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Department of Clinical Pharmacology

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Presentation on theme: "Department of Clinical Pharmacology"— Presentation transcript:

1 Department of Clinical Pharmacology
Pharmacotherapy of chronic ischemic heart disease Jerzy Jankowski, MD

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4 FORMS OF ANGINA PECTORIS (AP)
ATHEROSCLEROTIC (CLASSIC) ANGINA VARIANT (VASOSPASTIC ANGINA)

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7 Anginal conditions other than CAD causing chest discomfort
Non-CAD causes of chest discomfort Syndrome X: Chest pain syndrome with objective evidence of ischemia and normal coronary arteries on angiography Prinzmetals angina: Vasospastic angina with normal or near-normal coronary arteries; can have Prinzmetals angina with significant CAD Aortic stenosis: Myocardial ischemia can be caused by an imbalance between the increased myocardial oxygen demand related to left ventricular hypertrophy and increased wall stress and the available coronary blood supply in the absence of coronary atherosclerosis Esophageal disease: Esophagitis, reflux, motility disorders

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9 ANTIANGINAL DRUGS ORGANIC NITRATES
ΒETA- ADRENORECEPTOR- BLOCKING DRUGS CALCIUM CHANNEL- BLOCKING DRUGS METABOLIC AGENTS HEART – RATE LIMITING AGENTS

10 DRUG ACTION IN ANGINA DECREASE MYOCARDIAL O2 REQUIREMENT BY:
decreasing peripheral vascular resitance decreasing cardiac output both ways INCREASE MYOCARDIAL O2 DELIVERY nitrates calcium channel antagonists

11 ORGANIC NITRATES

12 ORGANIC NITRATES NTG, ISDN, IS-5-MN
Donors of NO in vascular smooth muscle cells Induce cross-tolerance when given in large doses All are highly lipophylic The lipophility (depending on the stereochemical configuration and the number of ONO2-groups) affects the degree of activation of guanylate cyclase, of the NO-release and of a rapid onset of efficacy (NTG > ISDN > IS-5-MN) Due to a slow denitration IS-5-MN maintaines the effects for hours

13 ORGANIC NITRATES The higher the lipophylity of a nitrate, the higher the velocity of its uptake in different tissues ( NTG > ISDN > IS-5-MN ), particularly in the smooth muscle cells of blood vessels Nitrates are acting via the release of NO – they need intracellular SH-groups to form NO

14 PHARMACOKINETICS CHARACTERISTICS
AFTER ORAL ADMINISTRATION EXTENSIVE FIRST-PASS EFFECT (90%) LOW BIOAVAILABILITY (10%) AFTER SUBLINGUAL ADMINISTRATION RAPID ONSET OF ACTION (1-3 min) BRIEF DURATION OF ACTION (up to 30 min)

15 MECHANISM OF ANTIANGINAL ACTION OF NITRATES
DECREASED MYOCARDIAL O2 CONSUMPTION - decreased LV dimension - decreased LV filling pressure - decreased LV systolic pressure - decreased vascular impedence INCREASED CORONARY BLOOD SUPPLAY - epicardial coronary artery dilation - coronary stenosis enlargement - dilation of coronary collaterals ANTIPLATELET ANTITHROMBOTIC ACTION

16 UNDESIRABLE EFFECTS OF NITRATES
INCREASED MYOCARDIAL O2 DEMAND - reflex tachycardia - reflex increase in contractility DECREASED MYOCARDIAL PERFUSION - decreased diastolic perfusion time due to tachycardia

17 Adverse effects of nitrates
OCCURRENCE Headache Common Nausea and vomiting Occasional Dizziness or overt syncope Palpitations and tachycardia Uncommon Tolerance and attenuation

18 MECHANISMS OF NITRATE TOLERANCE
BIOCHEMICAL TOLERANCE = CELLULAR - exhaustion of the cysteine (SH) store - decreased sensivity of guanylate cyclase PSEUDO-TOLERANCE = ACTIVATION OF NEUROHUMORAL MECHANISMS - increased sympathetic activity - increased ACE activity

19 Avoidance of nitrate tolerance
Use smallest effective dose Administer the fewest possible doses per day Avoid continuous or sustained exposure to nitrates Provide a nitrate-free interval of ≥10 h every day

20 EXCRETION OF NITRATES Primarily in the form of glucuronide derivatives of the denitrated metabolites Largely by way of the kidney

21 BETA-ADRENORECEPTOR BLOCKING DRUGS

22 MAJOR DIFFERENCES AMONG BBs
ISA Beta-receptor selectivity Cardioselective Nonselective Local anesthetic action Pharmacokinetic characteristics

23 Beta-blockers with ISA
Acebutolol Cartreolol Celiprolol Oxprenolol Penbutolol pindolol

24 Cardioselective beta-blokckers
Acebutolol Atenolol Betaxolol Bisoprolol Celiprolol Metoprolol

25 Non-selective beta-blockers
Labetalol Nadolol Penbutolol Pindolol Propranolol Sotalol Timolol

26 Generations of beta-blockers
I generation: non-selective BBs II generation: cardioselective BBs III generation: beta-blockers (non-selective or cardioselectve BBs) with vasodilator activity: carvedilol, celiprolol, nebivolol

27 Local anesthetic action
Acebutolol Betaxolol (slight) Labetalol Metoprolol Pindolol Propranolol

28 Pharmacokinetic differences
Lipid solubility: penbutolol, propranolol, labetalol, metoprolol, pindolol, timolol Low lipid solubility: acebutolol, atenolol, betaxolol, bisoprolol, esmolol, nadolol, sotalol

29 A. Solubility characteristics of -blocking agents
Hydrophilicity Lack of hepatic first-pass effect lowers the chance of drug interactions and food interference    Often results in longer half-life     Low penetrability into CNS, resulting in fewer side effects Lipophilicity     Requires hepatic metabolism     Greater chance of significant first-pass effect     Often results in shorter half-life     Higher penetrability into the CNS

30 Mechanism of action in angina and cardiovascular effects of -blocking agents
Decreased myocardial oxygen consumption     Decreased heart rate Decreased blood pressure Decreased myocardial contractility Increased coronary blood supply Preserved coronary blood flow because of prolonged diastole

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32 Adverse effects of -blocking agents
Cardiac     Increased ventricular volume resulting in congestive heart failure     Excessive heart rate slowing or heart block     Withdrawal syndrome Noncardiac     Fatigue     Mental depression     Insomnia Nightmare      Raynauds phenomenon      Worsened claudication symptoms      Bronchoconstriction Metabolic     Increased LDL cholesterol and triglycerides; lowered HDL cholesterol     Worsening of insulin-induced hypoglycemia; masking of hypoglycemic symptoms     Increased blood sugar in insulin-resistant diabetics

33 CALCIUM CHANNEL-BLOCKING DRUGS

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35 PHARMACOLOGIC EFFECTS OF CALCIUM CHANNEL BLOCKERS
VER DIL DHPS HR ↓ ↓ ↑↔ A-V CONDUCTION ↓↓↓ ↓ ↔ CONTRACTILITY ↓↓ ↓ ↓ ↔ PERIPHERAL VASODILATION ↑ ↑ ↑↑ CO v v v CBF ↑ ↑ ↑ MO2 DEMAND ↓ ↓ ↓ ↑INCREASE; ↓ DECREASE; v VARIABLE;

36 A. Adverse cardiovascular effects of calcium channel antagonists
SYMPTOM CAUSE IMPLICATED CALCIUM CHANNEL ANTAGONIST Dizziness, light-headedness, syncope, palpitation Excessive hypotension All Bradycardia Verapamil, diltiazem Reflex tachycardia Dihydropyridines Exacerbation or precipitation of congestive heart failure Negative inotropic action Most; amlodipine, felodipine are the safest to use, even in heart failure Severe bradycardia or heart block Negative chronotropic action, especially sick sinus node disease Precipitation of angina Hypotension, coronary steal Nifedipine and possibly other dihydropyridines

37 B. Noncardiac Side Effects Associated with Calcium Channel Blockers
SYMPTOM VERAPAMIL DILTIAZEM NIFEDIPINE Headache Rare Occasional Postural dizziness Common Flushing Peripheral edema Constipation Other gastrointestinal disorders Paresthesias

38 METABOLIC DRUGS METABOLIC INHIBITORS WITH CARDIO-CYTOPROTECTIVE EFFECT
RANOLAZINE (RANEXA 375mg, 500mg, 750mg) TRIMETAZIDINE (PREDUCTAL MR 35mg)

39 TRIMETAZIDINE 3 - ketoacylo – CoA thiolase inhibitor
In cells exposed to ischaemia, the drug: prevents a decrease in intracellular ATP levels - reduces intracellular acidosis - alterations in transmembrane ion flow - decreases the migration and infiltration of PNN

40 TRIMETAZIDINE In man the drug: - increases coronary flow reserve
- limits rapid swings in blood pressure - decreases the frequency of angina attacks - decreases the use of NTG

41 PK OF TRIMETAZIDINE Well absorbed with Cmax, on average, 5 hours after taking the tablet Protein binding is low Eliminated primarily in the urine, mainly in the unchanged form; T1/2 7 hours

42 TRIMETAZIDINE Side effects:
- gastrointestinal (dyspepsia, diarrhoea, nausea, vomiting, constipation) - nervous system (headaches, vertigo, sleep disorders) aggravation of Parkinsonian symptoms - cardiovascular (orthostatic hypotension) - skin disorders Special warnings: pregnancy and breastfeedindg

43 RANOLAZINE ( R ) Inhibitor of the late Na+ current (late INa)
Inhibitor of the fast rectifying K+ current (IKr) Reduces Ca++ overload in the ischemic myocyte Does not affect Na+- H+ and Na+- Ca++exchangers Antianginal effect related to decreased LV diastolic tension and improved myocardial perfusion

44 PHARMACOKINETICS OF R Sustained – release form
Prolonged absorption with Cmax 4 – 6 h after oral administration Bioavailability 30% - 55% Plasma protein binding ~ 62% T1/2 ~ 7h Steady state within 3 days

45 RANOLAZINE METABOLISM
CYP 3A4 – the major pathway Additional pathways include: - CYP 2D6 (10% - 15%) - glucuronidation (< 5%) ~ 5% excreted unchanged Weak inhibitor of CYP 3A4 and CYP 2D6 Inhibitors of CYPs 3A4 and 2D6 increase plasma R concentration 2 – 4 fold Clearance of R is reduced by renal insufficiency and moderate hepatic impairment

46 DRUG – DRUG INTERACTION
Inhibitors of CYP 3A4 (itraconazole, ketokonazole, voriconazole, HIV protease inhibitors, clarithromycin, verapamil, diltiazem, erythromycin, fluconazole grapefruit juice Inhibitors of CYP 2D6 (paroxetine) Inhibitors of P-gp (cyclosporin, verapamil) INCREASED EXPOSURE TO RANOZALINE

47 DRUG-DRUG INTERACTION
CYP 2D6 inducers (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s Wort) DECREASED EXPOSURE TO RANOZALINE

48 ADVERSE DRUG REACTIONS
Mild to moderate in severity Common ADRs: dizziness, headache, constipatin, vomiting, nausea, ECG effects: ↑QTc, ↓T wave amplitude, T wave notching

49 CONTRAINDICATIONS Hypersensitivity to the drug
Severe renal impairment (CrC < 30ml/min) Moderate or severe hepatic impairment Co-administration of potent CYP 3A4 inhibitors LQTS Co-administration QT-prolonging drugs (quinidine, dofetilide, sotalol)

50 HEART-RATE LOWERING DRUGS
Ivabradin (Procoralan 5 mg, 7,5 mg tablets) Selective and specific inhibitor of If current that controls the spontaneous diastolic depolarisation in the sinus node Dose-dependent reduction in heart rate and MO2

51 INDICATIONS Symptomatic treatment of chronic stable angina pectoris with normal sinus rhythm: - in adults unable to tolerate or with a contra- indication to the use of beta-blockers - or in combination with beta-blockers in pts inadequately controlled with an optimal beta- blocker dose and whose rate is > 60 bpm Treatment of chronic heart failure

52 PHARMACOKINETICS S-enantiomer, highly water-soluble
Rapidly and completely absorbed from the gut C max after 1 hour under fasting condition Food delays absorption by 1 h and increases plasma contrentation by 20 to 30% Plasma protein bounding 70% Half-life 11 hours

53 BIOTRANSFORMATION Metabolised by CYP 3A4 only
Active metabolite – N-desmethlated derivative Very low affinity for CYP 3A4 CYP 3A4 inhibitors and inducers influence its metabolism and pharmacokinetics Treatment including potent CYP 3A4 inhibitors as azole antifungals, macrolide antibiotics, HIV protease inhibitors, nefazodone is contraindicated

54 BIOTRANSFORMATION the combination of ivabradine with moderate CYP 3A4 inhibitors (diltiazem, verapamil) is not recommended CYP 3A4 inducers (rifampicin, barbiturates, phenytoin, St John,s Wort) may decrease ivabradine exposure and activity

55 CONTRAINDICATIONS Hypersensitivity to the active substance
Resting heart rate below 60 bpm prior to treatment Acs, cardiogenic shock, severe hypotension Severe hepatic insufficiency Sick sinus syndrom, sino-atrial block A-V block of 3rd degree Combination with strong CYP 3A4 inhibitors Pregnancy, lactation

56 UNDESIRABLE EFFECTS Headache Dizziness Bradycardia – 3,3%
Luminous phenomena (phosphenes) – 14,5% Uncontrolled blood pressure

57 Combinations of antianginal drugs
BENEFICIAL SHOULD BE AVOIDED OR IS RELATIVELY CONTRAINDICATED Nitrates + b-blocker X Nitrates + diltiazem, verapamil Nitrates + dihydropyridine b-blockers + dihydropyridine b-blockers + diltiazem, verapamil

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60 Thienopyridines Ticlopidine (2 x 250 mg) Clopidogrel (1 x 75 mg)
P2Y12 adenosine diphosphate receptor blocker For 1 year after NSTEMI, STEMI, PCI + DES

61 GASTROINTESTINAL RISKS OF ANTIPLATELET THERAPY
ASA causes topical injury to the mucosa and systemic effects induced by prostaglandin depletion Tissue PGs are produced via 2 pathways: COX-1 and COX-2 pathway Clopidogrel – impairs the healing of gastric ulcers by inhibiting platelet release of pro-angiogenic growth factors ( VEGF ) which promotes endothelial proliferation and accelerates the healing of ulcers

62 GASTROINTESTINAL RISKS OF ANTIPLATELET THERAPY
Recommendation: the use of low-dose ASA for cardioprophylaxis is associated with a 2-4 – fold increase in UGIE. Enteric-coated preparations do not reduce the risk of bleeding. For patients at risk of adverse events, gastroprotection should be prescribed. The risk of UGIE increases with dose of ASA; thus, doses greater than 81mg should not be prescribed

63 GASTROINTESTINAL RISKS OF ANTIPLATELET THERAPY
Recommendation: substitution of clopidogrel for ASA is not recommended strategy to reduce the risk of recurrent ulcer bleeding in high-risk patients and is inferior to the combination of ASA plus PPI Recommendation: when warfarin is added to ASA plus clopidogrel an INR of 2,0 to 2,5 is recommended Recommendation: PPIs are the preferred agents for the therapy and prophylaxis of ASA-associated UGIE

64 GASTROINTESTINAL RISKS OF ANTIPLATELET THERAPY
Esomeprazol and pantoprazol are preferred PPIs in patients treated with clopidogrel Omeprazol is not recommended due to a risk of significant interaction with clopidogrel

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66 EUROPA TRIAL EUropean trial on Reduction Of cardiac evens with Perindopril in stable coronary Artery disease Randomized, placebo controled, duble blind study 4 years follow-up 12218 patients at low risk; perindopril 8 mg vs placebo

67 EUROPA TRIAL - RESULTS The primary end-point ( cardiovascular death + nonfatal MI + non fatal cardiac arrest ) ↓ 20% Risk of MI ( fatal + nonfatal ) ↓ 24% Hospitalisation for HF ↓ 39%

68 PERTINENT TRIAL PERindopril, Thrombosis, INflammation, Endothelial dysfunction and Neurohormonal activaTion Rate of apoptosis of EC Activity and expression of NOS Proapoptotic protein Bax Antiapoptotic protein Bcl-2 Von Willebrand factor Levels of AT II, bradykinin, TNF Assesment at baseline and after 1 year of treatment

69 PERTINENT TRIAL - RESULTS
One year of treatment with perindopril was able significantly reduce the rate of apoptosis and increase the activity and expression of NOS

70 LIPID-LOWERING THERAPY
Statins – HMG-CoA reductase inhibitors Atorvastatin, simvastatin, fluvastatin, pravastatin, rosuvastatin Significant LDL reduction, relatively small reduction in TG, minor increas in HDL Lower is better ( LDL < 70 mg%) Fibrates – fenofibrate (↑ HDL) Ezetimib (Ezetrol 10mg)

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72 S T A T I N S Natural (fungal fermentation): lovastatin, simvastatin, pravastatin Synthetic: fluvastatin, atorvastatin, rosuvastatin Metabolized by CYP 3A4: lovastatin, simvastatin, atorvastatin CYP 2C9 for fluvastatin Pravastatin does not use CYP P450 Hydrophilic statins: pravastatin, fluvastatin

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74 ADVERSE EFFECTS OF STATINS
All statins are well tolerated Most common ADRs are mild, transient, reversible – dyspepsia, abdominal pain, flatulence The most important ADRs are liver toxicity (↑ ATs) and myopathy ( pain, weakness, ↑CK ≥ 10 X) Rhabdomyolysis and acute renal failure – very rare Risk of muscle toxicity increases during therapy with cyclosporine, erythromycin, clarithromycin, azole antifungals, protease inhibitors – CYP 3A4 inhibitors

75 Major purposes of the treatment
To improve short and long term prognosis by preventing MI and death and thereby increase the length of life To improve quality of life by reducing symptoms of angina and occurrence of ischemia

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78 Recommendations for Pharmacotherapy To Prevent MI and Death and To Reduce Symptoms
The following agents should be used in patients with symptomatic chronic stable angina to prevent MI or death and to reduce symptoms: Aspirin (level of evidence: A) or clopidogrel when aspirin is absolutely contraindicated (level of evidence: B) ß-Blockers in patients with previous MI (level of evidence: A) or without previous MI (level of evidence: B) Low-density lipoprotein cholesterol–lowering therapy with a statin (level of evidence: A) ACE inhibitor (level of evidence: A)

79 Recommendations for Pharmacotherapy To Prevent MI and Death and To Reduce Symptoms
The following agents should be used in patients with symptomatic chronic stable angina to reduce symptoms only: Sublingual nitroglycerin or nitroglycerin spray for the immediate relief of angina (level of evidence: B) Calcium antagonists (long-acting) or long-acting nitrates when ß-blockers are clearly contraindicated (level of evidence: B) Calcium antagonists (long-acting) or long-acting nitrates in combination with ß-blockers when ß-blockers alone are unsuccessful (level of evidence: B).

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81 TREATMENT OF STABLE ANGINA ACCORDINGLY TO CCS CLASSIFICATION
CLASS I correction of risk factors, nitroglycerin sl aspirin 75 mg CLASS II as above+ chronic therapy with LA nitrates or ß1-blockers or LA Calcium antagonists or Trimetazidine or combination of these drugs

82 TREATMENT OF STABLE ANGINA ACCORDINGLY TO CCS CLASSIFICATION
CLASS III and IV As above and establish indications for invasive treatment

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