Hypertension

1. Hypertension Angela Lamb Paediatric Renal Pharmacist

2. Summary • Hypertension • Management of hypertension • Adult guidelines (NICE 2006) • Paediatric/adolescent trials • Discussion • ACE protocol • ARBs

3. Hypertension • Most common diseases of the world affecting an estimated 20% of the adult population • Associated with marked morbidity and mortality (high financial cost) • Most important single, modifiable risk factor for • Coronary artery disease • Stroke • ESRF

4. Hypertension • Classified by aetiology into : • Essential hypertension: • No identifiable cause • Approx 95% of all case • Secondary hypertension: • Cause can be identified (Renal/endocrine/vascular/drugs) • Approx 5% of all cases

5. Hypertension • Malignant or accelerated hypertension • “benign” essential hypertension • Resistant hypertension • “White coat” hypertension

6. Hypertension • Ethnic group: • Black people have a higher incidence of hypertension than white people • Gender: • Women are less likely to develop hypertension at an early age

7. Hypertension: Aetiology • Arterial BP is a product of : • Cardiac output • Preload/contractility/afterload=stroke vol • Heart rate • Total peripheral vascular resistance • Arteriolar physiology • Vascular edothelium

8. Hypertension: Aetiology • Sympathetic nervous system: • Increases cardiac output • Increases vascular resistance • Stimulation of the renin-angiotensin system : • Release of angiotensin II • acts as a direct vasoconstrictor • Aldosterone release • Sodium & water retention

9. Hypertension: Treatment • Non pharmacological : • Lifestyle changes: • Weight • Diet • Alcohol • Exercise

10. Hypertension: Treatment • Pharmacological: • Thiazide diuretics • Beta-blockers BB • Angiotensin-converting enzyme inhibitors ACEI • Angiotensin II receptor blockers ARBs • Calcium channel blockers CCB • Alpha-blockers • Others include vasodilators/centrally acting agents

11. Thiazide Diuretic • Mechanism of action: • Inhibit sodium reabsorption at the beginning of the distal convoluted tubule • Increasing sodium excretion and urine volume • Direct vasodilator effect on arterioles • Diuretic effect is seen 1-2 hours after administration lasting 12-24 hours • Low doses • Less effective in renal impairment as effect depends on extent of their excretion

12. Thiazide diuretics • Side effects: • Hypokalaemia • Hyponatraemia • Hypomagnesaemia • Hypercalcaemia • Gout (hyperuricaemia) • Hyperglycaemia (impaired glucose tolerance)

13. Beta-blockers • Mechanism of action: • Block beta-adrenoceptors in the body • Sub classified into two types Heart Brain β1 Lung Skeletal muscle β2 Kidney Peripheral blood vessels

14. Beta-blockers • Stimulation of β1 & β2 receptors : • Increased cardiac output • Increased peripheral vascular resistance • Increased aldosterone-mediated sodium & water retention • Beta-blockers antagonise the above effect: • Resulting in reduction of BP

15. Beta-blockers • Selective (cardioselective not cardiospecific) mainly blocking β1 receptors • atenolol/metoprolol • Non selective blocking β1 & β2 receptors • propranolol • Partial beta agonist activity • acebutolol act as a beta-stimulant during sleep & beta-blocker during increased activity • Block peripheral α-adrenoceptors • labetolol

16. Pharmacokinetics • Elimination: • Lipid soluble – excreted by the liver usually require multiple dosing e.g. propranolol • Water soluble- excreted by the kidney usually have longer half lives & can be given od e.g. atenolol

17. Beta-blockers • Side effects • Bronchospasm • Bradycardia • Impairment of myocardial contractility • Cold extremities • Vivid dreams & nightmares e.g. propranolol • Reduce the awareness of hypoglycaemia (IDDM)

19. ACE inhibitors ACE I

20. ACE inhibitor • Pharmacokinetics are profoundly different ACE I • First dose should be administered at night • Low sodium levels – enhanced first dose drop in BP • Bradykinin breakdown (cough)

21. Angiotensin II Receptor Blockers ARBs

22. Angiotensin II Receptor Blockers • Many tissues contain enzyme systems that convert : • Angiotensin I Angiotensin II • Without using ACE • Do not inhibit breakdown of Kinins (no cough)

23. ACEI & ARBs • Side effects • Impaired renal function : renal function & electrolytes checked • Hyperkalaemia • Dry cough (ACEI 15% patients) • Teratogenic

24. Calcium Channel Blockers • Mechanism of action Extracellular CCB Calcium channel Calcium ions Intracellular

25. Calcium Channel Blockers • Myocardial cells - Reduce myocardial contractility • Cells within the specialised conducting system of the heart- Depress the formation & propagation of electrical impulses within the heart • Cells of the vascular smooth muscles-Promote vasodilatation

26. Calcium Channels Blockers • Three classes: • Dihydropyridines : peripheral dilator properties (nifedipine & amlodipine) • Phenylalkalamines: cardiac effects (verapamil) • Benzothiazipine: cardiac effects (diltiazem)

27. Calcium Channel Blockers • Side effects: • Facial flushing • Headache • Ankle swelling • Abdominal pain

28. Others antihypertensives • Alpha-blockers: • Block α1 adrenoceptors causing vasodilatation (doxazosin) • Vasodilators: • Relax vascular smooth muscle (hydralazine/minoxidil) • Centrally acting: • Block α2 adrenoceptors in the brainstem, reducing sympathetic outflow to the heart, blood vessels & kidney

29. NICE 34 Hypertension 2006 & BHS

30. NICE 34 Hypertension 2006 & BHS • “Moreover, the GDG felt that the benefits from ACE inhibitors and angiotensin-II receptor antagonists were closely correlated and that they should be treated as equal in terms of efficacy (although, because of cost differences, ACE inhibitors should be initiated first).” NICE clinical guideline 34 2006

31. HOPE trial FEVER trial EUROPA trial ACTION trial CAMELOT trial SCOPE study HOT study BPLTT collaboration meta-analysis HDFP trial ASCOT trial INVEST trial ALLHAT trial LIFE study MOSES trial JIKEY HEART trial VALUE trial EB Antihypertensives for Adults

32. EB Antihypertensives in Adults with Renal Disease • MDRD trial • RENAAL study • IDNT study • SYST-EUR trial • COOPERATE study

33. EB Antihypertensives for Children & adolescents • 1997 Food and Drug Administration Modernization Act (FDAMA) • 2002 Best Pharmaceuticals for Children Act (BPCA) • The EU Regulation on Paediatric Medicines was adopted on 12 December 2006 and came into force on 26 January 2007. 

34. Negative : lack of reliablepaediatric data for older, commonly used medicines with expiredpatent protection. Currently, no incentives exist for industry-sponsoredtrials of such drugs alternative methods of stimulatingpaediatric studies such as those contained in the Best Pharmaceuticalsfor Children Act have yet to come to fruition Positive: industry-sponsoredclinical trials single-centred case series will provide additionaldata that can be combined with prior recommendations expert opinion collective clinical experience to guide theuse of antihypertensive drugs in children and adolescents whorequire pharmacologic treatment EB Antihypertensives for Children & adolescents

35. ACE I • Completed studies: • Enalapril • Lisinopril • Ramipril(not BNF C) • Fosinopril (not BNF C) • Benazepril (not BNF C/BNF) • Quinapril (not BNF C)

36. Enalapril/Lisinopril Min effective dose of 0.08mg/kg/day Well tolerated dose was 0.6mg/kg/day BP  dose-dependent manner Extemporaneous suspension (Cf BNFC Enalapril 0.1-1mg/kg/day Lisinopril 0.07-0.6mg/kg/day) Fosinopril Failed to establish a dose response effect Only tablet form available 50kg ACEI

37. ARBs • Completed studies • Losartan • Irbesartan (not BNF C) • In progress: • Candesartan (not BNF C) • Valsartan (not BNF C)

38. Losartan Min effective dose of 0.75mg/kg/day Highest tolerated dose was 1.44mg/kg/day BP  dose-dependent manner GFR 30ml/min/1.73m² Extemporaneous suspension (Cf BNFC 20-50kg 25mg-50mg 50kg 50mg-100mg) Irbesartan Small pharmacokinetic study 75-100mg/day Failed to show a significant anti-hypertensive effect in children 6-16 years ARBs

39. Beta Blockers • Completed studies • Bisoprolol with hydrochlorothiazide (not BNF C) • Metoprolol ER x2(not BNF C) • Esmolol

40. Bisoprolol/HCTZ 8 weeks BP  0.04mg/kg/day (bisoprolol) Significant placebo effect High drop out rate Metoprolol ER Paper was discussed Beta Blockers

41. Calcium Channel Blockers • Completed studies • Amlodipine • Felodipine (not BNF C)

42. Amlodipine Dose response relationship starting doses 0.06mg/kg/day Max dose used was 5mg Extemporaneous suspension BNFC 0.1mg-0.2mg/kg/day max 10mg day Felodipine All doses lowered BP No dose response relationship established <30 subjects No suspension Calcium Channel Blockers

43. Others • In progress: • Sodium nitroprusside – sponsored by National Insitute for Child Health and Human Development

44. Discussion

45. Enalapril Test Dose • Not necessary for all patients • Recommended: • Strongly activated renin-angiotensin-aldosterone system • Renovascular hypertension • Salt and/or volume depletion • Cardiac decompensation • Severe hypertension

46. Enalapril Test Dose • May experience an excessive fall in blood pressure following initial dose • Start under medical supervision • Monitor BP 1-2 hours after starting • Stop high dose diuretics 2-3 days prior to starting

47. ARB • Which ARB ? • Who for ? • Addition with ACE

48. Renin Inhibitor • Aliskiren (Tekturna) • “first in class” orally active renin inhibitor • Excerts effect at the renin system’s point of activation • Directly inhibiting plasma renin activity

49. Any Questions please