Reducing side effects by reducing dose frequency
3. Which is the classes of drug will be an ideal candidate for prolonged-release dosage forms?
Drugs with high solubility and high permeability.
4. Define Delayed-release dosage forms?
These release the drug at a time later than immediately after administration.
5. Define release liner?
a protective liner that is removed and discharged immediately before the application of the patch to skin.
6. Define backing laminate?
a backing layer, used as support in Transdermal patches.
7. What is the release profile in osmotic pump drug delivery system?
Zero order
1. Mention three types of polymers used in preparation of sustained release tablets?
A. HPMC
B. Polyvenyl alcohol
C. polyethylene oxide
2. What are the objectives of Novel Drug Delivery System?
A. Keeping the drug in the therapeutic range
B. Maintaining drug levels overnight
C. Reducing side effects by reducing dose frequenc

1. 1 Anti-hypertension drugs

2. Hypertension(HTN) Introduction Definition : Sustained elevation of systemic arterial blood pressure ≥ 140/90 Classification of hypertension According to Etiology Primary Hypertension due to Environmental and genetic factors ,Primary or essential hypertension accounts for 90-95% of adult cases Secondary hypertension: small percentage of patients (2-10%) have a secondary cause . which has multiple etiologies, including renal, vascular, and endocrine causes . 2

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4. 4 Category Systolic (mm Hg)   Diastolic (mm Hg) Risk Optimal BP < 120 AND < 80 None Borderline BP 140 AND 90 None Stage 1 (mild) 140 – 160 OR 90 - 100 Long-term Stage 2 (moderate) 160 – 180 OR 100 - 110 50% in 5 years Stage 3 (severe) 180 – 210 OR 110-120 40% in 2 years Stage 4 (Very severe) > 210   > 120 Emergency According to blood pressure ( Grade) 1 : 1.From the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA 2003;289:2560

5. The classification in previous table is based on the average of 2 or more readings taken at each of 2 or more visits after initial screening. Sustained arterial hypertension damages blood vessels in kidney , heart , and brain , and leads to an increased incidence of renal failure , coronary disease , cardiac failure , and stroke . According to type: BP Notes Mean arterial blood pressure(MABP)= DBP+1/3PP Pulse pressure(PP)= SBP-DBP Normal rang for MABP = 65-110   5

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11. Blood Pressure Regulation: Physiology Frank's formula, BP regulation BP = CO x TPR CO = HR x SV Baroreceptor reflex : oppose changes in BP, rapid, moment-to-moment BP adjustments Renal system : Control of Na and H2O balance, responsible for long-term BP control 11

12. 12 FIGURE : Regulation of blood pressure. ECF = Extracellular fluid.

13. 13 FIGURE : Regulation of blood pressure by baroreceptor mechanism

14. 14 FIGURE : Regulation of blood pressure by renin angiotensin mechanism . ACE = Angiotensin converting enzyme

15. 15 Hormones which decrease arterial blood pressure Hormones which increase arterial blood pressure Vasoactive intestinal polypeptide (VIP) Bradykinin Prostaglandin Histamine Acetylcholine Atrial natriuretic peptide Brain natriuretic peptide C type natriuretic peptide Adrenaline* Noradrenaline Thyroxine* Aldosterone Vasopressin Angiotensin Serotonin TABLE : Hormones involved in regulation of arterial blood pressure * Adrenaline and thyroxine increase systolic pressure but decrease diastolic pressure.

16. 16 Local vasodilators Local vasoconstrictors (Endothelins) Endothelins (ET) Metabolic products EDRF: Nitric oxide Carbon dioxide Lactate Hydrogen Adenosine EDCF: ET1 ET2 ET3 TABLE : Local substances involved in the regulation of arterial blood pressure

17. Treatment of Hypertension Non-drug treatment (Life-style changes) ↓Salt intake (2.5g/d → 1 g/d) ↓Stress factors Stop smoking ↓Calorie intake, weight loss ↓Alcohol consumption ↓Caffeine intake ↑Physical activity Control of risk factors e.g. diabetes, hyperlipidemia etc . 17

18. Classification of antihypertensive agents Diuretics Sympatholytic agents Centrally α 2 agonist: Clonidine &  -methyldopa vasomotor center : Reserpine Peripherally Adrenergic Neuron blockers Inhibit synthesis : Metyrosine Inhibit storage :Reserpine Inhibit release : Guanethidine Ganglion blockers e.g. Trimethaphan e.g. Hexamethonium Thiazides diuretics Loop diuretics K-Retaining diuretics Adrenergic receptor blockers  -blockers : e.g. Prazosin 1 -blockers : e.g. Atenolol 1&2 -blockers: e.g. Propranolol  &  -blockers : e.g. Labetalol Direct Vasodilators Treatment of Hypertension B. Pharmacotherapy: 18

19. Vasodilators Classification of antihypertensive agents Renin Angiotensin system inhibitor Arteriolar – dilators :Hydralazine Diazoxide Minoxidil Venodilator dilators : Nitrates Mixed dilators : Na + Nitroprusside Calcium channel blockers Angiotensin converting enzyme inhibitors (ACEI ) Direct Renin Inhibitor Angiotensin II (AT1) Receptor Blockers(ARBS) Captopril Enalapril Lisinopril Ramipril Perindopril Losartan Valsartan Irbesartan Candesartan Telmisartan Aliskiren Phenyl alkaylamine :Verapamil Benzodiazepine: Diltiazem Dihydropyridine : amlodipine 19

20. 20 FIGURE: Sympatholytic agents

21. α-Methyldopa (Aldomet ®) Mechanism of Action Prodrug : α-methyldopa Decarboxylase → α- methy dopamine β -Hydroxylase → α- methy Noradrenaline → Stimulate α 2 → In Central → ↓ VM (Sympathetic outflow from C.N.S) → ↓HR → ↓COP& ↓TPR → ↓BL.P. ↑Presynaptic α 2 → ↓ Release of noradrenaline ↑ Kidney α 2 → ↓ Release of renin → Maintain renal blood flow Inhibit synthesis of catecholamines &serotonin by displace of dopa decarboxylase enzyme Clinical uses (dose 250mg tds up to 2g/day) Hypertension especially if accompanied by a- Renal impairment. b- Pregnancy . Centrally : 21 Sympatholytic agents:

22. 22 Side effects of α-methyldopa CNS: sedation, depression, parkinsonism , vertigo & night mares CVS : Bradycardia & Fluid retention (due to VD of efferent arterioles → ↓ Glomerular pressure → ↓ Glomerular filtration rate → Hypervolemia GIT : dryness of mouth( Xerostomia) and constipation Endocrine: ↓dopamine → ↑ prolactin secretion →Galactorrhea ,Gynecomastia & impotence. Allergic reactions : hepatotoxicity, hemolytic anemia(+ve Coombs test)

23. Clonidine (Catapres®) . Given orally , Bioavailability 95 %- 100% Plasma t½ is 8–12 hours. Effect of a single dose lasts for 6–24 hours 1/2 to 2/3 of an oral dose is excreted unchanged in urine Mechanism of Action of Clonidine: Antihypertensive effect Stimulate central α 2 & imidazolin I 1 receptor → ↓ VM (Sympathetic outflow from C.N.S) → ↓HR → ↓COP& ↓TPR → ↓BL.P. ↑ Presynaptic α 2 → ↓ Release of noradrenaline ↑ Kidney α 2 → ↓ Release of renin → Maintain renal blood flow . It may be partial agonist on α 1 & ↑ parasympathetic tone 23 Centrally : Sympatholytic agents:

24. 24 Clinical uses of Clonidine Hypertension especially if accompanied by a-Renal impairment B-high renin Prophylaxis of migraine headache & control of menopausal flushes. To relieve withdrawal of opiate, alcohol & tobacco Why? To control loose motions due to diabetic neuropathy Test for pheochromocytoma (Clonidine suppression test) Side effects of Clonidine I f used in large doe or I.V. → ↑ Postsynaptic α 2 →VC → Initial hypertension. Sedation and Xerostomia are most adverse effects Postural hypotension and erectile dysfunction . Less common CNS side effects include sleep disturbances with vivid dreams or nightmares, restlessness, and depression

25. 25 Side effects of Clonidine Symptomatic Bradycardia and sinus arrest in patients with dysfunction of the SA node and AV block in patients due to the sympatholytic action of this drugs Sudden withdrawal my result in sever hypertension nervousness, headache & Tachycardia ,(which can be treated by readministration of clonidine or by α-blocker or α+β- blocker but not β- blocker alone ) so stopped gradually. Note : Guanfacine is similar to Clonidine but less sedation & long duration → less withdrawal . Guanabenz are similar to Clonidine but has diuretic effect → pseudo tolerance.

26. 26 Inhibit synthesis: Metyrosine (DEMSER) It is (–)-α-methyl-L-tyrosine. Mechanism of action : Inhibits tyrosine hydroxylase Note: Tyrosine hydroxylase : It is the enzyme that catalyzes the conversion of tyrosine to DOPA and the rate-limiting step in catecholamine biosynthesis Clinical uses As adjuvant to phenoxybenzamine and other α adrenergic blocking agents for the management of pheochromocytoma. Adverse effects include Crystalluria, orthostatic hypotension, sedation, extrapyramidal signs, diarrhea, anxiety, and psychic disturbances. Adrenergic Neuron blockers B . Peripheral:

27. B . Peripheral: Inhibit storage: Reserpine Alkaloid of rauwolfia serpentine root ,given orally , Can cross BBB ,so cause parkinsonism or Psychic depression Mechanism of Action: Granular uptake of noradrenaline without affecting neural uptacke-1 → ↓ synthesis of NA & serotonin → Depletion of catecholamine and serotonin central & peripheral. This effect of reserpine end by synthesis of new granules (7-10 days) Action ↓ Sympathetic tone & ↑ Parasympathetic. CNS; Sedation CVS: hypotension & Bradycardia. Adrenergic Neuron blockers 27

28. 28 Clinical uses of Reserpine Mild &Moderate Hypertension . 2. Psychosis e.g. Schizophrenia Side effects of Reserpine CNS: Sedation , mental depression, night mares& suicidal tendency. Parkinsonism& Psychic depression (depletes dopamine in basal ganglia). CVS: Bradycardia & Fluid retention ,flush & Nasal congestion GIT : salivation , peptic ulcer & diarrhea. Weight gain due to increase appetite & salt retention . Endocrine: Feminization, libido, impotence& galactorrhea Contra-indication of Reserpine Parkinsonism , Psychic depression& peptic ulcer

29. Peripheral : Adrenergic Neuron blockers Mechanism of Action: I nhibit releasing of Adrenaline(A) and Noradrenaline(NA)from its vesicles in nerve endings. It is transported across sympathetic nerve membrane by same mechanism which transported noradrenaline (uptake-1)concentrated in vesicles and replace noradrenaline too small amount to induce any significant effect. During chronic administration, Guanethidine acts as a “false neurotransmitter ”. Inhibit release: Guanethidine ( Ismelin ®) & Guanadrel (Hylorel ®) Incomplete oral absorption so, bioavailability is variable(5-50%) retained in nerve and other tissues so slowly excreted by kidney slow onset (2-3 days) long plasma half-life (about 7-10days ) They can’t cross BBB → No parkinsonism OR Psychic depression . 29 Sympatholytic agents:

30. 30 Action If given rapid i.v. → produce Triphasic response Rapid drop in blood pressure due to direct arterial dilatation Rise in blood pressure due to release of noradrenaline Prolong hypotension due to ↓ release of noradrenaline ↓ Sympathetic tone → Bradycardia → ↓COP → ↓RBF → fluid retention → Edema ↑ GIT motility Miosis & ↓ I.O.P Clinical uses S ever Hypertension especially if accompanied by parkinsonism or Psychic depression Glaucoma A B C

31. Side effects Postural hypotension Fatigue and lassitude. Sexual dysfunction usually presents as delayed or retrograde ejaculation Parotid pain & Diarrhea . Contra-indication Hypertension due to Pheochromocytoma because it ↑ effect of circulating catecholamine Guanethidine (Ismelin®) & Guanadrel (Hylorel®)   Adrenergic Neuron blockers 31

32. Adrenergic receptor blockers :  1 -blockers : Prazosin, Terazosin & Doxazosin Is effective orally undergoes first pass hepatic metabolism , bound to alph 1 acid glycoprotein, excretion by bile Mechanism of Action: Selective α 1 -blockers and have direct vasodilators effect. Decrease B.p. by dilating arteries (resistance vessels)and venules(capacitance vessels)→ ↓ after and pre-load . Reduce plasma concentrations of triglycerides and total LDL cholesterol and increase HDL cholestero l 32 B . Peripheral:

33. 33 Clinical uses of Prazosin Hypertension not response to other agents (dose= 1mg raised to 20-30mg/d. Hypertensive patients with benign prostatic hyperplasia CHF (congestive heart failure). Neck bladder obstruction in benign prostate hypertrophy not preferred Why Peripheral vascular disease & Pheochromocytoma Side effects of Prazosin Initial syncope attack (so start by low dose& better given at bedtime). Nasal congestion ,Postural hypotension& Failure of ejaculation due to  -blockers. Headache , dizziness& salt retention .

34. Adrenergic receptor blockers :  -blockers: Propranolol(  1,  2 ) & Atenolol(  1 ) Mechanism of Action: Negative inotropic effect → ↓ CO → ↓ BP ↓ Renin release, ↓ sympathetic outflow ↓ Release of noradrenaline & increase prostaglandin . Clinical uses (effect appear after 4weeks of continued use). Mild &Moderate Hypertension specially in Yong age due to either high renin or stress Pheochromocytoma Angina , arrhythmia ,hypertrophic cardiomyopathy or hyperthyroidism 34

35. 35 Side effects of  - blockers  1-blockers lead to decrease all the properties of the heart 2 -blockers Worsen variant angina Lung: Bronchospasm Liver : ↓ Glycogenolysis , ↓ Hepatic blood flow by 30% → enzyme inhibitor . Limbs: Cold Extremities & intermittent claudication Metabolic: Hypoglycemia, ↑ Triglycerides & ↑ K+ CNS : Lipophilic  -blocker sedation, depression, night mares& vivid dreams Sudden stop → Death

36. Adrenergic receptor blockers :  &  -blockers: Labetalol & Carvedilol . Labetalol Mechanism of action α -block → V.D → ↓ T.P.R, 1 - block → ↓ renin,  2 -partial agonist → V.D. It used in treatment of hypertension especially in Pheochromocytoma or PVD . Because of its capacity to block α1 adrenergic receptors, labetalol given intravenously can reduce blood pressure sufficiently rapidly to be useful for the treatment of hypertensive emergencies Carvedilol similar to Labetalol + anti-oxidant . It is approved for the treatment of hypertension and symptomatic heart failure Note: Nebivolol is a β1 selective adrenergic antagonist that also promotes vasodilatation, nebivolol augments arterial smooth muscle relaxation via NO 36

37. Mechanism of Action: Blocks both sympathetic and parasympathetic at ganglion site. Clinical uses It is used in emergency condition like plastic and neurosurgery. Dose: 1:1000 IV infusion Side effects (S.E) Sympatholytic S.E: postural hypotension and sexual dysfunction. Parasympatholytic S.E: dryness of mouth, urine retention blurred vision tachycardia Ganglion blockers : Trimethaphan 37

38. 38 FIGURE: Sympatholytic agents

39. Hydralazine (Apresoline®): Mechanism of Action: Stimulates release of NO in arterioles only   TPR  B.p (DBP > SBP)  afterload  improve CO in patient with CHF . Clinical uses ( Dose: 40-200mg/d ) Hypertension( add blocker & diuretics). Heart failure . It s given oral or I.V. in emergencies Side effects (S.E) Headache, Flushing, tachycardia, palpitation & angina pain. Peripheral neuritis &Pyridoxine-responsive polyneuropathy. With Large doses in Slow acetylators develop s systemic lupus erythematous ( SLE) Vasodilators 1) Arteriolar –dilators 39

40. Minoxidil (Loniten ®) : Prodrug  Minoxidil sulfate(active) Mechanism of Action: Very effective potent oral ,long acting direct Arterio-vasodilator   TPR  B.p (DBP> SBP)  afterload  improve CO in patient with CHF . Act by opening of K channels . Clinical uses ( Dose: 5-10mg/d increased to 40mg/d) Hypertension(Server, with renal insufficiency and in patient needing high dose of hydralazine).should be combined with diuretic &beta-blocker. Heart failure. Topical in alopecia or baldness Side effects (S.E) Headache, tachycardia, palpitation, Hypertrichosis angina pain & . lower limbs oedema . 40

41. Diazoxide (Hyperstat®): Similar to thiazide diuretics, but without diuretic effect Pharmacokinetics: its highly bound to plasma protein ,metabolized in liver excreted in urine unchanged Mechanism of Action : Very effective potent parenteral ,long acting direct Arterio-vasodilator Opens K+ channel and makes stabilization of smooth muscle arterioles  VD  BP. C linical uses( Dose: 50-150mg IV infusion). Emergency Hypertension start with small dose then gradually increased WHY? Treatment of insulinoma(orally). Side effects (S.E) Excessive hypotensive, tachycardia, & angina pectoris. Salt retention, hypokalemia, hyperglycemia, hyperuricemia &thrombophlebitis . 41 Arteriolar vasodilators

42. Fenoldopam: Mechanism of Action: It is a dopamine(D1) agonist which dilates peripheral arterioles with t1/2 10 minutes. Clinical uses( IV infusion). Emergency Hypertension. Side effects (S.E) Headache, tachycardia, flushing & IOP 42 Vasodilators 1) Arteriolar –dilators

43. Sodium nitropuresside(Nipride®): Mechanism of Action : Nitroprusside  RBCs & Endothelium  No  ↑ Guanylate Cyclase (GC)  ↑ cGMP  VD of both arterioles and venules. Clinical uses ( Dose:0. 50-10µg /kg/min IV infusion). Emergency Hypertension. Emergency Heart failure. Controlled hypotension during plastic & neurosurgery. Acute aortic dissecting aneurysm(with B-blockers) Mixed dilators 43

44. Side effects of Sodium Nitroprusside Sever hypotension &shock in large dose. Sudden stop rebound hypertension. Prolong use in old age  accumulation of cyanide  acidosis & arrhythmia  death. Teratogenic 44

45. Classification of angiotensin converting enzymes inhibitors ACE inhibitors can be classified into three broad groups based on chemical structure: Sulf hydryl group e.g. Captopril Dicarboxyl group e.g. Enalapril ,Lisinopril, Benazepril, Quinapril, Moexipril, Ramipril, Trandolapril, Perindopril Phosphinate group e.g. Fosinopril . Angiotensin Converting Enzymes Inhibitors 45 Renin Angiotensin system inhibitor

46. Mechanism Of Action of ACEI: Inhibit Angiotensin Converting Enzyme(ACE) this lead to Decrease conversion of Angiotensin I to Angiotensin II → ↓synthesis of Angiotensin II: → ↓Noradrenaline release from sympathetic nerve →Vasodilation ↓ Aldosterone → Na+ and water reabsorption and ↓ secretion of K+ and H+ in u rine ↓ Hypertrophy &remodeling of heart and blood vessels ↑ Increase release of renin & Angiotensin I Inactivation of Bradykinin →↑ Bradykinin → Vasodilatation (Directly &by PGs) 46

47. 47 FIGURE : Sites of action of drugs that interfere with the renin-angiotensin-aldosterone system. ACE, angiotensin-converting enzyme; ARBs , angiotensin receptor blockers.

48. 48 Pharmacological Effects of ACEIs Mixed vasodilatation Arterial > Venous. Arterial VD   TPR   afterload &  B.p. Weak vein VD   V.R   E.D.V   Preload &  B.p . C.O .P. is maintained or improve in patient with CHF . ↑ Renal blood flow via vasodilation of the afferent & efferent arterioles but  GFR. Advantages No  C.O .P. it may ↑ C.O . P in HF No postural hypotension No reflex tachycardia (  Baroreceptor reflex &  sympathetic activity) No abnormality in glucose or lipid or cholesterol or uric acid metabolism

49. Uses of ACEI Hypertension especially in diabetic patients. Heart failure (HF). After myocardial infarction (  size of myocardial fibrosis ). Not effective in primary hyperaldosteronism. Adverse effects of ACEI : Severe hypotension in hypovolemic patients Angioedema, hyperkalemia Dry cough (associated with  bradykinin & PGs).Treated by NASIDs. Glossitis, oral ulceration, rash Altered sense of taste (loss of zinc) 49

50. Contraindication of ACEI: In 2 nd -3 rd trimesters pregnancy this lead to Fetal hypotension, renal failure sometimes associated with fetal malformations or death Bilateral renal artery stenosis this lead to Fetal renal failure. Drug interaction of ACEI: (  K +) with K-sparing diuretics, NSAIDs& β -Blockers NSAIDs such as diclofenac sodium & Ketoprofen (  effect ) Na –depleting diuretics  initial hypotensive effect of ACEIs 50

51. Angiotensin II( AT 1 )- receptor Blockers(ARBs): Classification Non- peptide : orally Drugs :Losartan , Valsartan , Irbesartan Candesartan, Eprosartan , and Telmisartan. Compete with Angiotensin II for AT1-receptors.they are pure antagonist. actions similar to ACEI but not associated with dry cough (no  bradykinin) 2.Peptide : I.V only Drugs : Saralasin It is a partial agonist. Now not use medically only experimentally 51 Renin Angiotensin system inhibitor

52. Direct Renin Inhibitor: Aliskiren newest agent, introduced 2005, Expensive. direct renin inhibitor →  production of angiotensin I actions similar to ACEI but not associated with dry cough (no  bradykinin) less likely to cause angioedema, glossitis, oral ulceration, rash adverse effects and contraindications similar to ACEIs/ARBs used if cannot tolerate ACEIs or ARBs poor bioavailability < 5%, may  [furosemide] (MOA unknown ) 52 Renin Angiotensin system inhibitor

53. 53 Antihypertensives to be avoided during pregnancy Diuretics. ACE inhibitors, ARBs Nonselective β blockers Sod . Nitroprusside Antihypertensives found safer during pregnancy Hydralazine, Methyldopa Dihydropyridine CCBs Cardioselective β blockers and those with ISA Prazosin and clonidine

54. 54 Hypertensive emergencies and urgencies Sodium nitroprusside Glyceryl trinitrate Diazoxide Hydralazine Trimethaphan Esmolol Phentolamine Labetalol Enlaprilate Nicardipine Furosemide .

55. Thank You 55