1. BLOOD PRESSURE AND HEART DRUGS Big money: >50 B$ / y~900,000 deaths/y in US 98% of heart attack victims have ATHEROSCLEROSIS (plaque build up in arteries) Latest theory is that inflammation promotes plaque deposits: excessive amounts of low density lipoprotein (LDL) in blood trigger this inflammation (see picture) plaque ruptures can initiate a blood clot and hence a stroke (picture)

3. CLOT plaque

4. The players: low density and high density lipoproteins

5. Lipoproteins transport cholesterol in bloodstream: LDL’s transport it FROM liver for use in membranes HDL’s transport it TO liver for recycling or excretion Excess LDL’s accumulate in artery walls and become oxidized: provokes inflammatory response and plaque buildup HDL’s help interfere with this oxidation Hence HDL is GOOD and too much LDL is BAD

6. RISK FACTORS: SMOKING HIGH BLOOD PRESSURE HIGH SATD FAT/CHOLESTEROL INTAKES HIGH STRESS BP = 120 / 80 at the beat / between beats >130/90 often NOW means fix it (Dave on medication 135/95) >150/110 fix it (Dave before medication 165/110) TREATMENT OF HIGH BP Lose weight Lose salt = DIURETICS, stimulates urine production, excrete Na + (sodium ions are part of the signal, less signal, less pumping!)

7. Furosemide (LASIX, URITOL, FUROSIDE, Novo-Semide) is common diuretic for BP in Canada Also very commonly used to treat ‘bleeders’ in horse racing

8.  -BLOCKERS (antagonists) (  -adrenergic blocking agents) Inhibit adenylcyclase enzyme: lowers c-AMP, reduces flow of Ca 2+ out of muscles = muscles relax less = smaller pumping action as the heart beats (cf  -agonists: VENTOLIN which activates this enzyme) ATENOLOL (Tenormin, 1988) apo-atenolol, novo-atenol (S)(-) enantiomer is active METOPROLOL [1978] apo-, novo- (Betaloc, Durules, Lopressor) PROPANOLOL [1967] apo-, novo- (Inderal)

9. CALCIUM CHANNEL BLOCKERS Reduces flow of Ca 2+ into and out of heart (in to causes contraction, out for relaxation): pumping action not as strong; also dilates coronary arteries In Canada: Amlodipine (Norvasc); Diltiazem; Felodipine; Flunarizine; Nifedipine; Nimodipine, Verapamil are used

10. ACE-INHIBITORS (Angiotensin converting enzyme inhibitor) most end in -pril: captopril, fosinopril, ramipril ACE produces angiotensin which causes coronary vasoconstriction which increases BP, so these relax the blood vessels and reduce pressure needed for flow Must not be used during pregnancy (2nd/3rd trimester, fetal death) Ramipril

11. CHOLESTEROL LOWERING DRUGS NORMAL 5.2 mmol/L HDL (high density lipoprotein) = good>1 mmol/L LDL (low density lipoprotein) = bad<3.4 mmol/L RATIO = TOTAL / HDL < 4.5 is good for LDL’s 3.4 = normal >4.2 = risk 2.6 mmol/L = great

12. Can reduce cholesterol by: a) FLUSH out BILE acids with cholestyramine resin (Questran) attraction Questrana bile acid Normally, bile acids carry fats and fatty acids into blood stream so they get absorbed and used resin binds to bile acids, excreted through intestines liver responds by converting CHOLESTEROL to bile acids

13. This reduces Cholesterol and LDL’s BUT need 30-55 g resin per day!! Gritty so mix with orange juice 30% lowering of cholesterol if you keep up the resin constipation is side effect 4 g sachet ~$1 so ~ $10/day

14. b) THE STATINS (75% of market) Liver makes cholesterol in a 27 step process!! The statin drugs inhibit the enzyme HMG-CoA [(3-hydroxy-3- methylglutaryl)-Coenzyme A], which synthesises MEVALONIC ACID, one of the intermediates in the synthesis: SHUTS DOWN CHOLESTEROL SYNTHESIS Since liver can’t make cholesterol, it responds by INCREASING the number of LDL receptors: more Cholesterol is picked up which reduces Cholesterol and LDL in the bloodstream Net Effect: CHOLESTEROL REDUCED, LDL REDUCED, HDL SAME

15. Merck’s LOVASTATIN was first (1970's): ~6 B$ market by ’96 replaced by their own ZOCOR, then Pfizer’s LIPITOR, Novartis’ LESCOL and Bristol-Myers-Sqibb’s PRAVACHOL (over) (Pravastatin)

16. CRESTOR (Rosuvastatin) from Astra Zeneca (2004) Lancet calls for removal after increases in muscle wasting and kidney failure - stay tuned Currently Lipitor ~$13B is the market leader of all drugs and this class accounts for >$35 B/y (all cholesterol and BP medications) Zocor generic in 2006, Lipitor generic in 2010 rosuvastatin

17. 2001: BAYCOL (cerivastatin) withdrawn by Bayer doctors prescribing it with GEMFIBROZIL (a non-statin type), DESPITE WARNINGS NOT TO = lead to muscle weakness, kidney failure 52 DEATHS worldwide; 1 in Canada 2006: Pfizer cancels torcetrapib – phase III trials to increase HDL’s (15,000 trial, 82 died; 51 died on Lipitor) c) NON-STATIN TYPES, GEMFIBROZIL = LOPID Decreases serum triglycerides (fats) CPS has clear warning about this + statins

18. CONTROLLING FAT : THE FEN-PHEN DIET (+)“Fen” [Redux] approved June 96; withdrawn Mar 97 (±) (racemate) used since 60's SSRI reduces desire to eat: can lose about 10% of initial weight Fatal heart valve problems: 150,000 Canadians in law suits; needed replacement heart valves FDA approved each separately BUT NEVER in combination

19. SSRI and noradrenaline RI (like Prozac) Can lose 5-10% weight in 6 months Approved 98, >1M on drug in US ($100/month) Basically appetite suppressant Warning: BP/heart rate increases Mentioned earlier: FDA warning as an illegal ingredient in some dietary supplements (Venon Hyperdrive) Many appetite suppresants: Newer one is Meridia (sibutramine)

20. Gastric and pancreatic lipase inhibitor stops breakdown of fats to fatty acids and monoglycerides for absorption reduces fat absorption by ~ 30 g/day BUT if you eat too much fat you get ‘anal leakage’ (YUCK!) Approved OTC in Feb 2007 (US) Xenical