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)

CLOT

plaque

The players: low density and high density lipoproteins

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

RISK FACTORS: SMOKING HIGH BLOOD PRESSUREHIGH 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!)

Furosemide (LASIX, URITOL, FUROSIDE, Novo-Semide) is common diuretic for BP in Canada

H2NSO2

Cl

COOH

NHO

furosemide

Also very commonly used to treat ‘bleeders’ in horse racing

-BLOCKERS (antagonists) (-adrenergic blocking agents)

Inhibit adenylcyclase enzyme: lowers c-AMP, reduces flow of Ca2+ out of muscles = muscles relax less = smaller pumping action as the heart beats

(cf -agonists: VENTOLIN which activates this enzyme)

H2NCOCH2 O NH

OH

CH3OCH2CH2 O NH

OH

O NH

OH

ATENOLOL (Tenormin, 1988)apo-atenolol, novo-atenol(S)(-) enantiomer is active

METOPROLOL [1978]apo-, novo- (Betaloc, Durules, Lopressor)

PROPANOLOL [1967]apo-, novo- (Inderal)

CALCIUM CHANNEL BLOCKERS

Reduces flow of Ca2+ 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

MeO

MeO

CNN OMe

OMe.HCl

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)

NHN

H

H

COOHO O

Ramipril

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

Can reduce cholesterol by:a) FLUSH out BILE acids with cholestyramine resin (Questran)

Polystyrene

CH2NMe3+ Cl-

Polystyrene CONHCH2COO- Na+OH

OHHO

attraction

Questran a 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

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

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

O

OR

O

H

HO O

Lovastatin, R=H, [Mevacor]Simvastatin, R=Me, [Zocor]

N

OH

CO2NaHO

F

N

OH

CO2)2CaHO

F

PhPhNHCO

Fluvostatin Atorvastatin [Lipitor][Lescol]

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)

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

N

CH3COCOONa

OHOH

F

cerivastatin

NaOOC

HO

O

HO

H

H

OH

O

pravastatinrosuvastatin

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

OCOOH

Decreases serum triglycerides (fats)

CPS has clear warning about this + statins

CONTROLLING FAT : THE FEN-PHEN DIET

NHEt

CF3

NH2

Fenfluramine Phentermine

(+)“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

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 suppressantWarning: BP/heart rate increases

Mentioned earlier: FDA warning as an illegal ingredient in some dietary supplements (Venon Hyperdrive)

Cl

NMe2

SIBUTRAMINE(Meridia)

Many appetite suppresants:Newer one is Meridia (sibutramine)

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)

O

O

NHCHO

C8H17

OO

C6H13

ORLISTAT(Xenical)

Xenical