Pharm Exam 1 Post-cardio Flashcards
Statins
- Drugs of choice for LDLreduction.
- Reduce cardiovascular mortality.
- Lower LDLlevels in all types of hyperlipidemias.
- Homozygotes for familial hypercholesterolemia lack functional LDL receptors and thus benefit much less from treatment with statins.
- Contraindicated in pregnancy.
OTHER EFFECTS
• Improve endothelial function.
• Decrease platelet aggregation
• Reduce inflammation.
• Decrease plasma levels of C-reactive protein.
ADVERSE
• Elevation of aminotransferases. Usually not associated with other evidence of liver toxicity.
• Myopathy and rhabdomyolysis. Rare.
• Creatine kinase levels should be determined
regularly.
• Rhabdomyolysis may cause myoglobinuria, leading to renal injury.
Niacin (nicotinic acid)
- Niacin favorably affects virtually all lipid parameters.
- Decreases VLDL, LDL and Lp(a) levels.
- It often increases HDL levels significantly.
- Niacin is the most effective agent for increasing HDL and the only agent that may reduce Lp(a).
MOA
• Activates Gi protein -> decreased cAMP -> decreased TAG lipase inactive
• Blocks hormone sensitive lipase -> decreased plasma free fatty acids
• Decreased TAG and FA synthesis -> decreased VLDL and LDL
• Stimulates lipoprotein lipase
• The catabolic rate for HDL is decreased -> HDL increases.
ADVERSE
• Intense cutaneous flush after each dose of niacin when the drug is started or the dose increased.
• Administration of aspirin prior to niacin decreases the flush, which is prostaglandin- mediated.
• Pruritus, rashes, dry skin and acanthosis nigricans.
• Hepatotoxicity is manifested as elevated serum transaminases.
• Niacin should be used cautiously in patients with diabetes mellitus, since niacin-induced insulin resistance can cause severe hyperglycemia.
• Niacin elevates uric acid levels and may precipitate gout.
Gemfibrozil Fenofibrate
- Fibrates lower VLDL levels and increase HDL levels.
- Fibrates activate peroxisome proliferator- activated receptor-a (PPAR-a).
- PPAR-a receptors are expressed primarily in liver and brown adipose tissue.
- Activation of PPAR-a by fibrates leads to a decrease in plasma TG levels and increase in plasma HDL levels.
- Only modest reductions of LDL occur in most patients.
- In patients with combined hyperlipidemia, LDL often increases as TGs are reduced.
- HDL increases moderately.
USES
• Hypertryglyceridemias and dysbetalipoproteinemia.
ADVERSE
• Mild GI disturbances.
• Myositis. Patients with renal insufficiency may be at risk. Rhabdomyolysis has occurred rarely.
• Lithiasis. Fibrates increase biliary cholesterol excretion, therefore they may cause gallstones.
Cholestyramine Colestipol Colesevelam
- Useful only in hyperlipidemias involving isolated increases in LDL.
- In patients who have hypertriglyceridemiaas well as elevated LDL levels, VLDL levels may increase.
- Bind to anionic bile acids in the intestinal lumen and prevent their reabsorption
- Up-regulation of LDL receptors in the liver.
- Liver uptake of LDLincreases, leading to a decrease in plasma LDL levels.
- HDL rises modestly.
USES
• Used with statins or niacin to increase LDL reduction.
• Drugs of choice for pregnant women and for children.
ADVERSE
• GI adverse effects: bloating, nausea, cramping and constipation.
• Colesevelam produces fewer GI adverse effects than cholestyramine or colestipol.
• They may increase TGs: contraindicated in hypertryglyceridemia.
• Cholestyramine and colestipol reduce absorption of several drugs and liposoluble vitamins.
Ezetimibe
- Inhibits intestinal absorption of cholesterol and phytosterols.
- Its primary clinical effect is to lower LDL.
- It also causes small increases in HDL and a mild decrease in TGs.
- Cholesterol synthesis increases.
- There is a decrease in the incorporation of cholesterol into chylomicrons. Less cholesterol is delivered to the liver by chylomicron remnants.
- This leads to upregulation of LDL receptors, enhancing LDL clearance from plasma.
Complementary to statins
ADVERSE
• Low incidence of reversible impaired hepatic function.
• Small increase in incidence when ezetimibe is given with a statin.
• Myositis has been reported rarely.
Eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)
- w-3 fatty acids. Reduce TG biosynthesis and increase fatty acid oxidation in the liver.
- With long-term intake, they may increase HDL.
- w-3 fatty acids may increase total LDL as they lower TAG levels.
Lovaza
- FDA-approved w-3 product. Ethyl esters of w-3 fatty acids.
- Adjunct to diet to reduce TG levels in adult patients with very high (> 500 mg/dL) TG levels.
Antihyperlipidemic drugs in pregnancy
- Statins: absolutely contraindicated in pregnancy. Category X.
- Fibrates: Category C.
- Niacin: Category C.
- Ezetimibe: Category C.
- Cholestyramine & colestipol: might interfere with absorption of nutrients. Category C.
- Colesevelam: Category B. Should be used during pregnancy only if clearly needed.
Aspirin
- Aspirin inhibits TXA2 synthesis by irreversible acetylation of the enzyme COX.
- The anuclear platelet can’t synthesize new proteins.
- Therefore it can’t synthesise new enzyme during its 10-day lifetime.
USES
• Prophylactic treatment of transient cerebral ischemia
• To reduce the incidence of recurrent MI
• To decrease mortality in post MI patients.
Clopidogrel Ticlopidine
• Irreversible inhibitors of P2Y12, one of the two
subtypes of ADP receptor on the platelet surface.
• Clopidogrel has fewer adverse effects than ticlopidine.
• Clopidogrel is preferred over ticlopidine.
USES
• Indicated to reduce the rate of stroke, MI, and death in patients with recent MI or stroke or acute coronary syndrome.
- Clopidogrel is a prodrug converted to an active metabolite, mainly by CYP2C19.
- Alternative treatments should be considered for CYP2C19 poor metabolizers
- Concomitant use of clopidogrel and CYP2C19 inhibitors should be avoided.
- Omeprazole, a CYP2C19 inhibitor, reduces plasma levels of the active metabolite of clopidogrel.
- Concurrent use of clopidogrel and omeprazole should be avoided.
Dipyridamole
- PDE inhibitor. Coronary vasodilator.
- Used to prophylactically treat angina pectoris.
USES
• Dipyridamole by itself has little beneficial effect.
• Used in combination with warfarin or aspirin.
Abciximab Eptifibatide Tirofiban
ABCIXIMAB
• Monoclonal antibody against the GPIIb/IIIa receptor.
EPTIFIBATIDE
• Cyclic peptide reversible antagonist of the GPIIb/IIIa receptor.
TIROFIBAN
• Nonpeptide reversible antagonist of the GPIIb/IIIa receptor.
Heparin
MOA
• Antithrombin III inhibits serine proteases, including several of the clotting factors, eg thrombin.
• In the absence of heparin, antithrombin III inhibitis thrombin very slowly.
• Binding of heparin to antithrombin III accelerates inhibition of thrombin.
MONITORING
• Monitoring is performed with the activated partial thromboplastin time (aPTT) assay.
• The aPTT is a test of the integrity of the intrinsic and common pathways of coagulation.
• Dosing of LMWH results in predictable plasma levels.
• It is not usually necessary to monitor LMWH blood levels.
USES
• DVT
• Pulmonary embolism
• MI
• DOC during pregnancy
ADVERSE
• Bleeding
• Hypersensitivity reactions
• Heparin-induced Thrombocytopenia (HIT)
Heparin-induced thrombocytopenia type II
• Antibodies recognize complexes of heparin and a platelet protein, Platelet Factor 4.
• This leads to platelet aggregation and release of platelet contents.
• This can result in thrombocytopenia and thrombosis that can be life-threatening.
• Therapy: Discontinuance of heparin and administration of a DTI or fondaparinux.
REVERSAL OF HEPARIN
• Excessive anticoagulant action of heparinis treated by discontinuance of the drug.
• If bleeding occurs, protamine sulfate is given.
LMWH
- Heterogeneous compounds produced by chemical or enzymatic depolymerization of UFH.
- LMWH inhibit Xa but have less effect on thrombin than UFH. (Ternary complex not needed to accelerate ATIII inhibition of Xa, but is needed for thrombin)
- LMWH have equal efficacy to UFH, higher bioavailability, longer half-life, and less frequent dosing requirements.
- LMWH are replacing UFH in many clinical situations.
Fondaparinux
- Selective Xa inhibitor. Sequence of five carbohydrates that bind to antithrombin III.
- Negligible antithrombin activity.
- Approved for prevention and treatment of DVT.
Lepirudin Bivalirudin Argotroban
- Hirudin is a specific thrombin inhibitor from the leech.
- Available in recombinant form as lepirudin.
- Its action is independent from antithrombin III, therefore lepirudin can inactivate fibrin-bound thrombin in thrombi.
- Given parenterally.
- No antidote exists.
• Monitored by the aPTT.
BIVALIRUDIN
• Synthetic derivative of hirudin.
ARGATROBAN
• Small molecule thrombin inhibitor.
Warfarin
- Thecoagulationfactorsinvolvedhavehalf-lives ranging from 6 - 60 hours.
- Several hours are required before an effect is seen.
- Anticoagulant effect is apparent within 24 h of warfarin administration.
- Peak anticoagulant effect may take 72 - 96 h.
- The duration of action of a single dose of warfarin is 2 to 5 days.
- The anticoagulant effects of warfarin can be overcome by the administration of vitamin K.
- Reversal following administration of vitamin K takes approximately 24 h.
MONITORING OF WARFARIN LEVELS
• Monitoring is performed with the prothrombin time (PT).
• This is a test of the integrity of the extrinsic and common pathways of coagulation.
• The results are expressed as INR.
ADVERSE
• Hemorrhage
• Cutaneous necrosis due to reduced activity of protein C.
• Warfarin crosses the placenta and can cause a hemorrhagic disorder in the fetus and serious birth defects.
• Warfarin should never be administered during pregnancy.
• Pregnancy category X.
Streptokinase
• Thrombolytic. Protein produced by B-hemolytic streptococci.
• Combines with plasminogen. This complex
catalyzes conversion of plasminogen into plasmin.
• The complex also catalyzes the degradation of fibrinogen as well as clotting factors V and VII.
• Rarely used since the advent of newer agents.
Urokinase
- Human enzyme synthesized by the kidney and found in the urine.
- Directly converts plasminogen into plasmin.
- Approved for lysis of pulmonary emboli.
Alteplase Reteplase Tenecteplase
• Tissue plasminogen activator (t-Pa) is aserine
protease produced by human endothelial cells.
• t-Pa activates plasminogen bound to fibrin in a thrombus.
• t-Pa is “fibrin-selective“, unlike streptokinase and urokinase, which are non-fibrin-selective.
ALTEPLASE
• Recombinant t-Pa.
• Indicated for management of acute MI, and acute ischemic stroke.
RETEPLASE
• Modified recombinant human t-Pa.
• Indicated for the management of acuteMI. TENECTEPLASE
• Mutant form of t-Pa.
• Indicated for reduction of mortality associatedwith
acute MI.
Aminocaproic acid
• Used to treat bleeding. Inhibits plasminogen activation.
Protamine sulfate
- Used to treat bleeding. Chemical antagonist of heparin.
- High in arginine.
- The cationic protein interacts with anionic heparin to form complex with no anticoagulant activity.
Vitamin K
• Used to correct the bleeding tendency or hemorrhage associated with its deficiency.
PREVENTION OF VITAMIN K DEFICIENCY BLEEDING IN NEWBORNS
• All babies should receive vitamin K.
• Standard treatment is with vitamin K1 IM at birth.
• VitaminK is available in oral and parenteral
forms.
• Onset of effect: 6 hours.
• The effect is complete by 24 hours.
• If immediate hemostasis is required, fresh-frozen plasma should be infused.
Deferoxamine Deferasirox
• Used as chelation therapy in patients with thalassemia major to retard the accumulation of iron.
Drugs that can induce folate deficiency
• Methotrexate, trimethoprim and pyrimethamine, inhibit dihydrofolate reductase and may cause megaloblastic anemia.
Progestins and androgenic activity
- Levonorgestrel and norgestrel: highest.
- Norethindrone: lower.
- Third-generation progestins, such as desogestrel and norgestimate: even lower.
- Drospirenone: antiandrogenic.
• Progestin thickens cervical mucus thus preventing sperm penetration, and induces changes in the endometrium that impair implantation.
Benefits of combined oral contraceptives
- Reduction in the risk of endometrial cancer
- Reduction in the risk of ovarian cancer
- Improved regulation of menstruation
- Relief of benign breast disease
- Prevention of ovarian cysts
- Reduction in the risk of symptomatic pelvic inflammatory disease
- Improvement in acne control
ADVERSE
• Many adverse effects (eg nausea, bloating, breakthrough bleeding) improve spontaneously by the third cycle.
• Many adverse effects can be avoided by adjusting the estrogen and/or progestin content of the oral contraceptive.
Breakthrough bleeding
• Most common adverse effect of oral contraceptives.
• It is more of a problem with lower doses of estrogen because estrogen stabilizes the endometrium.
Headache
• Usually mild and transient.
• However, migraine may be associated with cerebrovascular accidents.
• Women who develop migraines should stop taking the contraceptive.
Insulin Resistance
• Progestins may cause insulin resistance by competing with insulin for its receptor.
• Current oral contraceptives have a low progestin content and rarely cause hyperglycemia.
Hirsutism
• Acne, oily skin and hirsutism are adverse effects of androgenic progestins.
• The patient should be switched to a product with less androgenicity.
Melasma
• Due to estrogen stimulation of melanocyte production.
Amenorrhea
• Amenorrhea occurs in some patients.
Dyslipidemia
• Most low-dose oral contraceptives have no impact on HDL, LDL, triglycerides or total cholesterol.
Cardiovascular disorders
• Estrogens increase production of factor VII, factor X and fibrinogen, therefore increasing the risk of thromboembolic events.
• The risk is increased by obesity, smoking, hypertension and diabetes.
• These adverse effects are most common among women who smoke and who are older than 35 years.
Carcinogenicity
• Oral contraceptives decrease incidence of endometrial and ovarian cancer.
• Their ability to induce other cancers is controversial.
Depression
• Depression that requires cessation of therapy occurs in about 6% of patients treated with some preparations.
Oral contraceptive drug interactions
LIVER ENZYME INDUCTION
• Rifampin induces hepatic P450 enzymes and
increases metabolism of estrogen.
• Use of a backup nonhormonal contraceptive method during the course of rifampin therapy is recommended.
- Carbamazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, topiramate, vigabatrin and St John’s Wort are P450 inducers.
- They are known to increase metabolism of oral contraceptives.
ANTIBACTERIALS
• Ethinyl estradiol is conjugated in the liver, excreted in the bile, hydrolyzed by intestinal bacteria, and reabsorbed as active drug.
• Certain broad-spectrum antibiotics, by reducing the population of intestinal bacteria, may interrupt the enterohepatic circulation of the estrogen.
• This may decrease estrogen levels.
Contraindications for contraceptives
- History of thromboembolic disease
- History of stroke (or current cerebrovascular disease)
- History of (or current) coronary artery disease
- History of carcinoma of the breast (known or suspected)
- History of any estrogen-dependent neoplasm
- Undiagnosed abnormal uterine bleeding
- Pregnancy (known or suspected)
- Heavy smokers (15+ cigarettes per day) who are older than 35 years of age
- History of hepatic tumors (benign or malignant)
- Active liver disease
RELATIVE CONTRAINDICATIONS
• Smoking (less than 15 cigarettes per day) at any age
• History of migraine headache disorder
• Hypertension
• Fibroid tumors of the uterus
• Breast-feeding • Diabetes
Progestin-only pills
- Slightly less effective than combined oral contraceptives.
- No risk of thromboembolic events.
- Other benefits: decreased dysmenorrhea, decreased menstrual blood loss and decreased premenstrual syndrome symptoms.
- Unscheduled bleeding and spotting are common.
MOA
• Progestin-only pills are highly efficacious but block ovulation in only 60% to 80% of cycles.
• Their effectiveness is thought to be due largely to a thickening of cervical mucus, which decreases sperm penetration, and to endometrial alterations that impair implantation.
Depo-Provera
• Progestin-only injectable contraceptive.
• Contains depot medroxyprogesterone acetate
(DMPA).
• Given IM every 3 months.
• Extremely effective.
- High incidence of menstrual irregularities and weight gain.
- Causes significant loss of bone mineral density.
- A black-box warning cautions against the risk of potentially irreversible BMD loss associated with long-term use.
Implanon
- Single 4-cm long implant, containing a progestin.
- Placed under the skin of the upper arm using a preloaded inserter.
- Effective for 3 years.
- Major adverse effect: irregular menstrual bleeding.
Mirena
- Levonorgestrel-releasing intrauterine system.
- It has a polyethylene body with a levonorgestrel reservoir.
- Effective for 5 years.
PLAN B & NEXT CHOICE
• Both Plan B® and Next Choice® contain two
tablets of levonorgestrel.
• The first tablet is taken within 72 hours of unprotected intercourse and the second 12 hours later.
• Adverse effects include nausea and vomiting.
• Available without a prescription for consumers 17+.
PLAN B ONE-STEP®
• Plan B One-Step® contains one tablet of levonorgestrel to be taken within 72 hours after unprotected intercourse.
• Available without a prescription for consumers 17+.
ELLA
- Ella® contains ulipristal acetate.
- Ulipristal acetate is a selective progesterone receptor modulator (SPRM).
- It acts as a progesterone antagonist to inhibit or delay ovulation.
- A single tablet is taken within 5 days after intercourse.
- Adverse effects are similar to those of levonorgestrel.
- Available only by prescription.
