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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ischaemic heart disease
Ischaemic Heart Disease

Causes of IHD aren´t totally clear

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

slide3
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
slide6
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)

slide14
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

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
slide46
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.

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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