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DRUG THERAPY FOR HYPERCHOLESTEREMIA AND DYSLIPIDEMIA
Name the 6 Statins
Mevastatin, Lovastatin, Simvastatin, Pravastatin, Fluvostatin and Atorvastatin
Mevastatin

Mechanism
competition with HMG -CoA to prevent mevalonate synthesis, resulting in decrease of cholesterol synthesis and upregulation of LDL receptors.
Levastatin

Mechanism
competition with HMG -CoA to prevent mevalonate synthesis, resulting in decrease of cholesterol synthesis and upregulation of LDL receptors.
Simvastatin

Mechanism
competition with HMG -CoA to prevent mevalonate synthesis, resulting in decrease of cholesterol synthesis and upregulation of LDL receptors.
Pravastatin

Mechanism
competition with HMG -CoA to prevent mevalonate synthesis, resulting in decrease of cholesterol synthesis and upregulation of LDL receptors.competition with HMG -CoA to prevent mevalonate synthesis, resulting in decrease of cholesterol synthesis and upregulation of LDL receptors.
Fluvostatin

Mechanism
competition with HMG -CoA to prevent mevalonate synthesis, resulting in decrease of cholesterol synthesis and upregulation of LDL receptors.competition with HMG -CoA to prevent mevalonate synthesis, resulting in decrease of cholesterol synthesis and upregulation of LDL receptors.
Atorvastatin

Mechanism
competition with HMG -CoA to prevent mevalonate synthesis, resulting in decrease of cholesterol synthesis and upregulation of LDL receptors.competition with HMG -CoA to prevent mevalonate synthesis, resulting in decrease of cholesterol synthesis and upregulation of LDL receptors.
long-lasting statins:
atorvastatin and rosuvastatin single daily dose
short-lived statins
Lovastatin, Simvastatin, Pravastatin
Statins majority administered as active compounds except...
simvastatin
lovastatin
Statins:Adverse effects: myopathies
is the major adverse effect
characterized by intense myalgia which progresses with the use of statin.
serum creatin kinase levels 10x
risk of mypoathic symptoms is greatly increased by association of other lipid lowering drugs like the fibrates (gemfibrozil) and other drugs inhibiting the activities of P450 isoezymes. Therefore: association with fibrates, antibiotics (erythromycin, cyclosporine), antifungals (itraconazole) and HIV protease inhibitors should be avoided or use with extreme caution.
Statins: Adverse effects
Hepatotoxicity

contraindicated:
all statins induce dose related enhancement of hepatic transaminases in 1-3% of the patients.
Contraindicated:patients with active liver disease. Extra-care must be taken in treatment of individuals with heavy drinking history. Statins should be not taken with grapefruit juice
Statins: Adverse effects
Pregnancy
oral contraceptives
Don't know
Future pregos shouldn't take statins

oral contraceptives, as estrogens tend to increase the HDL and decrease the LDL
progestins opposite effects
Statins: Adverse effects
Children
atorvastatin, lovastatin and simvastatin  children > 11 years, provastatin  children age 8 or older.
Statins: Adverse effects
Statins and Cancer risk
Don't know
Niacin (Nicotinic Acid)
what is it?
Therapeutic dose?
Does What?
Water-soluble B vitamin complex. requires mega doses
Best agent available to increase HDL levels (30-40%).
Decrease triglyceride levels (35-45%). Reduce LDL levels (20-30%)
Niacin 

Mechanism?
liver: inhibiting synthesis and esterification of free fatty acids. Reduction in FFA leads to decrease VLDL production and LDL levels. -
Niacin

Admistration
Administration: - crystalline niacin (immediate release): available over the counter; best tolerated when starting with low doses (100 mg twice daily) and increased stepwise to 1.5-2 g/daily. - sustained release niacin: allows continuous release of the drug for 6-8 hours after ingestion. - extended-release niacin: requires prescription and is less hepatotoxic.
Niacin


Absorption

Absorption: Peak plasma concentration occurs 30-60 minutes after administration for the regular nyacin. Sustained-release niacin was developed to lessen the side effects
Niacin Adverse effects

name 5 things affected
Digestive tract
Cutaneous effects
Pregnancy
Hepatotoxycity
Hyperglycemia
Niacin: Adverse effects

Digestive tract
Digestive tract: dyspesia which is accentuated by coffee, tea or alcohol. It is reduced when the drug is administered after a meal. Niacin must be avoided in patients with antecedents of peptic ulcer.
Niacin: Adverse effects

Cutaneous effects:
Cutaneous effects: flushing and pruritus. Are prostaglandin mediated and can be prevented by aspirin
Niacin: Adverse effects

Pregnancy
Pregnancy: at doses used in humans, niacin induced birth defects in experimental animals and should be not taken by pregnant women.
Niacin: Adverse effects

Hepatotoxycity
Hepatotoxycity: elevated transaminases.
Niacin: Adverse effects

Hyperglycemia
Hyperglycemia: limits the use of niacin in patients with diabetes. Elevates uric acid levels and may reactivate gout.
Statin Niacin combo caveat
Both niacin and statins are causing myopathy and thus when used in combination the statin should be administered at no more of 25% of its maximal dose and the treatment should be discontinued at first signs of muscle pain.
Bile-acid sequestrants (Resins)

Biography
oldest, safest lipid lowering agents
Maximal doses may reduce LDL-C by up to 25% but are associated with side effects (constipation and bloating) which limit their use.
Bile-acid sequestrants: drug interaction
bind directly and may interfere with the absorption of many drugs, including statins
Bile-acid sequestrants (Resins)

Mechanism
Highly positively charged anion exchange resins that bind negatively charged bile acids. Due to their large size, the resins are not absorbed and arrest the bile acids. The resulted enhancement in the bile acid synthesis depletes the hepatic cholesterol content and upregulates LDL receptors, but also increase the triglyceride synthesis.
Bile-acid sequestrants Adverse Effects
constipation and bloating
Bile-acid sequestrants

administration
It is safe to recommend administration of other drugs one hour before or 3-4 hours after a dose of bileacid sequestrant. - resins are recommended for patients 11-20 years old and should be taken before eating. - administered as bulk (4-5 g/dose).
Fibric Acid Derivatives

Mechanism
Bind to peroxisome proliferator activated receptors (PPAR) and stimulate β-oxidation of fatty acids. Strongest agent to decrease triglycerides levels.
Fibric Acid Derivatives
Fibric Acid Derivatives

Administration
Clofibrate: 2g/day; Gemfibrozil: 600 mg twice daily. Fenofibrate: 145 or 200 mg/day
Fibric Acid Derivatives

recommended for who?
contra for who?
type III hyperlipoproteinemia severe hypertriglyceridemia
type II diabetes or metabolic syndrome
Should not be used by children or pregnant women
Fibric Acid Derivatives

beneficial effects aside from lipid lowering
antithrombotic
immunomodulation
antiinfllamatory actions
Inhibition of dietary cholesterol uptake: Ezetimibe

Mechanism
Specifically blocks the function of Niemann-Pick C1–like 1 (NPC1L1) protein, a newly identified sterol influx transporter, facilitating cholesterol absorption. The compensatory increase in the endogenous cholesterol synthesis is prevented by use of statins
Ezetimibe

Administration
20 mg/daily reduces the LDL levels by 15-20%. It is recommended as combinatorial therapy with statins (VYTORIN). Bile acid sequestrants inhibit ezetimibe absorption and should not be combined.
Ezetimibe: adverse effects
increase in cancer
fetal abnormalities
Therapeutic combinations of lipid lowering agents
Statins + Niacin - enhances the effects of statins but also increases the risk of myopathies. Statins + Bile-acid sequestrants – enhances the effects of statins on the LDL-C levels by 20-30%. Triple combinatory therapy (statins, resins, niacin) reduce LDL-C up to 70%. VYTORIN (combination of simvastatin with ezetimibe) decrease the LDL-C levels by 60 % after 24 weeks.
Pharmacological basis of the treatment of angina
Angina Pectoris: definition
Angina pectoris (latin): chest pain due to inadequate delivery of oxygen to the cardiac muscle. Characterized by periodic episodes of severe oppressive Angina Pectoris: definition substernal pain. Most frequent pathologic cause is coronary artery spasm leading to compromised blood flow and oxygen supply to a region of the myocardium Precipitating factors: exercise, emotional stress, cold, meals, posture, smoking, or drugs. Results from ischemia (hypoxia) of the myocardium.
Ischemia
definition
Ischemia: deficient supply of blood to a body part (as the heart or brain) that is due to obstruction of the inflow of arterial blood (because of the narrowing of arteries by spasm or disease).
Ischemia

pain or no pain?
which arm?
what causes the pain?
- In some individuals the ischemia is not accompanied by pain (silent angina) - In severe cases the pain migrates to the left arm. - The pain is caused by accumulation of metabolites in the myocardium.
Factors controlling coronary circulation are:
1. Arterial pressure 2. Cardiac cycle. Flow occurs mainly during diastole, much less during systole. Increase in heart rate reduces diastolic interval relative to systolic reducing coronary flow. 3. Direct sensitivity of arterioles to anaerobic metabolites (adenosine and ADP).
Angina is caused by the reduced coronary flow due to:
(a) atherosclerotic occlusion (the commonest cause) or
(b) coronary artery spasm (variant angina).
Relationship btwn MI and Anginal pain
MI  much higher in patients who are prone to angina attacks.
Types of Angina

Name 3 types
Stable Angina: Effort/ExertionalAngina
Variant Angina (Prinzmetal angina)
Unstable Angina
Stable Angina: (Effort/ExertionalAngina)
chronic stable angina pectoris -exertional myocardial oxygen demand > oxygen supply most common form of ischemic heart disease Cause: coronary artery occlusion (atherosclerosis or stenosis)
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