Department of Clinical Pharmacology

Pharmacotherapy of chronic ischemic heart disease

Jerzy Jankowski, MD

www.zfk.ump.edu.pl

www.ump.edu.pl/eng

FORMS OF ANGINA PECTORIS (AP)

• ATHEROSCLEROTIC (CLASSIC) ANGINA • VARIANT (VASOSPASTIC ANGINA)

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

ANTIANGINAL DRUGS

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

DRUG ACTION IN ANGINA

•

DECREASE MYOCARDIAL O 2 REQUIREMENT BY: decreasing peripheral vascular resitance decreasing cardiac output both ways

•

INCREASE MYOCARDIAL O 2 nitrates DELIVERY calcium channel antagonists

ORGANIC NITRATES

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

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

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)

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

UNDESIRABLE EFFECTS OF NITRATES

 INCREASED MYOCARDIAL O2 DEMAND - reflex tachycardia - reflex increase in contractility  DECREASED MYOCARDIAL PERFUSION - decreased diastolic perfusion time due to tachycardia

EFFECT

Headache

Adverse effects of nitrates OCCURRENCE

Common Occasional Nausea and vomiting Dizziness or overt syncope Palpitations and tachycardia Tolerance and attenuation Occasional Uncommon Common

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

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

EXCRETION OF NITRATES

 Primarily in the form of glucuronide derivatives of the denitrated metabolites  Largely by way of the kidney

BETA-ADRENORECEPTOR BLOCKING DRUGS

•

MAJOR DIFFERENCES AMONG BBs

ISA • Beta-receptor selectivity Cardioselective Nonselective • Local anesthetic action • Pharmacokinetic characteristics

Beta-blockers with ISA

 Acebutolol  Cartreolol  Celiprolol  Oxprenolol  Penbutolol  pindolol

Cardioselective beta-blokckers

 Acebutolol  Atenolol  Betaxolol  Bisoprolol  Celiprolol  Metoprolol

Non-selective beta-blockers

 Labetalol  Nadolol  Penbutolol  Pindolol  Propranolol  Sotalol  Timolol

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

Local anesthetic action

 Acebutolol  Betaxolol (slight)  Labetalol  Metoprolol  Pindolol  Propranolol

Pharmacokinetic differences

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

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

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

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

CALCIUM CHANNEL BLOCKING DRUGS

PHARMACOLOGIC EFFECTS OF CALCIUM CHANNEL BLOCKERS

VER DIL DHPS HR ↓ ↓ ↑↔ A-V CONDUCTION ↓↓↓ ↓ ↔ CONTRACTILITY ↓↓ ↓ ↓ ↔ PERIPHERAL VASODILATION ↑ ↑ ↑↑ CO v v v CBF ↑ ↑ ↑ MO 2 DEMAND ↓ ↓ ↓ ↑INCREASE; ↓ DECREASE; v VARIABLE;

A. Adverse cardiovascular effects of calcium channel antagonists

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

B. Noncardiac Side Effects Associated with Calcium Channel Blockers SYMPTOM VERAPAMIL DILTIAZEM NIFEDIPINE

Headache Rare Rare Occasional Postural dizziness Flushing Peripheral edema Constipation Other gastrointestinal disorders Paresthesias Rare Rare Rare Common Rare Rare Rare Rare Rare Rare Rare Rare Common Common Common Rare Rare Occasional

METABOLIC DRUGS

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

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

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

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; T 1/2 7 hours

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

RANOLAZINE ( R )

    Inhibitor of the late Na + current (late I Na ) Inhibitor of the fast rectifying K + current (I

Kr

) 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

PHARMACOKINETICS OF R

      Sustained – release form Prolonged absorption with C max administration 4 – 6 h after oral Bioavailability 30% - 55% Plasma protein binding ~ 62% T 1/2 ~ 7h Steady state within 3 days

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

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

DRUG-DRUG INTERACTION

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

ADVERSE DRUG REACTIONS

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

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)

HEART-RATE LOWERING DRUGS

 Ivabradin (Procoralan 5 mg, 7,5 mg tablets)  Selective and specific inhibitor of I controls the spontaneous diastolic depolarisation in the sinus node f current that  Dose-dependent reduction in heart rate and MO 2

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

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

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

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

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

UNDESIRABLE EFFECTS

 Headache  Dizziness 

Bradycardia – 3,3%



Luminous phenomena (phosphenes) – 14,5%

 Uncontrolled blood pressure

Combinations of antianginal drugs COMBINATION BENEFICIAL SHOULD BE AVOIDED OR IS RELATIVELY CONTRAINDICATED

Nitrates + b-blocker X Nitrates + diltiazem, verapamil Nitrates + dihydropyridine X X b-blockers + dihydropyridine X b-blockers + diltiazem, verapamil X

Thienopyridines

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

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

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

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

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

• • •

EUROPA TRIAL EU

ropean trial on

R

eduction

O

f cardiac evens with

P

erindopril in stable coronary

A

rtery disease

Randomized, placebo controled, duble blind study 4 years follow-up 12218 patients at low risk; perindopril 8 mg vs placebo

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%

• • • • • • •

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

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

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)

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

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

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

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)

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).

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 ß 1 -blockers or LA Calcium antagonists or Trimetazidine or combination of these drugs

TREATMENT OF STABLE ANGINA ACCORDINGLY TO CCS CLASSIFICATION CLASS III and IV

As above and establish indications for invasive treatment