Agents to Treat Hypertension:

1. Agents to Treat Hypertension:

2. What is Hypertension? • A serious disease affecting 1 in 3 adults in the United States • More commonly known as High Blood Pressure • Occurs when blood is forced through the heart and arteries under excessive pressure

3. What is Blood Pressure? • Blood pressure readings have two components: • Systolic pressure • Heart muscles contracted • Diastolic pressure • Heart muscles relaxed • With hypertension: • Arteries narrow thereby increasing blood pressure • Fluid volume in arteries increases which can increase pressure

4. Classifying Blood Pressure by Readings • High Blood Pressure = Elevated systolic pressure and/or elevated diastolic pressure. • The highest reading dictates classification. • Elevated readings must occur on multiple occasions to be diagnosed.

5. Classifying Hypertension by Causes • Primary or Essential Hypertension • Causes are unknown, but linked to risk factors, etiology is unknown. • Secondary Hypertension • 5-10% of hypertension cases • Caused by disease states

6. Some causes include: kidney disease, atherosclerosis, hormone imbalances, pregnancy, and some medications,renal,endocrinal or vascular disorder.

7. Who is Affected by Hypertension? • Affects 1 billion people worldwide • Affects 40 million Americans (15%) • 30% of people with hypertension don’t know they have it (Death rates per 100,000 people)

8. Why Should I Care? • Hypertension can elevate your risk for: • Stroke • Blood clots • Bleeding • Heart attacks • Heart enlargement • Heart failure • Kidney failure • Atherosclerosis

9. Treatment Options for Hypertension • Prevention is the best treatment strategy • The goal of treatment: • Lower blood pressure to prevent associated complications • Typically <140/90 mmHg

10. It is a syndrome affecting arterialblood vessels, caused largely by the accumulation of macrophagewhite blood cells and promoted by low-density lipoproteins (plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macrophages by functional high density lipoproteins (HDL), It is commonly referred to as a hardening or furring of the arteries. It is caused by the formation of multiple plaques within the arteries.

11. Treatment of HTN There are following steps in treating HTN • Lifestyle modification • First line treatment • Second line treatment • Third line treatment

12. Treatment Options for Hypertension • Then first drugs used to produce symptamatic relief of hypertension were α-adrenergic blocking agents. • Limitations- duration of action too short. • Side effects precluded long term therapy. Adrenergic drugs exert their effects by direct action on adrenergic receptors. α andβ receptors NE activates α receptors Epinephrine activates β receptors.

13. α receptors fall into two groups α 1 found in smooth muscles of iris,arteries,arterioles,veins. α 2- mediate the inhibition of adrenergic neurotransmitter release. β adrenergic receptors 3 types β1, β2,β3.

14. β1- found in myocardium, stimulation increases the force and rate of myocardial contraction. β2- found in bronchial and vascular smooth muscles, stimulation causes Smooth muscle dilation or relaxation. β3- on fat cells and their stimulation causes lipolysis

15. Symptathomimetic agents • Drugs stimulate the adrenergic nerve,directly by mimicing the action of NE.

16. Classification: • Centrally acting:- Clonidine,Methyldopa • Ganglionic blocking agents;- Pempidine,hexamethonium,Pentolinium • Adrenergic neuron blockers:- Guanethidine,reserpine,bethanidine,bretylium. • β- adrenergic blockers :-propanolol,atenolol. • α- adrenergic blockers :- Phenoxybenzamine, phentolamine, indoramine.

17. F) Mixed α and β adrenergic blockers:- Labetolol, Carvediol. • Diuretics :- Chlorthiazide. • Vasodilaors: eg: hydralazine,minoxidil,diazoxide,Na nitroprusside. • Calcium channel blockers; Verapamil,Nefidipine,Diltiazem,Beridil,Amlodipine. • Drugs acting on renin- angiotensin aldosterone axis: a)Angiotensin converting enzyme inhibitors:-

18. Sulfhydryl containing inhibitor:- captopril • Dicarboxylate containing inhibitor:- enalapril,lisinopril,quinapril,ramipril,trandopril,spirapril etc. • Phosphonate containing inhibitor: fosinopril • Angiotensin II receptor antagonist :- losartan,valsartan,candesartan,telmisartan etc.

19. First Line Treatment • Continue with lifestyle modification • Initial drug selection: • Diuretic • Beta-blocker • If inadequate, continue to second line treatment

20. Available Drug Therapies • Drug therapies available: • ACE (angiotensin-converting enzyme) inhibitors • Alpha blockers • Alpha-2-agonists • Angiotensin II receptor blockers • Beta blockers • Calcium channel blockers • Combined alpha and beta blockers • Combined ACE inhibitors and diuretics • Diuretics

21. Second Line Treatment • Adding drugs from the following categories • Angiotensin Converting Enzyme (ACE) Inhibitor • Calcium Channel Blocker • Angiotensin II Receptor Blocker (ARB) • α- blocker, α- and β-blocker • If inadequate, continue to third line treatment

22. Third Line Treatment • Increase drug dose, or • Substitute another drug, or • Add a second drug from another class • If inadequate, may need to do further studies • Serious organ damage may be present

23. Drug Therapies

24. Drugs Used to Treat HTN • Diuretics • Furosemide (Lasix); Hydrochlorothizide (HydroDIURIL) • Beta blockers • Atenolol (Tenormin); Propranolol (Inderal) • ACE inhibitors • Captopril (Capoten); Enalapril (Vasotec) • ARB’s • Irbesartan (Avapro); Losartan (Cozaar) • Calcium channel blockers • Amlodipine (Norvasc); Diltiazem (Cardizem)

25. Site Of Action of Antihypertensive Drugs • Action of Beta-Blockers • Block vasoconstriction • Decrease heart rate • Decrease cardiac muscle contraction • Tend to increase blood flow to the kidneys -> leading to a decrease in the release of renin

26. Classification of Beta Blockers • β1 receptors blockers • Atenolol (Tenormin) • Betaxolol (Kerlone) • Bisoprolol (Zabeta) • Metoprolol (Lopressor, Toprol-XL) • β1, β2 receptor blockers • Nadolol (Corgard) • Propranolol (Inderal) • β1, β2, α receptor blockers • Labetolol (Normodyne, Trandate)

27. Commonalities: • One chiral center • Aromatic ring • Side alkyl chain • Secondary hydroxyl group • Amine

28. DRUG AFFECTING CATECHOLAMINE STORAGE AND RELEASE • Reserpine is a prototypical drug affecting vesicle storage of NE in sympathetic neurons and neurons of the CNS. • Also of epinephrine of the adrenal medulla. • It also affect the storage of serotonin and dopamine in their respective neurons in the brain.

29. Agents that block adrenergic neurotransmitter synthesis and / or release. Reserpine,guanethidine, pargyline.

30. Mechanism of action: Interferes with the Mg2+- and ATP-dependent uptake of biogenic amines, • depleting NE, dopamine, and serotonin. • Reserpine decreases both cardiac output and PVR.

31. Rawolfia is an indole alkaloid obtained from the root of Rawolfia serpentina. • Other alkaloids possessing the same activity are deserpidine and rescinnamine.

32. Reserpine extremely binds tightly with the ATPdriven MOA transporter that transports NE and other biogenic amines from the cytoplasm to the storage vesicles. • This binding leads to a blockade of the transporter.

33. NE transported into the storage vesicle is metabolized by mitochondrial MAO in the cytoplasm. • There is a gradual loss of vesicle stored NE as it is used up by release resulting from sympathetic nerve activity.

34. Storage vesicles eventually become dysfunctional. • The end result is depletion of NE in the sympathetic neuron.

35. CATECHOLAMINE DEPLETORS-RESERPINE

36. Slow onset of action • Sustained effect (weeks) • Used in the treatment of hypertension • May precipitate depression • Both orally and parenterally.

37. Selective α2 AGONIST CLONIDINE(CATAPRESS) Phenyliminoimidazolidine derivative Antihypertensive effect followed by long lasting hypotensive effect. Stimulate α2receptors in brain. Decrease in peripheral resistance and B.P

38. Direct acting adrenergic receptor agonists:α2 receptors Clonidine (Catapres) Methyldopa (Aldomet) Guanabenz ( Wytensinr R Guanfacine (Tenex) Tizanidine (Zanaflex)

39. Chemical name:- N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine CLONIDINE R=H 4-HYDROXYCLONIDINE R=OH • Phenyl imino imidazoline derivtive that possess selective α2 adrenergic receptor • Antihypertensive agent.

40. Phenyliminoimidazolidine • Selective a2 receptor agonist • The basicity of the guanidine group (pKa = 13.6) is decreased (to pKa = 8.0) because of the attachment to the dichlorophenyl ring • Administration: Oral, parenteral, transdermal

41. Guanethidine(Ismelin) [2- (hexahydro-1H-azocinyl)ethyl]guanidine Guanidine act by interfering with adrenergic transmission.Attached to either an alicyclic or aromatic lipophilic ring

42. Uses: Hypertension, Vasodilation, increases venous capacitance. • Possess guanidino moiety (pKa > 12) They are essentially completely protonated. Do not get into the CNS. • Prevents NE release from sympathetic nerve terminals.

43. VASODILATORS • Drugs that act directly on the vascular smooth muscle, decreases vascular resistance and arterial B.P. • Hydralazine: Relax smooth muscle (SM) of arterioles (and sometimes veins).

44. Vasodilators • Types of vasodilators • Arteriodilators • reduce afterload • Venodilators • reduce preload • Mixed vasodilators

45. Moderate to severe hypertension. • Used in conjugation with hypertension and β blocker • 1-hydrazino-pthalazine.

46. Therapeutic use: • Hydralazine: Dilates arterioles but not veins. • Effect does not last long when used alone(tachyphylaxis); but combination therapy can be very effective for even severe hypertension.

47. Best effect is achieved when used together with β-blockers and loop diuretics.

48. USES: • Mild to moderate hypertension. • Topical use in baldness • Adverse Effects: • Due to vasodilatation: Reflex tachychardia, palpitation, may ↑ angina. Compensatory increase in fluid and electrolytes, edema (Better combine with β-blocker & diuretic)

49. Minoxidil (Loniten); • 2,4-diamino-6-piperidinopyramidine-3-oxide.

50. Minoxidil: Opens K+ channels in SM by its active metabolite, minoxidil sulfate, and stabilizes membrane at its resting potential. • Patients with renal failure and severe hypertension, who do not respond well to hydralazine, may be given minoxidil.