PM716 C11 Antihypertensives Slides PDF

PM 716 Pharmacology I Chapter 11 Antihypertensives RMRocco, PhD PM716 C11 Antihypertensives 1  Case Study 35 year old male, BP 150/95 mm Hg, drinks alcohol, sedentary, does not smoke. Family history of hypertension, patient is moderately obese. Total chole...

PM 716 Pharmacology I Chapter 11 Antihypertensives RMRocco, PhD PM716 C11 Antihypertensives 1  Case Study 35 year old male, BP 150/95 mm Hg, drinks alcohol, sedentary, does not smoke. Family history of hypertension, patient is moderately obese. Total cholesteorl is 220 mg/dL, HDL is 40 mg/dL, FBS is 105 mg/dL. How to treat? PM716 C11 Antihypertensives 2  Case Study Patient is Stage 1 hypertension (Table 11-1) Try behavior first:diet, exercise, reduced alcohol consumption. Low dose thiazide diuretic to start. Follow for a few months, evaluate then add a second drug if required, a calcium channel blocker or an ACE inhibitor. PM716 C11 Antihypertensives 3  Hypertension Normal BP is defined as 120/80 mmHg Hypertension is considered BP of 140/90 or higher. Diastolic blood pressure (DBP) used to stage hypertension Mild DBP 90 - 104 mmHg Moderate DBP 105-114 mmHg Severe DBP > 115 mmHg PM716 C11 Antihypertensives 4 Chapter 11 Antihyperintensive Agents PM716 C11 Antihypertensives 5 © The McGraw-Hill Companies, Inc,  Hypertension PRIMARY Over 95% of all hypertension (formally called essential). Cause unknown. 27% of US population has high BP. SECONDARY Less than 5% of total. Caused by specific disorder in a control mechanism for BP (renin system, tumors etc etc). PM716 C11 Antihypertensives 6  Hypertension Essential hypertension leads to: renal failure coronary disease cardiac failure stroke BP = cardiac output (peripheral resistance) PM716 C11 Antihypertensives 7  Aims of Drug Treatment of Hypertension (1) Diuretics: restrict dietary sodium intake, reduce blood volume (remove water). (2) Sympatholytics: reduce peripheral resistance. (3) Direct vasodilation: relax smooth muscle. (4) Block or decerease Angio II production. PM716 C11 Antihypertensives 8  Blood Pressure Home blood pressure monitors help eliminate “white-coat” hypertension and helps prevent unnecessary treatment. 20% of patients with elevated blood pressure have “white- coat” hypertension. PM716 C11 Antihypertensives 9 Staging of Primary Hypertension Stage 1 diastolic BP 90 - 99 Stage 2 100 - 109 Stage 3 > 110 Lowering diastolic BP by 5 - 6 mmHg reduces the risk of stroke by 40%, risk of coronary disease by 16%, risk of death from any cardiovascular cause by 20%. PM716 C11 Antihypertensives 10  Antihypertensive Drugs Diuretics: lower blood volume Sympathoplegics: block CNS output Direct Vasodilators: relax smooth muscles Block Angiotensin: decrease Angio II production PM716 C11 Antihypertensives 11  Drug Treatment Drug treatment of hypertenison lowers BP by 10 - 15%. Monotherapy is effective in about 50% of patients (although two drugs at low doses may produce less side effects compared to one drug at conventional higher doses). Stage 2 and 3 hypertension patient’s require polydrug therapy. PM716 C11 Antihypertensives 12  Drugs Alter water and sodium diuretics Alter sympathetic outflow methyldopa clonidine Adrenergic neuron-blocking drugs guanethidine reserpine PM716 C11 Antihypertensives 13  Drugs Adrenoceptor antagonists (alpha 1 blockers) prazosin Beta Adrenoceptor Blockers metoprolol bisoprolol labetalol nadolol pindolol carvedilol atenolol acebutolol propranolol betazolol penbutolol PM716 C11 Antihypertensives 14  Drugs Calcium channel blockers verapamil dilitazem ACE inhibitors captopril enalapril ANG II receptor blockers losartan candesartan irbesartan valsartan eprosartan telmisartan PM716 C11 Antihypertensives 15  Drugs Vasodilators hydralazine minoxidil sodium nitroprusside fenoldopam PM716 C11 Antihypertensives 16  Diuretics Lower BP by reducing blood volume. Diet restriction of sodium lowers BP Diuretics depletes sodium stores in the body. Most often used thiazides (hydrochlorothiazide) and the loop diuretics (furosemide) Thiazides used in mild hypertension. Loop diuretics used in all other forms. Katzung Chapter 15 on Diuretics PM716 C11 Antihypertensives 17  Alter Sympathetic Outflow Drugs cause reduction in venous tone, heart rate, contractile force of the heart, cardiac output, total peripheral resistance. Clonidine and methyldopa are alpha 2 selective agonists. Agonist (stimulation) of alpha 2 in CNS causes decrease in sympathetic outflow. PM716 C11 Antihypertensives 18 Alter Sympathetic Outflow methyldopa (prodrug) clonidine converted in CNS methylnorepinephrine PM716 C11 Antihypertensives 19  Methyldopa (Aldomet®) Methyldopa converted in the CNS neuron into alpha-methylnorepinephrine (MNE) which is stored within neuron synaptic granules. When neuron fires MNE is released instead of NE, which acts as an agonist at presynaptic alpha 2 neurons. Stimulation of presynaptic alpha 2 neurons inhibits release of NE and decreases adrenergic outflow to the PNS. Actions of clonidine are similar. PM716 C11 Antihypertensives 20  Methyldopa ADRs include Induction of Parkinson-like symptoms due to depletion of NE stores. CNS effects include sedation, mental lassitude, impaired mental concentration. PM716 C11 Antihypertensives 21 Clonidine (Catapres®) Activates (agonist) at Alpha 2 receptors in the CNS and PNS. (1) CNS: Causes decrease in sympathetic outflow and blocks stimulation of the heart. (2) PNS: Activates presynaptic Alpha 2 receptors on nerve endings and inhibits release of NE (blocks vasoconstriction). PM716 C11 Antihypertensives 22  Adrenergic-Blocking Drugs Nicotinic blockers (Ach) are too toxic for routine clinical use (hexamethonium, Johns Hopkins) Postganglionic Sympathetic Blockers NE depleted by reserpine NE stores blocked from release by guanethidine. PM716 C11 Antihypertensives 23 Reserpine First drug that was found to interfere with the function of the sympathetic nervous system. Its use began the modern era of treating hypertension. Drug isolated from Indian Rauwolfia serpentina plants. Reserpine binds to synaptic vesicles and blocks uptake of NE which causes depletion. No NE available for release. PM716 C11 Antihypertensives 24  Guanethidine Replaces NE in storage vesicles. Drug does not cross BBB, results in no CNS ADRs. Peripheral effects include postural hypotension, diarrhea. PM716 C11 Antihypertensives 25  Adrenergic Blocking Drugs These drugs cause major sodium retention. Major side effect (ADR) with reserpine is depression (biogenic amine hypothesis of depression, drug depletes NE stores, K Chapter 30). PM716 C11 Antihypertensives 26  Adrenoceptor Antagonists Alpha 1 selective blockers (prazosin) Alpha 1 blockers reduce vascular resistance. Nonselective alpha blockers not used because of excess compensatory response (tachycardia). K Chapter 10 PM716 C11 Antihypertensives 27 Prazosin (Minipres®) Drug blocks alpha 1 receptors in the arterioles and veins. Peripheral vascular resistance falls and BP falls. Drug may also reduce sympathetic outflow in the CNS. PM716 C11 Antihypertensives 28  Beta Blockers Beta blockers (propranolol) reduce cardiac output and decrease vascular resistance. Beta blockers also reduce renin release from kidney which reduces levels of the hypertensive Angio II. K Chapter 10 PM716 C11 Antihypertensives 29  Beta Blockers Propranolol: non selective (Beta 1 and 2). Wide range of CNS effects due to passage into the brain. Sleep disorders, impotence etc. Metoprolol: Beta1 selective (heart). 50-100 fold less affinity for beta2 (lung) receptors. Good choice drug for patients with asthma. PM716 C11 Antihypertensives 30 NE Receptors PM716 C11 Antihypertensives 31  Vasodilators Oral Vasodilators: hydralazine minoxidil Parenteral Vasodilators: nitroprusside diazoxide fenoldopam PM716 C11 Antihypertensives 32  Vasodilators Drugs dilate the blood vessels by acting directly on the smooth muscle cells through nonautonomic mechanisms: (1) Release of Nitric Oxide (NO) (2) Hyperpolarization by opening potassium channels (3) Block calcium channels (4) Activate dopamine (D1) receptors. PM716 C11 Antihypertensives 33  Vasodilators Hydralazine: Release NO from endothelial cells Hydralazine’s mechanism of action Toxic in high doses (tachycardia, salt retetion, lupus erythematosus) dilates arterioles, not veins. Less toxic at < 200 mg/d PM716 C11 Antihypertensives 34  Vasodilators Minoxidil: Opens potassium channels in smooth muscle. hyperpolarized cell is relaxed Minoxidil is a prodrug converted to minoxidil sulfate which binds to potassium channels. Dilates arterioles not veins. PM716 C11 Antihypertensives 35  Vasodilators Calcium Channel Blockers nifedipine, verapamil, diltiazem cause vasodilation K Chap 12 Nitroprusside IV drug used to lower BP in emergencies Direct source of NO PM716 C11 Antihypertensives 36  CCB All block voltage gated L-Type calcium channels in cardiac smooth muscle. PM716 C11 Antihypertensives 37  CCB CCBs block influx of Ca++ and muscle will not fire. L-Channels not found on neurons. (1) Ca++ flows into muscle and binds to calmodulin. (2) Ca-Calmodulin activates myosin-light-chain kinase (MLCK) enzyme (3) MLCK phosphorylates myosin light chain (MLC) (4) Phosphorylated MLC forms cross bridges with actin and muscle fires. PM716 C11 Antihypertensives 38  Nitroprusside Within smooth muscle drug becomes denitrated which releases NO. NO stimulates guanylyl cyclase which increase cGMP. Increased cGMP dephosphorylates mysoin light chains (dephosphorylation causes inactivation of myosin). Muscle relaxes. PM716 C11 Antihypertensives 39 Nitroprusside Used since 1929 to lower blood pressure. Drug acts through release of NO which causes vasodilation. Metabolism releases cyanide mitochondrial rhodanase converts cyanide to thiocyanate which is cleared by the kidney. Dilates both venous and artery vessels. PM716 C11 Antihypertensives 40  Vasodilators Fenoldopam Dopamine D1 receptor agonist results in arterial vasodilation iv only, used for hypertensive crisis PM716 C11 Antihypertensives 41  ACE Inhibitors Captopril, enalapril block the enzyme ACE which lowers Angiotensin II levels and aldosterone levels. PM716 C11 Antihypertensives 42  ACE Inhibitors Reduced renal arterial pressure causes release of renin (an enzyme) by the kidney. Renin converts angiotensinogen (a polypeptide) into Angiotensin I (inactive Ang I) Ang I converted by angiotensin converting enzyme (ACE) in vascular tissue to Ang II. Ang II is 40x more potent vasoconstrictor than NE. Aminopeptidase enzyme converts Ang II to inactive fragments. PM716 C11 Antihypertensives 43 Chapter 11 Antihyperintensive Agents PM716 C11 Antihypertensives 44 © The McGraw-Hill Companies, Inc,  Renin Angio System Angio II Vasoconstriction Aldosterone Secretion Increased peripheral Increased Na+ and H2O resistance retention Increased BP PM716 C11 Antihypertensives 45  ACE Inhibitors captopril (Capoten®) enalapril (Vasotec®) benazepril (Lotensin®) Typical doses 6 - 150 mg tablets 2-3 times per day. PM716 C11 Antihypertensives 46  ACE Inhibitors 30% of patients develop a cough Renal damage to the fetus (never to be used in pregnancy). PM716 C11 Antihypertensives 47  Angiotensin Antagonists Block Angio II formation (ACE inhibitors) A second class of drugs used in CHF which are antagonistic to the renin-angiotensin system. Block Angio II receptor (receptor blockers) PM716 C11 Antihypertensives 48  Angio II Receptor Blockers Also called angiotensin II type-I receptor blockers (ARB) Losartin and other analogs block the receptor for Angio II. Same clinical effects as ACE inhibitors with a lower incidence of cough. Still cause fetal kidney damage and must never be used in pregnancy. PM716 C11 Antihypertensives 49  Ang II Receptor Blockers angiotensinogen renin Ang I Ang II receptor ACE Ang II PM716 C11 Antihypertensives 50  BNP Agonist Brain natriuretic peptide (BNP) are naturally occurring peptide hormone synthesized in the ventricles. 32 amino acid ring structure. Atrial natriuretic peptide (ANP) 28 amino acid peptide hormone synthesized in the atria. PM716 C11 Antihypertensives 51  BNP Both BNP and ANP act to counter balance the renin-angiotensin-aldosterone system which raises BP. BNP as the drug nesiritide (Natrecor®) used as a slow iv drip to lower BP. PM716 C11 Antihypertensives 52  BNP High Arterial Pressure BNP/ANP Release vasoconstriction Na+/H2O loss Na+/H2O retention vasodilationrenin/aldosterone release Low Arterial Pressure PM716 C11 Antihypertensives 53 PM716 C11 Antihypertensives 54  BiDil® The first drug FDA approved for one particular ethnic group. A combination drug containing Isosorbide (Isordil®) Hydralazine (Apresoline®) Both antihypertensive drugs released over twenty-five years ago. PM716 C11 Antihypertensives 55  BiDil Isosorbide a direct acting source of nitric oxide (NO) with potent vasodilation actions. Drug enhances NO production in blood vessels. PM716 C11 Antihypertensives 56  BiDil 750 000 African Americans (AA) with hypertension and heart failure. Group has higher rate of cardiovascular disease compared to whites. ACE inhibitors are first drugs of choice in whites often as monotherapy appear to not work as well in AA. AA appear to hve a much less active renin- angiotensin system compared to whites. PM716 C11 Antihypertensives 57  BiDil A large clinical trial with hypertensive patients in the 1980’s using (1) ACE inhibitors, or (2) beta blockers or (3) hydralazine and isosorbide demonstrated no significance between the three treatment protocols. Dr. Jay Cohn examined the data, found that the few AA patients in the trial improved significantly with the vasodilator combination (hydralazine and isosorbide) and filed a patent on the combination. Patent issued 1989. PM716 C11 Antihypertensives 58  BiDil Genetic polymorphism in the MSD720 gene in AA results in less NO production in blood vessels. AA patients do not benefit from ACE inhibitors (compared to whites). PM716 C11 Antihypertensives 59  BiDil Hydralazine dilates blood vessels through release of NO from endothelial cells. PM716 C11 Antihypertensives 60  Patient Compliance Osterberg, L. and Blaschke, T. Adherence to medication New Eng J. Med 353(5):487-497 (2005) August 4 PM716 C11 Antihypertensives 61  Compliance Adherence rates higher in patients with acute vs chronic conditions. Chronic condition patients report 43 - 78% adherence rates. 33-69% of all drug related hospital admissions in US related to poor compliance at a cost of $100 billion/year. PM716 C11 Antihypertensives 62  Compliance Direct measure of monitoring: ask the patient. Indirect measure of compliance: count pills count prescription refills (at pharmacy) electronic medication monitors have patient keep diary use nurses, family to administer the medication PM716 C11 Antihypertensives 63 Electronic Medication Monitor Electronic devices count pills as they are removed from the box. No proof that the pill was taken. Cost of devices not covered by insurance. Not widely used. PM716 C11 Antihypertensives 64  Compliance “white-coat adherence” is when patient takes medication correctly for the five days before a doctor’s appointment. PM716 C11 Antihypertensives 65  Compliance The 1/6th Rule: 1. perfect adherence 2. some timing irregularity 3. occasional single day’s dose missed 4. take drug holiday 3-4 times a year 5. take drug holiday once per month. 6. take none of the dose (but say they do). PM716 C11 Antihypertensives 66 Compliance PM716 C11 Antihypertensives 67  Patient Compliance NY Times March 11, 2006 article on patient compliance. Results of a survey of 9 290 patients: (1) 26% delayed filling prescriptions (2) 18% did not fill prescriptions (3) 14% took smaller doses than prescribed (4) 30% took prescription less often than required (5) 21% stopped drugs sooner than prescribed. PM716 C11 Antihypertensives 68  Patient Compliance Reasons cited by patients for noncompliance (1) 24% forgot to take drugs or forgot to get prescription refilled. (2) 20% wanted to avoid the side effects. (3) 17% claimed the high cost of drugs made full compliance difficult. (4) 14% were not convinced that the drug was really needed. (5) 10% claimed that they had no one to get prescriptions filled or picked up. PM716 C11 Antihypertensives 69  Summary I (1) Alter water and sodium (diuretics) (2) Alter sympathetic outflow (clonidine, methydopa) (3) Adrenergic neuron blockers (guanethidine) (4) Alpha1 blockers (prazosin) (5) Beta blockers (metoprolol, propranolol) PM716 C11 Antihypertensives 70  Summary II (6) Vasodilators (hydralazine) (7) Ca++ channel blockers (verapamil) (8) ACE inhibitors (captopril) (9) ANG II receptor blockers (losartan) (10) BNP agonist (nesiritide) (11) BiDil (isosorbide/hydralazine) (12) Patient compliance. PM716 C11 Antihypertensives 71