Pharmocotherapy of ischaemic heart disease
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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.

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Pharmocotherapy of Ischaemic Heart Disease

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Pharmocotherapy of ischaemic heart disease

Pharmocotherapy of Ischaemic Heart Disease


Ischaemic heart disease

Ischaemic Heart Disease

Causes of IHD aren´t totally clear

No satisfactory causal treatment, we eliminate only symptoms and treat complications


Pharmocotherapy of ischaemic heart disease

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


Clinical forms of ihd

Clinical Forms of IHD

Acute – unstable angina pectoris

acute myocardial infarction

sudden heart death

Chronic – asymptomatic IHD

angina pectoris- after excercise

- combined

- variant

- Prinzmetal´s

state after MI

dysrythmic IHD

chronic heart failure


Types of ap

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

  • Prinzmetal´s – caused by spasmus, elevation of ST segment on ECG


Pharmocotherapy of ischaemic heart disease

Deffects of blood perfusion can develop slowly and progressively (chronic) or can develop abruptly (acute form; even MI).

Changes caused by ischaemia 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.

AP was the first time described in the second half of 18th century by Wiliam Heberden and treated with nitroglycerin in the year 1879.


Angina pectoris

Angina pectoris

  • Anginous pains is symptom of IHD

  • Not every ischaemia is accompanied with pain – silent ischaemia (only at ECG – depression of ST segment)


Patologically anatomical ground

Patologically-anatomical ground

Coronary atherosclerosis

Organ damage – embolia, vasculitis

Function impairment – spasms, defects in relaxation of arteriolas


Non pharmacologic approach

Non-pharmacologic approach

Changes of lifestyle (nicotine, food) → lowering lipids

Psychosocial factors (excercise, taking care of oneself) → primary and secondary prevention


Risk factors

Risk factors

  • Hyperlipoproteinaemia

  • Hypertension

  • Diabetes mellitus

  • Smoking

  • Obesity

  • Family disposition

  • Male gender

  • Age

CAN BE INFLUENCED

CAN´T BE

INFLUENCED


Primary prevention

Primary prevention

Active monitoring and searching for persons having risk factors with the goal to prevent formation of atherosclerosis

!! Low doses of acetylsalicylic acid!!

Males – accorcing to clinical studies taking aspirin din´t decrease mortlity, decreased occurrence of MI, increased cerebral bleeding (US Physician´s Health Study)


Pharmocotherapy of ischaemic heart disease

females even more unclear – prospective study 1991 showed that occurrence of the first MI decreased, but overall or cardiovascular mortality didn´t decrease

HST – postmenopausal women

Women´s Health Initiative Study proved, that among women in the first year of using HST significantly increases risk of coronary event occurrence


Secondary prevention

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


Stabilised ihd

Stabilised IHD

  • We make better prognosis through prevention of occurrence of MI and cardiovascular death

  • We eliminate and decrease symptoms of patient – medications, catetrisation, aortocoronary bypass


Therapy of stable ap

Therapy of stable AP

  • Antiaggregatory drugs

  • Nitrates – EBM didn´t prove benefit

  • Calcium channel blockers

  • Betablockers

  • Others (molsidomin, trimetasidin, ivabradin)


Drugs inhibiting platelet aggregation

Drugs Inhibiting Platelet Aggregation

Antiaggregatory therapy decreases among patients with AP risk of complications (MI, sudden heart death) by 23 %.


Drugs inhibiting platelet aggregation devided according to mechanism of action

Drugs inhibiting platelet aggregation devided according to mechanism of action

  • Inhibition of TXA A2 formation through prostaglandin pathway – inhibition of COX-1 (ASA, indobufen)

  • 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)

    - inhibition of receptor for fibrinogen on thrombocyte membrane – glykoprotein IIb/IIIa (fibans, abciximab)


Examples of drugs inhibiting platelet aggregation

Examples of Drugs Inhibiting Platelet Aggregation

  • Aspirin

  • Ticlopidine

  • Clopidogrel

  • Indobufen

  • Dipyridamole


Aspirin

Aspirin

  • Antiaggregatory effect is given by irreversible blockade of COX-1 (thromboxane A2 is missing)

  • Optimal dose is between 1 mg/1kg daily

  • IND.- manifested IHD, AP, silent ischaemia

  • KI – allergy, ulcer, GIT bleeding


Ticlopidine

Ticlopidine

  • Inhibition of platelet activation, mediated with adenosindiphosphate, starting after several days

  • 2 times per day 250 mg

  • Risk of leukopenia occurance


Clopidogrel

Clopidogrel

  • Tienopyridine

  • 1 times per day 75 mg

  • Good tollerance

  • According to CAPRIE lowers atherotrombotic complication occurance regardless of its localisation by 9% more than ASA


Indobufen

Indobufen

  • Dose 2 times per day 200 mg effective in already 2 hours

  • Effect is reversible, vanishes till 24 hours

  • 10 days before planned surgery we administer instead of ASA


Dipyridamole

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

Nitrates

Lower intensity and also frequency of episodes, but according to EBM doesn´t influence morbidity and mortality


Nitrates mechanism of action

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

  • In system 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

Tollerance

  • 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)


Nitroglycerin

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


Ca2 channel blockers

Ca2+ Channel Blockers

  • Different chemical structures, with different haemodynamic and clinic effects

  • According to chemical structure divided to:

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

    - phenylalkylamins (verapamil, gallopamil)

    - benzothiazepins (diltiazem)


Ca2 cb mechanism of action

Ca2+CB – Mechanism of Action

Block influx of calcium to cell through slow L-type channels, lower its intracellular concentration what causes relaxation of smooth muscle in vessel wall, decrease of contractility, decrease of electrical irritability and conductivity


Antianginal effect of ca2 cb

Antianginal effect of Ca2+CB

Direct dilation of coronary arteries and so increased oxygen supply

Decreased demand of myocardium to oxygen with systemic arterial dilation, with subsequent decrease of peripheral vascular resistance, decrease of

contractility and decrease of frequency


Selectivity of ca2 cb

Selectivity of Ca2+CB


Nifedipine

Nifedipine

  • The oldest Ca2+CB

  • If nowadays administered, only as retarded form!

  • Otherwise occurs fast vasodilation with subsequent reflex activation of sympathicus – tachycardia

  • 2nd and 3rd generation of DHP are much more convenient


More convenient dhp

More Convenient DHP

  • 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

Verapamil

  • Only phenylalkylamine in practice

  • Administered to patients, which can´t take BB

  • KI – combination with BB

    AV blocks II., III. degree

    Lowers renal excretion of digoxin


Diltiazem

Diltiazem

  • Suitable for monotherapy

  • KI combination with BB, AV block

  • Retard form 2 times per day


Beta blockers

Beta Blockers

  • Decrease oxygen consumption

  • Increase fibrilation base

  • Antiarrhytmic effect

  • Stopping of administration can´t be abrupt


Ki bb

KI BB

  • Atrial bradycardia

  • Bradycardia below 50 per min

  • Ischaemic disease of lower extremities, worsening claudication


Pharmocotherapy of ischaemic heart disease

BB

  • We try to chose cardioselective drugs

  • Importance of ISA is still questionable – not recommended after overcomed MI


Representatives

Representatives

  • Metipranol – nonselective

  • Pindolol – nonselective with ISA

  • Metoprolol – cardioselective

  • Atenolol – cardioselective

  • Carvedilol – hybrid (alfa1 also beta)


Molsidomin

Molsidomin

  • At its administration no tollerance

  • Not suitable for acute episode of AP

  • Effective in long-term prevention


Trimetazidin

Trimetazidin

  • Metabolic modulator

  • Influence metabolism of cardiomyocytes

  • At ischaemia transfers ATP production from to oxygen more demanding b-oxidation of fatty acids to glykolysis, which demands less oxygen

  • Has no haemodynamic effects


Ivabradin

Ivabradin

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

  • Causes atrial bradycardia


Hyperhomocysteinaemia

Hyperhomocysteinaemia

Marker of increased cardiovaskular risk, no its reason

Preventive taking of niacin has no proven benefit

No pharmacologic proofs, that lowering of homocysteinaemia is connected with lower risk of CVD occurance


Dyslipidemia

Dyslipidemia

Is disorder of plasmatic protein metabolism, can have different manifestation. Disorder can have genetic or dietetic reason, or connected disease.


Classification of lipids

Classification of Lipids


Pharmacotherapy of dyslipoprotinemias

Pharmacotherapy of dyslipoprotinemias

  • Affecting mainly cholesterol

    • Statins – atorvastatin

    • Bile acid sequestrants – cholestyramine

    • Ezetimibe – selective inhibitor of CH resorbtion

  • Affecting cholesterol and TAG

    - fibrates – fenofibrate

    - derivates of nicotinic acid – lower synthesis of VLDL in liver and so also formation of LDL


  • Statins

    Statins

    Inhibit enzyme HMGCoA reductase, and so decreases intracellular synthesis of new cholesterol a decreases concentration of LDL


    Fibrates

    Fibrates

    Bind as ligand for PPAR α – receptor activated with peroxisome proliferator

    Increase lipolysis of lipoprotein lipases


    State after mi

    State after MI

    • Modification of life-style

    • Antiagreggatory therapy

    • Anticoagulant therapy

    • Betablockers

    • iACE

    • Ca2+CB

    • Coronary angioplastic


    Unstable ap

    Unstable AP

    • Anticoagulant therapy

    • Antiaggregatory therapy

    • Nitrates

    • BB

    • Urgent angiography


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