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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