Pharmocotherapy of Ischaemic
Heart Disease
Ischaemic Heart Disease
Causes of IHD aren´t totally clear
No satisfactory causal treatment, we eliminate
only symptoms and treat complications
Is condition/disease, at which requirements of
myocardium exceed possibilities of its supply with
oxydized blood.
The cause of this imbalance is wide spectrum of
patophysiologic mechanisms and reasons:
- cardiac: coronary, extracoronary
- extracardiac
Disturbances of blood perfusion can develop slowly
and progressively (chronic) or can develop abruptly
(acute form; even MI).
Changes caused by ischemia can be temporary or
permanent (irreparable damage of myocard).
Conditions are usually interconnected, without
sharp limits and IHD needs to be understood
dynamically and individually.
Angina pectoris
• Anginous pain is symptom of IHD
• Not every ischemia is accompanied with
pain – silent ischemia (only at ECG –
depression of ST segment)
Patologically-anatomical ground
Coronary atherosclerosis
Organ damage – embolia, vasculitis
Function impairment – spasms, defects in
relaxation of arteriolas
Risk factors
Diabetes mellitus
Family disposition
Male gender
Radiation of pain at IHD
Chronic forms:
Stable angina pectoris
(Chronic heart failure)
Acute coronary syndromes (ACS):
Unstable angina pectoris
ACS without ST elevation
AMI without ST segment elevation (NSTEMI)
AMI with ST segment elevation
Sudden heart death
Types of AP
• Stable – occurence of problems at standard situations and their frequency,
intensity and duration not changed
• Unstable – sudden beginning, longer duration of pain. Reason is disruption of an
atherosclerotic plaque.
• Prinzmetal´s (variant, vasospastic) – caused by spasmus, elevation of
ST segment on ECG
• Cardial syndrome X – decreased blood flow to heart tissue but with normal
coronary arteries. Findings of microvascular dysfunction.
Non-pharmacologic approach
Changes of lifestyle (nicotine, alcohol, diet –
lowering lipid intake, excercise)
Psychosocial factors (stress, relaxation)
Primary prevention
Active monitoring and searching for persons
having risk factors with the goal to prevent
formation of atherosclerosis
HST – postmenopausal women
Women´s Health Initiative Study proved, that among
women in the first year of using HST, it significantly
increases risk of coronary event occurrence
Primary prevention – low doses of aspirin
Males – accorcing to clinical studies taking aspirin
din´t decrease mortlity, decreased occurrence of MI,
increased cerebral bleeding (US Physician´s Health
Females – even more unclear – prospective study
1991 showed that occurrence of the first MI
decreased, but overall or cardiovascular mortality
didn´t decrease
Secondary prevention
Consistent pharmacologic intervention to
influence all risk factors among persons
with clinically manifested IHD, among
persons after MI, with the goal to prevent or
at least slower disease progression
Antiplatelet drugs
Antiplatelet drugs
(inh. thrombocyty)
(inh. coagulation factors) (dissolve clots)
Antiplatelet drugs (Antiaggregatory
drugs) – secondary prevention
Antiplatelet therapy decreases among
patients with AP risk of complications
(MI, sudden heart death) by 23 %.
Antiplatelet drugs devided according to mechanism
of action
Inhibition of TXA A2 formation through prostaglandin pathway inhibition of COX-1 (aspirin)
Inhibition of TXA A2 formation through increasing level of cAMP
in thorbocyte
- inhibition of fosfodiesterase (dipyridamole)
- stimulation of adenylatcyclase (prostacyclin)
Inhibition of fibrinogen bridges formation between thrombocytes
- inhibition of receptor for ADP on thrombocyte membrane
(thienopyridines – ticlopidine, clopidogrel, prasugrel)
- inhibition of receptor for fibrinogen on thrombocyte membrane glykoprotein IIb/IIIa (fibans, abciximab)
• Antiaggregatory effect is given by irreversible blockade of
COX-1 (thromboxane A2 is missing)
• Optimal dose is about 100 mg/day
• IND.- manifested IHD, AP, silent ischemia
• KI - allergy, ulcer, GIT bleeding
• Interactions – e.g. warfarin, ibuprofen
ADP receptor antagonists
• Thienopyridines: inhibition of platelet activation through
adenosine diphosphate by irreversible blockade of ADP
receptor; administered as prodrug
ticlopidine – risk of leukopenia
clopidogrel – good tollerance, according to CAPRIE
dicreases atherothrombotic complications by 9% more than
ASA (acetylsalicylic acid, aspirin)
prasugrel – more effective than clopidogrel
• ticagrelor – not prodrug as thienopyridines and reversible
blockade of ADP receptor; efficacy cca as prasugrel, maybe
↓ risk of bleeding
• Alone not recommended because of low
antiaggregatory effect and making worse IHD
„steal phenomenon“
• Combination of dipyridamole with retarded
release 200 mg and 30 mg ASA (Aggrenox) is
used in neurology in prevention of stroke
Nitrates Mechanism of Action
• Nitrates are changed by sulfhydrylic groups of gluthation
to nitrosotiol, from which in endothelium is released NO
(equivalent of EDRF)
• Vasodilation of epicardial coronary arteries
• Systemic venodilation, lower blood return and lower
metabolic requirements of myocardium
• In higher doses occurs vasodilation also in arterial portion
with subsequent BP reduction, which is compensated by
reflex tachycardia
Tollerance to Nitrates
• Maintaining of high plasmatic levels of nitrates
leads to their antianginal effect decrease
• Reason is depletion of free sulfhydrylic groups in
vessel wall
• We avoid tollerance by skipping one dose (10-12
hours without nitrates)
Lower intensity and also frequency of episodes,
but according to EBM doesn´t influence
morbidity and mortality
Stable IHD
1. We improve prognosis through prevention of
occurrence of MI and cardiovascular death
2. We eliminate and decrease symptoms of
patient – medications, catetrisation,
aortocoronary bypass
• Different application forms
• At sublingual administration pain subsides in 1-5 minutes
• At peroral administration effect starts in 20-40 minutes and
lasts 2-6 hours
• Used mainly at acute episodes
• ADRs: headache, facial flushing, palpitations, orthostatic
History of Nitroglycerin
• AP was the first time described in the second half of 18th century by
Wiliam Heberden and treated with nitroglycerin in the year 1879.
• Alfred Bernhard Nobel - a Swedish chemist, engineer.
• His established the most prestigious award in the field of physics,
chemistry, literature, physiology, medicine and peace-making (the
Nobel Prize).
• He invented dynamite in 1867 (the original composition: 75%
nitroglycerin, diatomaceous earth 24.5% and 0.5% soda).
• When Nobel suffered from heart problems, his doctor prescribed him
nitroglycerin. Nobel refused to take it. In a letter he wrote: It's irony
that I was now prescribed by the physician to eat nitroglycerin.
Isosorbide Dinitrate, Isosorbide Mononitrate
• For the prevention of angina pectoris
• KI: acute circulatory failure, cardiogenic shock,
systolic blood pressure below 90 mmHg, use of
sildenafil, tadalafil, vardenafil
Ca Channel
Blockers (CCB)
• Different chemical structures, with different hemodynamic
and clinical effects
• According to chemical structure divided to:
- dihydropyridins (amlodipine, felodipine, lacidipine, nifedipine SR,
- phenylalkylamins (verapamil)
- benzothiazepins (diltiazem)
CCB – Mechanism of Action
Block influx of calcium to cell through slow L-type
channels and lower its intracellular concentration,
what causes relaxation of smooth muscles in vessel
Verapamil and diltiazem influence also conduction
system of the heart
Antianginal effect of CCB
Direct dilation of coronary arteries, can cause "steal
Systemic arterial dilation with a consequent
reduction in peripheral vascular resistance
Verapamil ˃ diltiazem impact on the conduction
system of the heart
Selectivity of CCB
Nifedipine (dihydropyridine CCB)
• The oldest CCB
• If nowadays administered, only as sustained-release form!
• Otherwise occurs fast vasodilation with subsequent reflex
activation of sympathicus – tachycardia
• 2nd and 3rd generation of DHP are much more convenient
More Convenient Dihydropyridine CCB
• Amlodipine – 1 times per day 5-10 mg,
possible combination with BB
• Felodipine – 1 times per day 5-10 mg
• Isradipine – 2 times per day 2.5 mg
• Lacidipine – 4-8 mg daily
• Nitrendipine – 1 times per day 10-40 mg
Verapamil (non-dihydropyridine CCB)
• Only phenylalkylamine in practice
• Administered to patients, who can´t take BB
• KI – combination with BB
AV blocks II., III. degree
Lowers renal excretion of digoxin
Diltiazem (non-dihydropyridine CCB)
• Suitable for monotherapy
• KI: combination with BB, AV block
• Retard form 2 times per day
Beta Blockers (BB)
• Decrease oxygen consumption
• Increase fibrilation treshold
• Antiarrhytmic effect
• Stopping of administration can´t be abrupt
• Atrial bradycardia
• Bradycardia below 50 per min
• Ischemic disease of lower extremities,
worsening claudication
• We try to chose cardioselective drugs
• Importance of ISA is still questionable – not
recommended after overcomed MI
Representatives of BB
Metipranol – nonselective
Pindolol – nonselective with ISA
Metoprolol – cardioselective
Atenolol – cardioselective
Carvedilol – hybrid (alfa1 also beta)
• At its administration no tollerance (its effect unlike organic
nitrates does not require - SH groups)
• Its metabolite activates guanylyl cyclase and
subsequently increases cGMP (like organic nitrates) +
increases cAMP in platelets (antiplatelet effects)
• Not suitable for acute episode of AP
• Effective in long-term prevention
• 3-KAT inhibitor (metabolic modulator)
• Influences metabolism of cardiomyocytes
• At ischemia transfers ATP production from to
oxygen more demanding beta-oxidation of fatty
acids to glykolysis, which demands less oxygen
• Has no hemodynamic effects
• Is blocker of sinus node, in which it blocks
If flow
• Causes atrial bradycardia
Is disorder of plasmatic protein metabolism
and can have different manifestation.
Disorder can have genetic or dietetic reason,
possible also other associated disease.
Classification of Lipids
•  endothelial dysfunction  coronary vessels are less prone to
vasoconstriction = endothelium-protective + antithrombogenic
• instead of "normal levels" of lipids is currently used term
"target levels" of lipids, which better reflects the scientific
evidence that the risk of atherosclerosis is continuously growing
with LDL> 2.0 mmol/l
1. Affecting mainly cholesterol
bile acid-binding resins – cholestyramine,
colestipol (bind bile acids in the small intestine,
reduce CH in the liver and increase the catabolism
of LDL)
ezetimibe – selective inhibitor of CH resorbtion
2. Affecting cholesterol and TAG
- fibrates
- derivates of nicotinic acid – lower synthesis of
VLDL in liver and so also formation of LDL
• cholesterol-independent or “pleiotropic” effects of statins
• improving endothelial function, enhancing the stability of
atherosclerotic plaques, decreasing oxidative stress and
inflammation, and inhibiting the thrombogenic response.
Have beneficial extrahepatic effects on the immune
system, CNS, and bone.
• e.g.: pravastatin, lovastatin, flluvastatin, simvastatin,
atorvastatin, rosuvastatin
Mechanism of lipid
lowering action by
• Inhibit enzyme HMG – CoA
– reductase in hepatocytes;
resulting in attenuation of
cholesterol synthesis and
subsequent induction of the
LDL receptor production
(increased uptake of LDL
from blood)
Statins ADRs
• Myopathy
• the biggest problem, controll of CK
• th CERIVASTATINE 16 – 80x more => deregistration
• higher risk: at combination with drugs increasing concentration
of statins or other drugs with possible myotoxicity
• Rhabdomyolysis – 5-10 cases / 1 000 000 treated
• drugs inhibiting metabolism of statins dependent from
cytochrome CYP3A4, increase occurence of statin toxicity, it is
important to lower doses at the combination with these
• Neuropathy
• manifested is by sensory and sensorimotor disorders
• association with DM, increasing incidence of diabetic patients,
especially difficulties in the differential diagnosis of
• Rebound effect
• abrupt discontinuation of statin therapy results in worsening of
the underlying disease
• occurs increase of pathological lipid levels (LDL cholesterol,
• occurs increased incidence of thromboembolic events (AP,
• Bind as a ligand to PPAR α = receptor alfa activated with peroxisome
proliferator =>  activity of lipoprotein lipase   lipolysis of TAG
and chylomicrones =>  catabolism
• ADRs:
e.g.: fenofibrate, gemfibrozil
Nicotinic acid - Niacin
• the oldest hypolipidemic drug (from 1950)
•  HDL-ch +  TAG a LDL
• ADRs – flush, pruritus (nowadays little used – only with
combination with laropiprant)
Therapy of stable AP- improving prognosis
• Antiplatelet drugs (mainly ASA and clopidogrel)
• Hypolipidemic drugs (statins)
• ACE inhibitors
• Betablockers
Therapy of stable AP- therapy/prevention of
• Nitrates
• Betablockers
• Calcium channel blockers
• Others (nicorandil – activator of pottassium channels,
ivabradine, trimetazidine, molsidomine)

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