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B1 Drugs Flashcards

1
Q

mechanism of up-regulation of LRL-r (via statins)

A
  • SREBP precursor protein anchored in the ER by two membrane-spanning helices.
  • SCAP: cholesterol-sensing protein: SREBP cleavage activating protein (Scap)
  • Sterols (like cholesterol) bind to SCAP and prevent release from ER membrane
  • When cholesterol decreases, SREBP-SCAP transported to Golgi and is cleaved by two different proteases called site-1 protease (S1P) and site-2 protease (S2P).
  • Now have a “ transcriptionally active SREBP” which travels to the nucleus where it activates transcription of target genes.
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2
Q

Pharmacokinetics of Statins

A
  • Extensive first-pass metabolism by the liver
  • LIMITS SYSTEMIC BIOAVAILABILITY
  • TARGETS LIVER/SITE OF ACTION
  • first-pass hepatic uptake of these statins by transporter OATP1B1 after their oral administration helps to exert the pharmacological effect and also minimizes the escape of drug molecules into the circulating blood, thereby minimizing the exposure in a target of adverse response
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3
Q

Statin Metabolism

A
  • All the statins, except simvastatin and lovastatin, are administered in the -hydroxy acid form, which is the form that inhibits HMG-CoA reductase.
  • Simvastatin and lovastatin are administered as inactive lactones, which must be transformed in the liver to their respective -hydroxy acids, simvastatin acid and lovastatin acid.
  • Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYP3A4.
  • Under steady-state conditions, small amounts of the parent drug and its metabolites produced in the liver can be found in the systemic circulation.
  • Table is summary comparing different statin drugs
  • In 2001 cerivastatin was removed from market because of increased # of fatal adverse effects • The withdrawal of cerivastatin demonstrates that all statins are not interchangeable.
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4
Q

Statin Adverse Effects

A

MAJOR adverse effect
• Myopathy
• muscle pain (usually symmetrical, involving proximal muscles) without creatinine kinase (CK) elevation [or less frequently with mild CK elevation.]
• Muscle disease/weakness

  • Rhabdomyolysis
  • muscle symptoms with marked CK elevation (typically > 10 × upper limit of normal) and with creatinine elevation
  • breakdown of muscle fibers that leads to the release of myoglobin into the bloodstream. Myoglobin is harmful to the kidney and often causes kidney damage.

MINOR
• GI side effects
• Increase in liver enzymes

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5
Q

Genetics and Statin Intolerance

A
  • A single nucleotide polymorphism in SLCO1B1, which encodes an organic anion transporter that regulates the hepatic uptake of statins, was strongly associated with statin induced myopathy.
  • Genetic variants of SLCO1B1 lead to reduced hepatic uptake and increased levels of statins in the blood, providing the mechanism for increased risk of myopathy.
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6
Q

Pharmacokinetic mechanisms by which drugs (specifically STATINS) increase myopathy risk

A

Drugs are those metabolized primarily by CYP3A4
• (certain macrolide antibiotics (e.g., erythromycin )
• azole antifungals (e.g., itraconazole )
• cyclosporine
• HIV protease inhibitors.
• These pharmacokinetic interactions are associated with increased plasma concentrations of statins and their active metabolites.

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7
Q

Mechanism for statin-induced myopathy

A

• Depletion of secondary metabolic intermediates

The mevalonate pathway. Statins block the conversion of HMG-CoA to mevalonate by inhibiting HMG-CoA reductase, decreasing cholesterol production but also suppressing formation of isoprenoids required for the normal function of the muscle.

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8
Q

Contraindications to Statin Therapy

A
  • Hypersensitivity
  • Active liver disease
  • Women who are pregnant, lactating, or likely to become pregnant should not be given statins
  • Statins reaching the embryo may down-regulate biosynthesis of cholesterol as well as many important metabolic intermediates, and may have secondary effects on sterol-dependent signaling molecules that contribute to development such as Sonic Hedgehog
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9
Q

Statin Lipoprotein Profile

A

• TG
• > 250 mg/dl: decrease by 20-55%
•

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10
Q

statin clinical uses

A

First line therapy in hypercholesterolemia when at risk for myocardial infarction

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11
Q

cholestyramine (MOA)

A

Bile-Acid Binding Agents

• anion-exchange resins
• highly positively charged and binds negatively charged bile acids • Because of their large size, the resins are not absorbed, and the
bound bile acids are excreted in the stool.
• more than 95% of bile acids are normally reabsorbed.
• interruption of this process depletes the pool of bile acids, and hepatic bile-acid synthesis increases.
• What’s the precursor to bile acid? How are bile acids synthesized?
• As a result, hepatic cholesterol content declines, stimulating the production of LDL receptors, an effect similar to that of statins.

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12
Q

cholestyramine (pharmacokinetics)

A

not absorbed

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13
Q

cholestyramine (adverse effects)

A

Adverse effects
• most common-constipation/bloating sensation
• gritty consistency
• nausea and vomiting (small frequent meals, frequent mouth care, sucking lozenges, or
chewing gum may help)
• constipation (increased exercise, fluids, fruit, or fiber may help)
• interferes with absorption of other drugs & fat soluble vitamins
• Digitalis, thiazides, warfarin, statins, aspirin • A,D,E,K
• modest INCREASE in TG/with time returns to baseline values
• less common side effects
• In hand-out/not necessary to know
• hyperchloremic metabolic acidosis • increase in liver enzymes
• excess fat in stool (steatorrhea)

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14
Q

Cholestyramine Lipoprotein Profile

A

TG
• Normal levels: only transient increase
• Levels > 250 mg/dl; further significant increase

LDL decrease by 12-25% • Dose-dependent
• Larger dose, more side effects

HDL increase by 4-5%

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15
Q

Cholestyramine Clinical Uses

A

Hypercholesterolemia
• Not recommended for individuals with hypercholesterolemia and increased TG
• should not be used in patients with baseline fasting triglyceride levels ≥300 mg/dL or type III hyperlipoproteinemia since severe triglyceride elevations may occur. Use with caution in patients with triglyceride levels 250-299 mg/dL and evaluate a fasting lipid panel in 4-6 weeks after initiation; discontinue use if triglycerides are >400 mg/dL
• most often used as second agents if statin therapy does not lower LDL-C levels sufficiently
• recommended for patients 11-20 years of age.

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16
Q

Ezetimibe (MOA)

A

Cholesterol Absorption Inhibitor

  • Protein transporter called Niemann Pick C10-like protein or NPC1L1
  • Decreased rate of cholesteryl ester incorporation into chylomicrons
  • Reduced cholesterol flux from intestine to liver
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17
Q

Ezetimibe (Pharmacokinetics)

A
  • Oral administration
  • Metabolized (glucuronidation) to active metabolite
  • Half-life 22 hours
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18
Q

Ezetimibe (Adverse Effects)

A
  • Well tolerated

* Side effects (i.e. muscle-related) increase if combined with other drugs, like statins

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19
Q

Ezetimibe Lipoprotein Profile

A
  • TG decrease by 5%
  • LDL decrease by 15-20%
  • HDL increase by 1-2%
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20
Q

Ezetimibe Clinical uses

A 
• Primary hypercholesterolemia
Combined with statins
• Simvastatin + ezetimibe
• Further decrease in LDL-cholesterol
• Two differing pharmacological approaches*****
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21
Q

Nicotinic Acid (summary + MOA)

A
  • Also called niacin
  • Water-soluble B-complex vitamin
  • Lipid lowering effect is unrelated to its effect as a vitamin
  • Much larger doses required
  • MAIN EFFECT IS TO DECREASE TG!!!
  • But it does decrease cholesterol!

MOA
• In adipose tissue, inhibits FFA mobilization
• role for niacin receptor 1 (GPR109A) in adipose tissue

  • In liver, decreases synthesis of VLDL-TG
  • Inhibits uptake of HDL-apoA1
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22
Q

Niacin Pharmacokinetics

A
  • Oral administration
  • 3 different formulations
  • immediate release (2-3 x/day)
  • Long acting release
  • extended release preparation (once day/bedtime)
  • Remember that doses used for lowering cholesterol/TG much greater than those used as vitamin
  • Prescription only
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23
Q

Niacin Adverse effects

A 
MAJOR ADVERSE EFFECT
• Intense cutaneous flush/pruritus
• Occurs soon after taking the drug
• poor compliance
Mediated by vasodilatory PGs
• PGD2 from dermal macrophages • use of NSAIDs to block the effect
  • Luckily, tolerance to this effect occurs with continued use
  • Also can reduce this effect by giving lower doses and then gradually increasing to higher dose
  • Give the drug at bedtime when flushing effect may be more tolerable to patient

Other more SERIOUS but less frequent adverse effects
• GI effects
• nausea/vomiting, abdominal pain, diarrhea
• Avoid in patients with peptic ulcer

  • elevated liver enzymes/usually no hepatic toxicity
  • BUT MAJOR concern if combined with statins
  • Hyperurecemia
  • Contraindicated in patients with gout

• Increases fasting glucose levels/niacin-induced insulin resistance • Questionable use in patients with diabetes

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24
Q

Niacin contraindications

A
  • Peptic Ulcer
  • Gout
  • Hepatic Disease
  • Diabetes
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25
Q

Niacin Drug Interactions

A
  • Combined use with statin increases risk of myopathy
  • Mechanism not known
  • Patients of Chinese descent more susceptible
  • FDA approved prep that combines both drugs • Interesting….

• Substituting time release formulation with immediate release have resulted in severe hepatic toxicity

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26
Q

Niacin Lipoprotein Profile

A
  • TG decreased by 35-50% • Within 4-7 days
  • LDL decreased by 25% • 3-6 weeks for maximal effect
  • HDL increased by 15-30% • added benefit is increased HDL
  • Lp(a) reduced by 40% • May be risk factor
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27
Q

Niacin Clinical Uses

A
  • Hypercholesterolemia & hypertriglyceridemia
  • High LDL and low HDL
  • Typically not first line therapy for hypercholesterolemia • Severe cases that do not respond to resins
  • Not first choice because of side effects

• Only lipid-lowering drug that reduces Lp(a)**

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28
Q

Fibric Acids/Fibrates/PPAR activators (drugs, and summary)

A

Gemfibrozil
Fenofibrate (2nd generation drug)

• Primarily lower the levels of TG-rich lipoproteins

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29
Q

Fibric Acids/Fibrates/PPAR activators (MOA)

A

• Ligands for the nuclear transcription regulator
• peroxisome proliferator-activated receptor (PPAR-􏰏)
• Expressed in liver, adipose tissue
• regulate gene transcription (number
of different genes)

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30
Q

Fibric Acids/Fibrates/PPAR activators (pharmacokinetics)

A
  • Oral administration
  • Plasma protein binding
  • Half-life varies (1 hr for gemfibrozil/20 hrs for fenofibrate (increased with renal impairment)
  • Fenofibrate is metabolized to active metabolite
  • excreted predominantly as glucuronide conjugates; 60-90% of an oral dose is excreted in the urine

• Gemfibrozil metabolized into inactive metabolites

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31
Q

Fibric Acids/Fibrates/PPAR activators (Adverse Effects/drug interactions/contraindications)

A

Generally well-tolerated**
• GI symptoms-most common
• Increased risk of gall stones
• Less common are hematological/hepatic function abnormalities
• increased creatine kinase if also being treated with a statin….lead to renal failure
• Use is contraindicated in patients with renal impairment
• Gemfibrozil can increase systemic statin concentrations by blocking transporter in liver

32
Q

GEMFIBROZIL-RELATED DRUG INTERACTION

A
  • Fibric acid used to lower TGs
  • Gemfibrozil inhibits uptake of active hydroxy acid forms of statins by transporter
  • first-pass hepatic uptake of these statins by transporter OATP1B1 after their oral administration
  • If not taken up into liver, increased plasma concentration
33
Q

Fibric Acids/Fibrates/PPAR activators (lipoprotein profile)

A
  • Dependent on starting lipoprotein profile
  • TG decrease 30-50%
  • LDL decrease 15-20%
  • HIGHLY VARIABLE
  • 2nd generation drugs (fenofibrate) more likely to decrease LDL 15-20% in patients with TG
34
Q

Fibric Acids/Fibrates/PPAR activators (clinical uses)

A
  • patients with high TGs and low HDL associated with metabolic syndrome or type 2 diabetes
  • not used as primary therapy in patients with elevated hypercholesterolemia without hypertriglyceridemia
  • treatment of hypertriglyceridemia (Fredrickson types IV [Familial hypertriglyceridemia] and V [high VLDL and chylomicrons]) Patients at greater risk for pancreatitis and who have not responded to dietary intervention
  • reduces the risk of CHD development in Fredrickson type IIb (Familial combined hyperlipidemia) patients without a history or symptoms of existing CHD who have not responded to dietary and other interventions (including pharmacologic treatment) and who have decreased HDL, increased LDL, and increased TGs
35
Q

DRUGS OF CHOICE FOR HYPERCHOLESTEROLEMIA

A

HMG CoA reductase inhibitors-first choice agents
• Which one?
• Safety?
• Lifetime treatment

Bile acid resins
• Long-term safety
• Younger patient age range • Add on to statins

Ezetimibe
• Safety as monotherapy vs MAYBE…add-on to statins

Niacin
• Patient compliance side effects
• Both elevated TG and cholesterol 
• Low HDL
• Care when combined with statins
36
Q

Drugs of choice for hypertriglyceridemia

A
  • Gemfibrozil/Fenofibrate-should be first choice
  • Niacin
  • Omega-3 Fatty Acids
37
Q

Omega-3-Acid-Ethyl Ester (summary + MOA)

A
  • lipid-lowering effects of fish (marine) oils
  • despite a diet high in saturated fat and cholesterol, serum lipids— particularly TG —were significantly lower in the Greenland Eskimos.
  • Eicosapentaenoic acid • (EPA 20:5 n−3)
  • Docosahexaenoic acid • (DHA 22:6 n−3)
  • omega-3 FAs appeared to have unique TG-lowering properties not shared by the omega-6 FAs*******
  • Fish oil and fatty fish such as salmon, mackerel, herring, and tuna are the primary dietary sources of EPA and DHA
  • Potential mechanisms?
  • inhibit (−) lipogenesis
  • inhibit diacylglycerol acyl transferase (DGAT), phosphatidic acid phosphohydrolase (PA), and hormone- sensitive lipase
  • stimulate (+) β-oxidation, phospholipid synthesis, and apolipoprotein (apo) B degradation.
  • The end result is a reduced rate of secretion of very-low-density lipoprotein (VLDL) TG
OTHER EFFECTS:
• reductions in risk for fatal arrhythmias
• enhanced plaque stability
• reductions in heart rate
• improved endothelial function
38
Q

Omega-3-Acid-Ethyl Ester (pharmacokinetics)

A
  • Many omega-3 FA dietary supplements on the market
  • only one FDA-approved omega-3 FA
  • Oral: 4 g/day as a single daily dose or in 2 divided doses.
  • Onset of action is slow; typically stop drug if no benefit seen after 2 months of therapy
39
Q

Omega-3-Acid-Ethyl Ester (adverse effects)

A
  • Fish allergy
  • May increase LDL levels
  • May increase liver enzymes.
  • Prolongation of bleeding time has been observed in some clinical studies
40
Q

Omega-3-Acid-Ethyl Ester (clinical use)

A

• Adjunct to diet therapy in the treatment of hypertriglyceridemia (≥500 mg/dL)

41
Q

Alirocumab (MOA)

A

PCSK9 antibody prevents binding of PCSK9 to the LDLR-LDL complex, increasing the availability of cell-surface LDLRs.
• Approved July 2015
• Injectable cholesterol- lowering drug

42
Q

Alirocumab -Pharmacokinetics

A
  • Subq administration (once/every 2 weeks)

* Half-life (elimination) ~ 17-20 days

43
Q

Alirocumab –Adverse Effects

A
  • Injection site reactions
  • Hypersensitivity (less common)
  • Elevation in liver enzymes
  • Potential for immunogenicity
44
Q

Alirocumab –Therapeutic Use

A

• adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C

45
Q

Lomitapide- Mechanism of Action

A
  • directly binds to and inhibits MTP
  • MTP inhibition prevents the assembly of apo-B containing lipoproteins in enterocytes and hepatocytes resulting in reduced production of chylomicrons and VLDL and subsequently reduces plasma LDL-C concentrations.
46
Q

Lomitapide- Pharmacokinetics

A
  • Oral administration

* Primarily hepatic (extensive) through CYP3A4 to M1 and M3 (major [inactive in vitro] metabolites)

47
Q

Lomitapide – Adverse Effects

A
  • Significant gastrointestinal events (eg, diarrhea, nausea, dyspepsia, vomiting) occur commonly
  • Hepatotoxicity
48
Q

Lomitapide- Clinical Use

A

• Adjunct to dietary therapy and other lipid-lowering treatments to reduce LDL-C, total cholesterol, apolipoprotein B, and non-HDL-C in patients with homozygous familial hypercholesterolemia

these patients don’t have any LDL receptors…

49
Q

Mipomersen-Mechanism of Action

A
  • 20-base sequence second-generation antisense oligonucleotide developed to inhibit synthesis of apoB-100 in the liver.
  • hybridizes within the coding region of apoB-100 mRNA and activates RNase H. RNase H degrades the mRNA strand but leaves the antisense oligonucleotide intact
50
Q

Mipomersen-Pharmacokinetics

A
  • Once/week via subcutaneous injection

* lipid-lowering effect persisted for up to 3 months after the last dose

51
Q

Mipomersen–Adverse Effects

A

• injection site reactions

  • erythema, pain, hematoma, pruritus, swelling and discoloration
  • flu-like symptoms
  • Increase in anti-mipomersen antibodies
  • Headache
  • elevation of liver enzymes (risk of hepatotoxicity)
52
Q

Mipomersen–Clinical Use

A

• FDA approved in January 2013 as an orphan drug
• first-in-class drug for treatment of homozygous familial
hypercholesterolemia
• Adjunct to dietary therapy and other lipid-lowering treatments to reduce LDL-C, total cholesterol, apolipoprotein B, and non-HDL-C in patients with homozygous familial hypercholesterolemia

53
Q

Pentoxyfylline

A

Methylxanthine derivative

Hemorrheologic agent

Weak antiplatelet activity

Some vasodilation

54
Q

Cilostazol

A

Phosphodiesterase III inhibitor

Platelet aggregation inhibitor

Vasodilation

increase􏰜􏰜 HDL-C (10%)
􏰝􏰝decrease Triglycerides (15%)

Inhibits smooth muscle cell proliferation in vitro

****do not use this with cardiomyopathy with low EF

55
Q

Cyclophosphamide

A
  • GPA drug
  • used in combination with corticosteroids
  • remission increased to 48.2 months as opposed to dying within 5 months

-targets other beta-lymphocytes but not very specific….****

56
Q

Rituximab

A

Chimeric monoclonal antibody directed against CD20

  • CD20 functions as a calcium channel subunit and plays role in b-lymphocyte activation, proliferation, and differentiation
  • binding of rituximab to CD20 causes death of target cell
  • circulating peripheral b-lymphocytes remain undetectable in peripheral blood for 6-12 months after treatment with rituximab
57
Q

RAVE trial conclucions

A

-Rituximab was not inferior to cyclophosphamide treatment for induction remission in severe ANCA associated vasculitis (p

58
Q

Nitrates (biochem MOA)

A

• General vasodilator, but much greater effect on venous blood vessels

• Mechanism of action:
– Enzymatically denitrated in smooth muscle
– Free nitrate/nitrite is converted to nitric oxide (NO)
– NO activates guanylyl cyclase (GC) increasing cyclic guanosine monophosphate (cGMP)
– cGMP activates cGMP-dependent protein kinase (PKG)
– PKG phosphorylates various targets leading to decreased calcium and dephosphorylation of myosin

59
Q

Nitrates: Effects on the Ischemic Heart

A

• Increase venous capacitance (decreases preload)
– Results in reduced diastolic wall tension and therefore oxygen demand
– Decreased preload also has a minor effect to increase subendocardial blood flow

• Small reduction in systemic arterial blood pressure (afterload)
– Reduces systolic wall tension
– Can cause slight reflex tachycardia and increased contractility due to reduction in blood pressure

• Coronary dilator
– May be little value in patients with angina where maximal dilation has already occurred due to accumulation of local metabolites
– Beneficial if ischemia is due to vasospasm

60
Q

Nitrates: Pharmacokinetics

A

• Nitroglycerin inactivated by a high capacity organic nitrate reductase in the liver
– Low bioavailability due to extensive 1st pass metabolism

• Isosorbide dinitrate metabolized by the liver to form the mononitrate form
– Mononitrate is biologically active • Mononitrate is not metabolized

61
Q

Nitrates: Acute Therapy

A

Administered sublingually to avoid 1st pass metabolism and to achieve high blood concentration rapidly

Nitroglycerin
• Rapidly dissolvable tablets or aerosol spray both for sublingual (under the tongue) administration
• Fast onset (few minutes) & short duration of action (15- 30 min)

62
Q

Nitrates: Chronic Therapy

A

Provides prophylaxis against angina episodes in patients with more than occasional angina

Isosorbide Dinitrate
• 25% orally bioavailable
• Longer DOA (4-6 h) compared to nitroglycerin
• Metabolized to mononitrate form that is biologically active
• Available in controlled release forms

Isosorbide Mononitrate
• No 1st pass metabolism
- t 1⁄2 ~5 h

Nitroglycerin

  • Orally as controlled-release tablets/capsules
  • Available as a patch and ointment/paste applied to skin
63
Q

Nitrates: Tolerance

A

Complete tolerance can develop if used continually for more than a few hours
– But also reverses rapidly (24 h after stopping drug) – Develops with all nitrates
– Mechanism unclear

Limits the effectiveness of slow-release forms of nitrates with maintenance therapy
– Use smallest effective dose
– Schedule nitrate-free period (on-off therapy) of at least 8 h to reduce or prevent tolerance particularly with patches

64
Q

Nitrates: Adverse Effects

A 
Due to cardiovascular actions 
– Headache
– Hypotension
– Reflex tachycardia
– Flushing
65
Q

Dihydropyridines

A

CCB

• Potent vasodilators

• Relieve ischemia by:
– Decreasing oxygen demand (vasodilation primarily decreases afterload and thereby reduces wall stress)
– Increasing oxygen supply by coronary vasodilation

  • Potent agents for the relief of vasospasm
  • Nifedipine, amlodipine
66
Q

Non-Dihydropyridines

A

CCB

• Vasodilators (but less potent than dihydropyridines)

• Relieve ischemia primarily by:
– Decreasing oxygen demand by reducing the force of contraction and heart rate

• Verapamil, diltiazem

67
Q

Calcium Channel Blockers: Adverse Effects

A
  • Headache, flushing
  • Decrease contractility (V,D)
  • Bradycardia (V, D)
  • Edema (especially N, D)
  • Constipation (especially V)
68
Q

Combination Therapy (beta, nitrates, CCB)

A

• The three classes of anti-anginal drugs can be used alone or in combination

• Potential benefits of combining a nitrate with a b blocker: – b blockers prevent the potential reflex increase in heart rate and contractility produced by nitrates
– Nitrates prevent the potential increase in wall tension produced by b blockers

• Care should be taken in combining a b blocker with a non-dihydropyridine calcium channel blocker
– Additive negative inotropic effect can cause excessive cardiodepression

69
Q

Ranolazine

A

• Fourth type of anti-ischemic therapy (recently available)
• Decreases frequency of anginal episodes and increases exercise capacity
• Does not work by affecting heart rate of vasodilation
• Believed to inhibit the late sodium current (INa+) in cardiac myocytes
-indirectly prevent Ca++ from entering the cell….decreases ATP that is consumed….


70
Q

• Antiplatelet agents

A

Cyclooxygenase inhibitors
• Aspirin

ADP receptor inhibitors
• Clopidogrel
• Prasugrel
• Ticagrelor

Glycoprotein IIb/IIIa inhibitors
• Abciximab
• Eptifibatide

71
Q

Thienopyridines

A
  • Inhibit ADP-mediated activation of platelets
  • ADP simultaneously activates two purinergic receptors, P2Y1 and P2Y12
  • P2Y1􏰮increase PLC􏰮 increase calcium
  • P2Y12􏰮decrease cAMP􏰮 increase calcium
  • Drugs inhibit P2Y12 receptor
  • Note which drugs are irreversible and which drugs are reversible

Clopidogrel, ticlopidine and prasugrel are pro-drugs that are metabolized to active metabolite
• Prasugrel more readily metabolized and increased potency

Side effects include bleeding and GI related symptoms
• Ticlopidine associated with life- threatening adverse effects (severe neutropenia and thrombotic thrombocytopenic purpura)

Clopidogrel is metabolized by CYP2C19
• Variability of response in patients with
CYP2C19 polymorphisms
• Co-administration with protein pump inhibitor (PPI) (omeprazole) a concern since PPI inhibit CYP2C19

As monotherapy, drugs are modestly superior to aspirin in reducing risk of myocardial infarction
• Increased risk of side effects
• Increased cost

Combination of clopidogrel with aspirin has increased benefit compared to aspirin alone
• Increased bleeding risk

Irreversible
clopidigrel
prasugrel

Reversible
cangrelor
ticagrelor
elinogrelor

72
Q

Irreversible Thienopyridines

A

clopidigrel

prasugrel

73
Q

Reversible Thienopyridines

A

cangrelor
ticagrelor
elinogrelor

74
Q

Glycoprotein IIb/IIIa Receptor Antagonists (MOA)

A

• Reversibly inhibit the final common pathway of platelet aggregation –
binding of GPIIb/IIIa receptors to fibrinogen and vWF

• So platelets can’t ‘stick’ to each other, don’t get formation of the hemostatic plug

75
Q

Abciximab

A
  • Chimeric human-mouse monoclonal antibody
  • blocks access of fibrinogen, vWF and other adhesive molecules to the GP IIb-IIIa receptor
  • Non-competitive
  • IV administration
  • Patients undergoing PCI, including angioplasty or stent placement
  • In combination with aspirin and heparin (or LMWH)
  • Also used with alteplase for thrombolysis
76
Q

Eptifibatide

A
  • Synthetic peptide antagonist
  • Contains a sequence motif that binds specifically to GP IIb-IIIa receptors
  • Competitive
  • IV administration • Renal clearance
  • Patients undergoing PCI, including angioplasty or stent placement
  • Patients with unstable angina and myocardial infarction, often with LMWH
77
Q

Dipyridamole

A
  • Occasionally prescribed to patients that cannot tolerate aspirin; relatively ineffective
  • Mechanism of action-unclear
  • Increase in platelet cAMP
  • Blockingphosphodiesterase
  • Blocking cellular uptake and destruction of adenosine
  • Given alone, the drug has no proven cardiac benefits

CV (5 decks)

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