Download Slajd 1 - Zakład Farmakologii Klinicznej w Poznaniu

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 nearnormal 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 O2 REQUIREMENT BY:
decreasing peripheral vascular resitance
decreasing cardiac output
both ways
• INCREASE MYOCARDIAL O2 DELIVERY
nitrates
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 NOrelease 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
Adverse effects of nitrates
EFFECT
OCCURRENCE
Headache
Common
Nausea and vomiting
Occasional
Dizziness or overt syncope
Occasional
Palpitations and tachycardia
Uncommon
Tolerance and attenuation
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 CHANNELBLOCKING DRUGS
PHARMACOLOGIC EFFECTS OF
CALCIUM CHANNEL BLOCKERS
HR
A-V CONDUCTION
CONTRACTILITY
PERIPHERAL
VASODILATION
CO
CBF
MO2 DEMAND
VER
↓
↓↓↓
↓↓
↑
v
↑
↓
DIL DHPS
↓
↑↔
↓
↔
↓
↓↔
↑
v
↑
↓
↑↑
v
↑
↓
↑INCREASE; ↓ DECREASE; v VARIABLE;
A. Adverse cardiovascular effects of calcium channel
antagonists
SYMPTOM
CAUSE
Dizziness, light-headedness, syncope, Excessive hypotension
palpitation
IMPLICATED CALCIUM
CHANNEL ANTAGONIST
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
Verapamil, diltiazem
Precipitation of angina
Hypotension, coronary
steal
Nifedipine and possibly other
dihydropyridines
B. Noncardiac Side Effects Associated with Calcium
Channel Blockers
SYMPTOM
VERAPAMIL
DILTIAZEM
NIFEDIPINE
Headache
Rare
Rare
Occasional
Postural dizziness
Rare
Rare
Common
Flushing
Rare
Rare
Common
Peripheral edema
Rare
Rare
Common
Common
Rare
Rare
Other gastrointestinal
disorders
Rare
Rare
Rare
Paresthesias
Rare
Rare
Occasional
Constipation
METABOLIC DRUGS
METABOLIC INHIBITORS WITH CARDIOCYTOPROTECTIVE 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; T1/2 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 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
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
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 If current that
controls the spontaneous diastolic depolarisation
in the sinus node

Dose-dependent reduction in heart rate and MO2
INDICATIONS


Symptomatic treatment of chronic stable angina
pectoris with normal sinus rhythm:
- in adults unable to tolerate or with a contraindication to the use of beta-blockers
- or in combination with beta-blockers in pts
inadequately controlled with an optimal betablocker 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
Nitrates + b-blocker
X
Nitrates + diltiazem,
verapamil
X
Nitrates + dihydropyridine
b-blockers + dihydropyridine
b-blockers + diltiazem,
verapamil
SHOULD BE
AVOIDED OR IS
RELATIVELY
CONTRAINDICATED
X
X
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
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
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)
STATINS






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
ß1-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