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

IHD

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

- Hyperlipoproteinemia- Hypertension- Diabetes mellitus- Smoking- Obesity- Family disposition- Male gender- Age

CAN BE INFLUENCED

CAN´T BE INFLUENCED

Radiation of pain at IHD

IHDChronic 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 (STEMI)

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 Study)

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

Antithrombotics

Antiplatelet drugs Anticoagulants Fibrinolytics

Antithrombotics

Antiplatelet drugs Anticoagulants Fibrinolytics (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

1. Inhibition of TXA A2 formation through prostaglandin pathway - inhibition of COX-1 (aspirin)

2. Inhibition of TXA A2 formation through increasing level of cAMP in thorbocyte - inhibition of fosfodiesterase (dipyridamole)

- stimulation of adenylatcyclase (prostacyclin)

3. Inhibition of fibrinogen bridges formation between thrombocytes - inhibition of receptor for ADP on thrombocyte membrane (thienopyridines –

ticlopidine, clopidogrel, prasugrel)(ticagrelor) - inhibition of receptor for fibrinogen on thrombocyte membrane - glykoprotein IIb/IIIa (fibans, abciximab)

Aspirin

• 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

Dipyridamole

• 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)

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

Nitroglycerin

• 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 disorders

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

Ca2+ Channel Blockers (CCB)

• Different chemical structures, with different hemodynamic and clinical effects

• According to chemical structure divided to:

- dihydropyridins (amlodipine, felodipine, lacidipine, nifedipine SR, isradipine)

- 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 wall

Verapamil and diltiazem influence also conduction system of the heart

Antianginal effect of CCB

Direct dilation of coronary arteries, can cause "steal phenomenon"

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

KI BB

• Atrial bradycardia

• Bradycardia below 50 per min

• Ischemic disease of lower extremities, worsening claudication

BB

• 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)

Molsidomine

• 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

Trimetazidine

• 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

Ivabradine

• Is blocker of sinus node, in which it blocks If flow

• Causes atrial bradycardia

Dyslipidemia

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

Hypolipidemics

endothelial dysfunction coronary vessels are less prone to

vasoconstriction = endothelium-protective + antithrombogenic

effects

• 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

Hypolipidemics

1. Affecting mainly cholesterol- statins

- 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

Statins

• 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 statins

• Inhibit enzyme HMG – CoA – reductase in hepatocytes; resulting in attenuation of cholesterol synthesis andsubsequent 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 pharmacons:

- ERYTHROMYCINE, CYCLOSPORINE, AZOLS

• Neuropathy• manifested is by sensory and sensorimotor disorders

• association with DM, increasing incidence of diabetic patients, especially difficulties in the differential diagnosis of neuropathy

• Rebound effect• abrupt discontinuation of statin therapy results in worsening of

the underlying disease

• occurs increase of pathological lipid levels (LDL cholesterol, TAG)

• occurs increased incidence of thromboembolic events (AP, IM)

Fibrates• Bind as a ligand to PPAR α = receptor alfa activated with peroxisome

proliferator => activity of lipoprotein lipase lipolysis of TAG and chylomicrones => catabolism

• ADRs:

• NAUSEA, DIARRHEA

• MYOPATHY (MORE OFTEN AT KIDNEY DISORDERS)

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 symptoms

• Nitrates

• Betablockers

• Calcium channel blockers

• Others (nicorandil – activator of pottassium channels, ivabradine, trimetazidine, molsidomine)