Department of Clinical Department of Clinical PharmacologyPharmacology

Pharmacotherapy Pharmacotherapy

of chronic ischemic heart of chronic ischemic heart diseasedisease

Jerzy Jankowski, MDJerzy Jankowski, MD

www.zfk.ump.edu.plwww.zfk.ump.edu.pl

www.ump.edu.pl/engwww.ump.edu.pl/eng

FORMS OF ANGINA FORMS OF ANGINA PECTORIS (AP)PECTORIS (AP)

• ATHEROSCLEROTIC (CLASSIC) ATHEROSCLEROTIC (CLASSIC) ANGINAANGINA

• VARIANT (VASOSPASTIC VARIANT (VASOSPASTIC ANGINA)ANGINA)

Anginal conditions other than CAD causing Anginal conditions other than CAD causing chest discomfortchest discomfort

Non-CAD causes of chest discomfortNon-CAD causes of chest discomfortSyndrome X:Syndrome X: Chest pain syndrome with objective Chest pain syndrome with objective evidence of ischemia and normal coronary arteries evidence of ischemia and normal coronary arteries on angiographyon angiography

Prinzmetals angina:Prinzmetals angina: Vasospastic angina with Vasospastic angina with normal or near-normal coronary arteries; can have normal or near-normal coronary arteries; can have Prinzmetals angina with significant CADPrinzmetals angina with significant CAD

Aortic stenosis:Aortic stenosis: Myocardial ischemia can be Myocardial ischemia can be caused by an imbalance between the increased caused by an imbalance between the increased myocardial oxygen demand related to left myocardial oxygen demand related to left ventricular hypertrophy and increased wall stress ventricular hypertrophy and increased wall stress and the available coronary blood supply in the and the available coronary blood supply in the absence of coronary atherosclerosisabsence of coronary atherosclerosis

Esophageal disease:Esophageal disease: Esophagitis, reflux, motility Esophagitis, reflux, motility disordersdisorders

ANTIANGINAL DRUGSANTIANGINAL DRUGS

• ORGANIC NITRATESORGANIC NITRATES

• ΒΒETA- ADRENORECEPTOR- BLOCKING ETA- ADRENORECEPTOR- BLOCKING DRUGSDRUGS

• CALCIUM CHANNEL- BLOCKING DRUGSCALCIUM CHANNEL- BLOCKING DRUGS

• METABOLIC AGENTSMETABOLIC AGENTS

• HEART – RATE LIMITING AGENTSHEART – RATE LIMITING AGENTS

DRUG ACTION IN ANGINADRUG ACTION IN ANGINA

• DECREASE MYOCARDIAL ODECREASE MYOCARDIAL O22 REQUIREMENT REQUIREMENT BY:BY:

decreasing peripheral vascular resitancedecreasing peripheral vascular resitance

decreasing cardiac outputdecreasing cardiac output

both waysboth ways

• INCREASE MYOCARDIAL OINCREASE MYOCARDIAL O22 DELIVERY DELIVERY

nitratesnitrates

calcium channel antagonistscalcium channel antagonists

ORGANIC NITRATESORGANIC NITRATES

ORGANIC NITRATESORGANIC NITRATES NTG, ISDN, IS-5-MNNTG, ISDN, IS-5-MN Donors of NO in vascular smooth muscle cellsDonors of NO in vascular smooth muscle cells Induce cross-tolerance when given in large Induce cross-tolerance when given in large

dosesdoses All are highly lipophylicAll are highly lipophylic The lipophility (depending on the The lipophility (depending on the

stereochemical configuration and the number stereochemical configuration and the number of ONO2-groups) affects the degree of of ONO2-groups) affects the degree of activation of guanylate cyclase, of the NO-activation of guanylate cyclase, of the NO-release and of a rapid onset of efficacy (NTG release and of a rapid onset of efficacy (NTG >> ISDN ISDN >> IS-5-MN) IS-5-MN)

Due to a slow denitration IS-5-MN maintaines Due to a slow denitration IS-5-MN maintaines the effects for hoursthe effects for hours

ORGANIC NITRATESORGANIC NITRATES

The higher the lipophylity of a nitrate, the The higher the lipophylity of a nitrate, the higher the velocity of its uptake in different higher the velocity of its uptake in different tissues tissues

( NTG ( NTG >> ISDN ISDN >> IS-5-MN ), particularly in IS-5-MN ), particularly in the smooth muscle cells of blood vesselsthe smooth muscle cells of blood vessels

Nitrates are acting via the release of NO – Nitrates are acting via the release of NO – they need intracellular SH-groups to form they need intracellular SH-groups to form NONO

PHARMACOKINETICS PHARMACOKINETICS CHARACTERISTICSCHARACTERISTICS

• AFTER ORAL ADMINISTRATIONAFTER ORAL ADMINISTRATION• EXTENSIVE FIRST-PASS EFFECT (90%)EXTENSIVE FIRST-PASS EFFECT (90%)• LOW BIOAVAILABILITY (10%)LOW BIOAVAILABILITY (10%)

• AFTER SUBLINGUAL ADMINISTRATIONAFTER SUBLINGUAL ADMINISTRATION• RAPID ONSET OF ACTION (1-3 min)RAPID ONSET OF ACTION (1-3 min)• BRIEF DURATION OF ACTION (up to 30 BRIEF DURATION OF ACTION (up to 30

min)min)

MECHANISM OF MECHANISM OF ANTIANGINAL ACTION OF ANTIANGINAL ACTION OF

NITRATESNITRATES DECREASED MYOCARDIAL O2 CONSUMPTION DECREASED MYOCARDIAL O2 CONSUMPTION - decreased LV dimension- decreased LV dimension - decreased LV filling pressure- decreased LV filling pressure - decreased LV systolic pressure- decreased LV systolic pressure - decreased vascular impedence- decreased vascular impedence

INCREASED CORONARY BLOOD SUPPLAYINCREASED CORONARY BLOOD SUPPLAY - epicardial coronary artery dilation- epicardial coronary artery dilation - coronary stenosis enlargement- coronary stenosis enlargement - dilation of coronary collaterals- dilation of coronary collaterals

ANTIPLATELET ANTITHROMBOTIC ACTION ANTIPLATELET ANTITHROMBOTIC ACTION

UNDESIRABLE EFFECTS UNDESIRABLE EFFECTS OF NITRATESOF NITRATES

INCREASED MYOCARDIAL O2 DEMANDINCREASED MYOCARDIAL O2 DEMAND - reflex tachycardia- reflex tachycardia - reflex increase in contractility- reflex increase in contractility

DECREASED MYOCARDIAL PERFUSIONDECREASED MYOCARDIAL PERFUSION - decreased diastolic perfusion - decreased diastolic perfusion

timetime due to tachycardiadue to tachycardia

Adverse effects of nitratesAdverse effects of nitrates

EFFECT EFFECT OCCURRENCEOCCURRENCE

HeadacheHeadache CommonCommon

Nausea and vomitingNausea and vomiting OccasionalOccasional

Dizziness or overt Dizziness or overt syncopesyncope

OccasionalOccasional

Palpitations and Palpitations and tachycardiatachycardia

UncommonUncommon

Tolerance and Tolerance and attenuationattenuation

CommonCommon

MECHANISMS OF NITRATE MECHANISMS OF NITRATE TOLERANCETOLERANCE

BIOCHEMICAL TOLERANCE BIOCHEMICAL TOLERANCE == CELLULAR CELLULAR - exhaustion of the cysteine (SH) - exhaustion of the cysteine (SH)

storestore - decreased sensivity of guanylate - decreased sensivity of guanylate

cyclasecyclase

PSEUDO-TOLERANCE PSEUDO-TOLERANCE == ACTIVATION OF ACTIVATION OF NEUROHUMORAL MECHANISMSNEUROHUMORAL MECHANISMS

- increased sympathetic activity- increased sympathetic activity - increased ACE activity- increased ACE activity

Avoidance of nitrate Avoidance of nitrate tolerancetolerance

Use smallest effective doseUse smallest effective dose

Administer the fewest possible Administer the fewest possible doses per daydoses per day

Avoid continuous or sustained Avoid continuous or sustained exposure to nitratesexposure to nitrates

Provide a nitrate-free interval of Provide a nitrate-free interval of ≥≥10 h every day10 h every day

EXCRETION OF EXCRETION OF NITRATESNITRATES

Primarily in the form of glucuronide Primarily in the form of glucuronide derivatives of the denitrated derivatives of the denitrated metabolitesmetabolites

Largely by way of the kidneyLargely by way of the kidney

BETA-BETA-ADRENORECEPTOR ADRENORECEPTOR BLOCKING DRUGSBLOCKING DRUGS

MAJOR DIFFERENCES MAJOR DIFFERENCES AMONG BBsAMONG BBs

• ISAISA

• Beta-receptor selectivityBeta-receptor selectivity CardioselectiveCardioselective NonselectiveNonselective

• Local anesthetic actionLocal anesthetic action

• Pharmacokinetic characteristicsPharmacokinetic characteristics

Beta-blockers with ISABeta-blockers with ISA

AcebutololAcebutolol CartreololCartreolol CeliprololCeliprolol OxprenololOxprenolol PenbutololPenbutolol pindololpindolol

Cardioselective beta-Cardioselective beta-blokckersblokckers

AcebutololAcebutolol AtenololAtenolol BetaxololBetaxolol BisoprololBisoprolol CeliprololCeliprolol MetoprololMetoprolol

Non-selective beta-Non-selective beta-blockersblockers

LabetalolLabetalol NadololNadolol PenbutololPenbutolol PindololPindolol PropranololPropranolol SotalolSotalol TimololTimolol

Generations of beta-Generations of beta-blockersblockers

I generation: non-selective BBsI generation: non-selective BBs II generation: cardioselective BBsII generation: cardioselective BBs III generation: beta-blockers (non-III generation: beta-blockers (non-

selective or cardioselectve BBs) with selective or cardioselectve BBs) with vasodilator activity: carvedilol, vasodilator activity: carvedilol, celiprolol, nebivololceliprolol, nebivolol

Local anesthetic actionLocal anesthetic action

AcebutololAcebutolol Betaxolol (slight)Betaxolol (slight) LabetalolLabetalol MetoprololMetoprolol PindololPindolol PropranololPropranolol

Pharmacokinetic Pharmacokinetic differencesdifferences

Lipid solubilityLipid solubility: penbutolol, propranolol, : penbutolol, propranolol, labetalol, metoprolol, pindolol, timolollabetalol, metoprolol, pindolol, timolol

Low lipid solubilityLow lipid solubility: acebutolol, : acebutolol, atenolol, betaxolol, bisoprolol, esmolol, atenolol, betaxolol, bisoprolol, esmolol, nadolol, sotalolnadolol, sotalol

A. Solubility characteristics of -A. Solubility characteristics of -blocking agentsblocking agents

HydrophilicityHydrophilicity

Lack of hepatic first-pass effect lowers Lack of hepatic first-pass effect lowers the chance of drug interactions and the chance of drug interactions and food interferencefood interference

     Often results in longer half-lifeOften results in longer half-life

        Low penetrability into CNS, resulting Low penetrability into CNS, resulting in fewer side effectsin fewer side effects

LipophilicityLipophilicity

        Requires hepatic metabolismRequires hepatic metabolism

        Greater chance of significant first-pass Greater chance of significant first-pass effecteffect

        Often results in shorter half-lifeOften results in shorter half-life

        Higher penetrability into the CNSHigher penetrability into the CNS

Mechanism of action in angina and Mechanism of action in angina and cardiovascular effects of -blocking cardiovascular effects of -blocking agentsagents

Decreased myocardial oxygen Decreased myocardial oxygen consumptionconsumption

        Decreased heart rateDecreased heart rate

Decreased blood pressureDecreased blood pressure

Decreased myocardial contractilityDecreased myocardial contractility

Increased coronary blood supplyIncreased coronary blood supply

Preserved coronary blood flow Preserved coronary blood flow because obecause of f prolonged diastoleprolonged diastole

Adverse effects of -blocking agentsAdverse effects of -blocking agentsCardiacCardiac

        Increased ventricular volume resulting in congestive heart failureIncreased ventricular volume resulting in congestive heart failure

        Excessive heart rate slowing or heart blockExcessive heart rate slowing or heart block

        Withdrawal syndromeWithdrawal syndrome

NoncardiacNoncardiac

        FatigueFatigue

        Mental depressionMental depression

        InsomniaInsomnia

NightmareNightmare

          Raynauds phenomenonRaynauds phenomenon

          Worsened claudication symptomsWorsened claudication symptoms

         BronchoconstrictionBronchoconstriction

MetabolicMetabolic

        Increased LDL cholesterol and triglycerides; lowered HDL cholesterolIncreased LDL cholesterol and triglycerides; lowered HDL cholesterol

        Worsening of insulin-induced hypoglycemia; masking of hypoglycemic Worsening of insulin-induced hypoglycemia; masking of hypoglycemic symptomssymptoms

        Increased blood sugar in insulin-resistant diabeticsIncreased blood sugar in insulin-resistant diabetics

CALCIUM CHANNEL-CALCIUM CHANNEL-BLOCKING DRUGSBLOCKING DRUGS

PHARMACOLOGIC EFFECTS OF PHARMACOLOGIC EFFECTS OF CALCIUM CHANNEL BLOCKERSCALCIUM CHANNEL BLOCKERS

VER DIL DHPSVER DIL DHPSHR ↓ ↓ ↑↔HR ↓ ↓ ↑↔A-V CONDUCTION ↓↓↓ ↓ ↔A-V CONDUCTION ↓↓↓ ↓ ↔CONTRACTILITY ↓↓ ↓ ↓ ↔CONTRACTILITY ↓↓ ↓ ↓ ↔PERIPHERAL PERIPHERAL VASODILATION ↑ ↑ ↑↑VASODILATION ↑ ↑ ↑↑CO v v vCO v v vCBF ↑ ↑ ↑CBF ↑ ↑ ↑MOMO2 2 DEMAND ↓ ↓ ↓DEMAND ↓ ↓ ↓

↑↑INCREASE; ↓ DECREASE; v VARIABLE;INCREASE; ↓ DECREASE; v VARIABLE;

A. Adverse cardiovascular effects of A. Adverse cardiovascular effects of calcium channel antagonistscalcium channel antagonistsSYMPTOMSYMPTOM CAUSECAUSE IMPLICATED CALCIUM IMPLICATED CALCIUM

CHANNEL ANTAGONISTCHANNEL ANTAGONIST

Dizziness, light-headedness, Dizziness, light-headedness, syncope, palpitationsyncope, palpitation

Excessive Excessive hypotensionhypotension

AllAll

BradycardiaBradycardia Verapamil, diltiazemVerapamil, diltiazem

Reflex Reflex tachycardiatachycardia

DihydropyridinesDihydropyridines

Exacerbation or Exacerbation or precipitation of congestive precipitation of congestive heart failureheart failure

Negative Negative inotropic actioninotropic action

Most; amlodipine, felodipine Most; amlodipine, felodipine are the safest to use, even are the safest to use, even in heart failurein heart failure

Severe bradycardia or heart Severe bradycardia or heart blockblock

Negative Negative chronotropic chronotropic action, especially action, especially sick sinus node sick sinus node diseasedisease

Verapamil, diltiazemVerapamil, diltiazem

Precipitation of anginaPrecipitation of angina Hypotension, Hypotension, coronary stealcoronary steal

Nifedipine and possibly Nifedipine and possibly other dihydropyridinesother dihydropyridines

B. Noncardiac Side Effects Associated B. Noncardiac Side Effects Associated with Calcium Channel Blockerswith Calcium Channel BlockersSYMPTOMSYMPTOM VERAPAMILVERAPAMIL DILTIAZEMDILTIAZEM NIFEDIPINE NIFEDIPINE

HeadacheHeadache RareRare RareRare Occasional Occasional

Postural dizzinessPostural dizziness RareRare RareRare CommonCommon

FlushingFlushing RareRare RareRare CommonCommon

Peripheral edemaPeripheral edema RareRare RareRare CommonCommon

ConstipationConstipation CommonCommon RareRare RareRare

Other Other gastrointestinal gastrointestinal disordersdisorders

RareRare RareRare RareRare

ParesthesiasParesthesias RareRare RareRare Occasional Occasional

METABOLIC DRUGSMETABOLIC DRUGS

METABOLIC INHIBITORS WITH CARDIO-METABOLIC INHIBITORS WITH CARDIO-CYTOPROTECTIVE EFFECTCYTOPROTECTIVE EFFECT

RANOLAZINE (RANEXA 375mg, 500mg, RANOLAZINE (RANEXA 375mg, 500mg, 750mg)750mg)

TRIMETAZIDINE (PREDUCTAL MR 35mg)TRIMETAZIDINE (PREDUCTAL MR 35mg)

TRIMETAZIDINETRIMETAZIDINE

• 3 - ketoacylo – CoA thiolase inhibitor3 - ketoacylo – CoA thiolase inhibitor

• In cells exposed to ischaemia, the drug: In cells exposed to ischaemia, the drug: - - prevents a decrease in intracellular ATP levelsprevents a decrease in intracellular ATP levels

- reduces intracellular acidosis- reduces intracellular acidosis

- alterations in transmembrane ion flow - alterations in transmembrane ion flow

- decreases the migration and infiltration of - decreases the migration and infiltration of PNNPNN

TRIMETAZIDINETRIMETAZIDINE

In man the drug:In man the drug:

- increases coronary flow reserve- increases coronary flow reserve

- limits rapid swings in blood - limits rapid swings in blood pressurepressure

- decreases the frequency of angina - decreases the frequency of angina attacksattacks

- decreases the use of NTG- decreases the use of NTG

PK OF TRIMETAZIDINEPK OF TRIMETAZIDINE

Well absorbed with Cmax, on average, Well absorbed with Cmax, on average, 5 hours after taking the tablet5 hours after taking the tablet

Protein binding is lowProtein binding is low

Eliminated primarily in the urine, Eliminated primarily in the urine, mainly in the unchanged form; Tmainly in the unchanged form; T1/2 1/2 7 7 hours hours

TRIMETAZIDINETRIMETAZIDINE

Side effects:Side effects:

- gastrointestinal (dyspepsia, diarrhoea, nausea,- gastrointestinal (dyspepsia, diarrhoea, nausea,

vomiting, constipation)vomiting, constipation)

- nervous system (headaches, vertigo, sleep - nervous system (headaches, vertigo, sleep disorders)disorders)

aggravation of Parkinsonian symptomsaggravation of Parkinsonian symptoms

- cardiovascular (orthostatic hypotension)- cardiovascular (orthostatic hypotension)

- skin disorders - skin disorders Special warnings: pregnancy and Special warnings: pregnancy and

breastfeedindg breastfeedindg

RANOLAZINE ( R )RANOLAZINE ( R )

Inhibitor of the late NaInhibitor of the late Na++ current (late current (late IINaNa))

Inhibitor of the fast rectifying KInhibitor of the fast rectifying K+ + current (current (IIKrKr))

Reduces CaReduces Ca++++ overload in the ischemic myocyteoverload in the ischemic myocyte

Does not affect NaDoes not affect Na++- H- H+ + and Naand Na++- Ca- Ca++

++exchangers exchangers Antianginal effect related to decreased LV Antianginal effect related to decreased LV

diastolic tension and improved myocardial diastolic tension and improved myocardial perfusionperfusion

PHARMACOKINETICS PHARMACOKINETICS OF ROF R

Sustained – release formSustained – release form Prolonged absorption with CProlonged absorption with Cmaxmax 4 – 6 h 4 – 6 h

after oral administrationafter oral administration Bioavailability 30% - 55%Bioavailability 30% - 55% Plasma protein binding Plasma protein binding ~~ 62% 62% TT1/21/2 ~~ 7h 7h Steady state within 3 daysSteady state within 3 days

RANOLAZINE RANOLAZINE METABOLISMMETABOLISM

CYP 3A4 – the major pathwayCYP 3A4 – the major pathway Additional pathways include:Additional pathways include:

- CYP 2D6 (10% - 15%)- CYP 2D6 (10% - 15%)

- glucuronidation (< 5%)- glucuronidation (< 5%) ~~ 5% excreted unchanged 5% excreted unchanged Weak inhibitor of CYP 3A4 and CYP 2D6Weak inhibitor of CYP 3A4 and CYP 2D6 Inhibitors of CYPs 3A4 and 2D6 increase Inhibitors of CYPs 3A4 and 2D6 increase

plasma R concentration 2 – 4 foldplasma R concentration 2 – 4 fold Clearance of R is reduced by renal Clearance of R is reduced by renal

insufficiency and moderate hepatic insufficiency and moderate hepatic impairmentimpairment

DRUG – DRUG DRUG – DRUG INTERACTIONINTERACTION

Inhibitors of CYP 3A4 (itraconazole, Inhibitors of CYP 3A4 (itraconazole, ketokonazole, voriconazole, HIV protease ketokonazole, voriconazole, HIV protease inhibitors, clarithromycin, verapamil, diltiazem, inhibitors, clarithromycin, verapamil, diltiazem, erythromycin, fluconazole grapefruit juiceerythromycin, fluconazole grapefruit juice

Inhibitors of CYP 2D6 (paroxetine)Inhibitors of CYP 2D6 (paroxetine) Inhibitors of P-gp (cyclosporin, verapamil)Inhibitors of P-gp (cyclosporin, verapamil)

INCREASED EXPOSURE TO RANOZALINE INCREASED EXPOSURE TO RANOZALINE

DRUG-DRUG DRUG-DRUG INTERACTIONINTERACTION

CYP 2D6 inducers (rifampicin, CYP 2D6 inducers (rifampicin, phenytoin, phenobarbital, phenytoin, phenobarbital, carbamazepine, St. John’s Wort)carbamazepine, St. John’s Wort)

DECREASED EXPOSURE TO DECREASED EXPOSURE TO RANOZALINERANOZALINE

ADVERSE DRUG ADVERSE DRUG REACTIONSREACTIONS

Mild to moderate in severityMild to moderate in severity Common ADRs: dizziness, headache, Common ADRs: dizziness, headache,

constipatin, vomiting, nausea, constipatin, vomiting, nausea, ECG effects: ↑QTc, ↓T wave ECG effects: ↑QTc, ↓T wave

amplitude, T wave notchingamplitude, T wave notching

CONTRAINDICATIONS CONTRAINDICATIONS

Hypersensitivity to the drugHypersensitivity to the drug Severe renal impairment (CrC < Severe renal impairment (CrC <

30ml/min)30ml/min) Moderate or severe hepatic impairmentModerate or severe hepatic impairment Co-administration of potent CYP 3A4 Co-administration of potent CYP 3A4

inhibitorsinhibitors LQTSLQTS Co-administration QT-prolonging drugs Co-administration QT-prolonging drugs

(quinidine, dofetilide, sotalol) (quinidine, dofetilide, sotalol)

HEART-RATE LOWERING HEART-RATE LOWERING DRUGSDRUGS

Ivabradin (Procoralan 5 mg, 7,5 mg Ivabradin (Procoralan 5 mg, 7,5 mg tablets)tablets)

Selective and specific inhibitor of Selective and specific inhibitor of IIff current that controls the spontaneous current that controls the spontaneous diastolic depolarisation in the sinus nodediastolic depolarisation in the sinus node

Dose-dependent reduction in heart rate Dose-dependent reduction in heart rate and MOand MO22

INDICATIONSINDICATIONS

Symptomatic treatment of chronic stable Symptomatic treatment of chronic stable angina pectoris with normal sinus rhythm: angina pectoris with normal sinus rhythm:

- in adults unable to tolerate or with a - in adults unable to tolerate or with a contra- contra-

indication to the use of beta-blockersindication to the use of beta-blockers

- or in combination with beta-blockers in - or in combination with beta-blockers in pts pts

inadequately controlled with an optimal inadequately controlled with an optimal beta- beta-

blocker dose and whose rate is blocker dose and whose rate is >> 60 bpm 60 bpm Treatment of chronic heart failureTreatment of chronic heart failure

PHARMACOKINETICSPHARMACOKINETICS

S-enantiomer, highly water-solubleS-enantiomer, highly water-soluble Rapidly and completely absorbed from the Rapidly and completely absorbed from the

gutgut C max after 1 hour under fasting conditionC max after 1 hour under fasting condition Food delays absorption by 1 h and Food delays absorption by 1 h and

increases plasma contrentation by 20 to increases plasma contrentation by 20 to 30%30%

Plasma protein bounding 70%Plasma protein bounding 70% Half-life 11 hoursHalf-life 11 hours

BIOTRANSFORMATIONBIOTRANSFORMATION

Metabolised by CYP 3A4 Metabolised by CYP 3A4 onlyonly Active metabolite – N-desmethlated Active metabolite – N-desmethlated

derivativederivative Very low affinity for CYP 3A4Very low affinity for CYP 3A4 CYP 3A4 inhibitors and inducers influence CYP 3A4 inhibitors and inducers influence

its metabolism and pharmacokineticsits metabolism and pharmacokinetics Treatment including Treatment including potent CYP 3A4 potent CYP 3A4

inhibitorsinhibitors as azole antifungals, macrolide as azole antifungals, macrolide antibiotics, HIV protease inhibitors, antibiotics, HIV protease inhibitors, nefazodone is nefazodone is contraindicatedcontraindicated

BIOTRANSFORMATIONBIOTRANSFORMATION

the combination of ivabradine withthe combination of ivabradine with moderate CYP 3A4 inhibitorsmoderate CYP 3A4 inhibitors (diltiazem, verapamil)(diltiazem, verapamil) is not is not recommendedrecommended

CYP 3A4 inducers (rifampicin, CYP 3A4 inducers (rifampicin, barbiturates, phenytoin, St barbiturates, phenytoin, St JohnJohn,,s Wort) s Wort) may may decreasedecrease ivabradine exposure and activityivabradine exposure and activity

CONTRAINDICATIONSCONTRAINDICATIONS

Hypersensitivity to the active substanceHypersensitivity to the active substance Resting heart rate below 60 bpm prior to Resting heart rate below 60 bpm prior to

treatmenttreatment Acs, cardiogenic shock, severe hypotensionAcs, cardiogenic shock, severe hypotension Severe hepatic insufficiencySevere hepatic insufficiency Sick sinus syndrom, sino-atrial blockSick sinus syndrom, sino-atrial block A-V block of 3rd degreeA-V block of 3rd degree Combination with strong CYP 3A4 inhibitorsCombination with strong CYP 3A4 inhibitors Pregnancy, lactationPregnancy, lactation

UNDESIRABLE EFFECTSUNDESIRABLE EFFECTS

HeadacheHeadache DizzinessDizziness Bradycardia – 3,3%Bradycardia – 3,3% Luminous phenomena Luminous phenomena

(phosphenes) – 14,5%(phosphenes) – 14,5% Uncontrolled blood pressureUncontrolled blood pressure

Combinations of antianginal drugsCombinations of antianginal drugsCOMBINATIONCOMBINATION BENEFICIALBENEFICIAL SHOULD BE SHOULD BE

AVOIDED OR IS AVOIDED OR IS RELATIVELY RELATIVELY CONTRAINDICATCONTRAINDICATEDED

Nitrates + Nitrates + bb-blocker-blocker XXNitrates + diltiazem, Nitrates + diltiazem, verapamilverapamil

XX

Nitrates + Nitrates + dihydropyridinedihydropyridine

XX

b-blockers + b-blockers + dihydropyridinedihydropyridine

XX

b-blockers + b-blockers + diltiazem, verapamildiltiazem, verapamil

XX

ThienopyridinesThienopyridines

Ticlopidine (2 x 250 mg)Ticlopidine (2 x 250 mg) Clopidogrel (1 x 75 mg)Clopidogrel (1 x 75 mg) P2Y12 adenosine diphosphate P2Y12 adenosine diphosphate

receptor blockerreceptor blocker For 1 year after NSTEMI, STEMI, For 1 year after NSTEMI, STEMI,

PCI + DESPCI + DES

GASTROINTESTINAL GASTROINTESTINAL RISKS OF ANTIPLATELET RISKS OF ANTIPLATELET

THERAPYTHERAPY

ASA causes topical injury to the mucosa ASA causes topical injury to the mucosa and systemic effects induced by and systemic effects induced by prostaglandin depletionprostaglandin depletion

Tissue PGs are produced via 2 pathways: Tissue PGs are produced via 2 pathways: COX-1 and COX-2 pathwayCOX-1 and COX-2 pathway

Clopidogrel – impairs the healing of gastric Clopidogrel – impairs the healing of gastric ulcers by inhibiting platelet release of pro-ulcers by inhibiting platelet release of pro-angiogenic growth factors ( VEGF ) which angiogenic growth factors ( VEGF ) which promotes endothelial proliferation and promotes endothelial proliferation and accelerates the healing of ulcersaccelerates the healing of ulcers

GASTROINTESTINAL GASTROINTESTINAL RISKS OF ANTIPLATELET RISKS OF ANTIPLATELET

THERAPY THERAPY

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

GASTROINTESTINAL GASTROINTESTINAL RISKS OF ANTIPLATELET RISKS OF ANTIPLATELET

THERAPYTHERAPY Recommendation: substitution of clopidogrel for Recommendation: substitution of clopidogrel for

ASA is not recommended strategy to reduce the ASA is not recommended strategy to reduce the risk of recurrent ulcer bleeding in high-risk risk of recurrent ulcer bleeding in high-risk patients and is inferior to the combination of ASA patients and is inferior to the combination of ASA plus PPIplus PPI

Recommendation: when warfarin is added to ASA Recommendation: when warfarin is added to ASA plus clopidogrel an INR of 2,0 to 2,5 is plus clopidogrel an INR of 2,0 to 2,5 is recommendedrecommended

Recommendation: PPIs are the preferred agents Recommendation: PPIs are the preferred agents for the therapy and prophylaxis of ASA-associated for the therapy and prophylaxis of ASA-associated UGIEUGIE

GASTROINTESTINAL GASTROINTESTINAL RISKS OF ANTIPLATELET RISKS OF ANTIPLATELET

THERAPYTHERAPY Esomeprazol and pantoprazol are Esomeprazol and pantoprazol are

preferred PPIs in patients treated with preferred PPIs in patients treated with clopidogrelclopidogrel

Omeprazol is not recommended due to Omeprazol is not recommended due to a risk of significant interaction with a risk of significant interaction with clopidogrelclopidogrel

EUROPA TRIALEUROPA TRIALEUEUropean trial on ropean trial on

RReduction eduction OOf cardiac f cardiac

evens with evens with PPerindopril in erindopril in

stable coronary stable coronary AArtery rtery disease disease • Randomized, placebo controled, duble Randomized, placebo controled, duble

blind studyblind study• 4 years follow-up4 years follow-up• 12218 patients at low risk; perindopril 12218 patients at low risk; perindopril

8 mg vs placebo8 mg vs placebo

EUROPA TRIAL - EUROPA TRIAL - RESULTSRESULTS

• The primary end-point ( cardiovascular The primary end-point ( cardiovascular death + nonfatal MI + non fatal cardiac death + nonfatal MI + non fatal cardiac arrest ) arrest ) ↓ 20%↓ 20%

• Risk of MIRisk of MI ( fatal + nonfatal ) ( fatal + nonfatal ) ↓ ↓ 24%24%

• Hospitalisation for HF Hospitalisation for HF ↓ ↓ 39%39%

PERTINENT TRIALPERTINENT TRIALPERindopril, Thrombosis, PERindopril, Thrombosis,

INflammation,INflammation,Endothelial dysfunction and Endothelial dysfunction and

NeurohormonalNeurohormonalactivaTionactivaTion• Rate of apoptosis of ECRate of apoptosis of EC

• Activity and expression of NOSActivity and expression of NOS• Proapoptotic protein BaxProapoptotic protein Bax• Antiapoptotic protein Bcl-2Antiapoptotic protein Bcl-2• Von Willebrand factorVon Willebrand factor• Levels of AT II, bradykinin, TNFLevels of AT II, bradykinin, TNF• Assesment at baseline and after 1 year of Assesment at baseline and after 1 year of

treatmenttreatment

PERTINENT TRIAL - PERTINENT TRIAL - RESULTSRESULTS

One year of treatment with One year of treatment with perindopril was able significantly perindopril was able significantly reduce the rate of apoptosis and reduce the rate of apoptosis and increase the activity and increase the activity and expression of NOSexpression of NOS

LIPID-LOWERING LIPID-LOWERING THERAPYTHERAPY

Statins – HMG-CoA reductase inhibitorsStatins – HMG-CoA reductase inhibitors

Atorvastatin, simvastatin, fluvastatin, pravastatin, Atorvastatin, simvastatin, fluvastatin, pravastatin, rosuvastatinrosuvastatin

Significant LDL reduction, relatively small Significant LDL reduction, relatively small reduction in TG, minor increas in HDLreduction in TG, minor increas in HDL

Lower is better ( LDL Lower is better ( LDL << 70 mg%) 70 mg%)

Fibrates – fenofibrate (↑ HDL)Fibrates – fenofibrate (↑ HDL)

Ezetimib (Ezetrol 10mg)Ezetimib (Ezetrol 10mg)

S T A T I N SS T A T I N S

Natural (fungal fermentation): lovastatin, Natural (fungal fermentation): lovastatin, simvastatin, pravastatinsimvastatin, pravastatin

Synthetic: fluvastatin, atorvastatin, Synthetic: fluvastatin, atorvastatin, rosuvastatinrosuvastatin

Metabolized by CYP 3A4: lovastatin, Metabolized by CYP 3A4: lovastatin, simvastatin, atorvastatinsimvastatin, atorvastatin

CYP 2C9 for fluvastatinCYP 2C9 for fluvastatin Pravastatin does not use CYP P450Pravastatin does not use CYP P450 Hydrophilic statins: pravastatin, fluvastatinHydrophilic statins: pravastatin, fluvastatin

ADVERSE EFFECTS OF ADVERSE EFFECTS OF STATINSSTATINS

All statins are well toleratedAll statins are well tolerated Most common ADRs are mild, transient, reversible Most common ADRs are mild, transient, reversible

– dyspepsia, abdominal pain, flatulence– dyspepsia, abdominal pain, flatulence The most important ADRs are liver toxicity (↑ The most important ADRs are liver toxicity (↑

ATs) and myopathy ( pain, weakness, ↑CK ≥ 10 X)ATs) and myopathy ( pain, weakness, ↑CK ≥ 10 X) Rhabdomyolysis and acute renal failure – very Rhabdomyolysis and acute renal failure – very

rarerare Risk of muscle toxicity increases during therapy Risk of muscle toxicity increases during therapy

with cyclosporine, erythromycin, clarithromycin, with cyclosporine, erythromycin, clarithromycin, azole antifungals, protease inhibitors – CYP 3A4 azole antifungals, protease inhibitors – CYP 3A4 inhibitorsinhibitors

Major purposes of the Major purposes of the treatmenttreatment

To improve short and long term To improve short and long term prognosis by preventing MI and prognosis by preventing MI and death and thereby increase the death and thereby increase the length of lifelength of life

To improve quality of life by To improve quality of life by reducing symptoms of angina and reducing symptoms of angina and occurrence of ischemiaoccurrence of ischemia

Recommendations for Recommendations for Pharmacotherapy To Pharmacotherapy To

Prevent MI and Death and Prevent MI and Death and To Reduce Symptoms To Reduce Symptoms

The following agents should be used in patients The following agents should be used in patients with symptomatic chronic stable angina to with symptomatic chronic stable angina to prevent MI or death and to reduce symptoms: prevent MI or death and to reduce symptoms:

AspirinAspirin (level of evidence: A) or clopidogrel (level of evidence: A) or clopidogrel when aspirin is absolutely contraindicated when aspirin is absolutely contraindicated (level of evidence: B) (level of evidence: B)

ß-Blockersß-Blockers in patients with previous MI (level in patients with previous MI (level of evidence: A) or without previous MI (level of of evidence: A) or without previous MI (level of evidence: B) evidence: B)

Low-density lipoprotein cholesterol–lowering Low-density lipoprotein cholesterol–lowering therapy with a therapy with a statinstatin (level of evidence: A) (level of evidence: A)

ACE inhibitorACE inhibitor (level of evidence: A) (level of evidence: A)

Recommendations for Recommendations for Pharmacotherapy To Pharmacotherapy To

Prevent MI and Death and Prevent MI and Death and To Reduce SymptomsTo Reduce Symptoms

The following agents should be used in patients The following agents should be used in patients with symptomatic chronic stable angina to with symptomatic chronic stable angina to reduce symptoms only: reduce symptoms only:

Sublingual Sublingual nitroglycerin nitroglycerin or nitroglycerin or nitroglycerin spray for the immediate relief of angina (level spray for the immediate relief of angina (level of evidence: B) of evidence: B)

Calcium antagonistsCalcium antagonists (long-acting) or long- (long-acting) or long-acting acting nitrates nitrates when ß-blockers are clearly when ß-blockers are clearly contraindicated (level of evidence: B) contraindicated (level of evidence: B)

Calcium antagonistsCalcium antagonists (long-acting) or long- (long-acting) or long-acting acting nitratesnitrates in combination with ß-blockers in combination with ß-blockers when ß-blockers alone are unsuccessful (level when ß-blockers alone are unsuccessful (level of evidence: B).of evidence: B).

TREATMENT OF STABLE ANGINA TREATMENT OF STABLE ANGINA ACCORDINGLY TO CCS ACCORDINGLY TO CCS

CLASSIFICATIONCLASSIFICATIONCLASS I correction of risk factors, CLASS I correction of risk factors,

nitroglycerin sl nitroglycerin sl aspirin 75 mg aspirin 75 mg

CLASS II as above+ chronic therapy withCLASS II as above+ chronic therapy with LA nitrates or LA nitrates or

ßß11-blockers or-blockers or LA Calcium antagonists orLA Calcium antagonists or Trimetazidine orTrimetazidine or combination of these drugscombination of these drugs

TREATMENT OF STABLE ANGINA TREATMENT OF STABLE ANGINA ACCORDINGLY TO CCS ACCORDINGLY TO CCS

CLASSIFICATIONCLASSIFICATION

CLASS III and IV CLASS III and IV

As above and As above and

establish indications for invasive establish indications for invasive treatmenttreatment