Pharmocotherapy of Ischaemic Heart Disease

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Pharmocotherapy of Ischaemic Heart Disease
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Ischaemic Heart Disease

• Causes of IHD arent totally clear
• No satisfactory causal treatment, we eliminate
  only symptoms and treat complications

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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

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Clinical Forms of IHD

• Acute unstable angina pectoris
• acute myocardial infarction
• sudden heart death
• Chronic asymptomatic IHD
• angina pectoris - after excercise
• - combined
• - variant
• - Prinzmetals
• state after MI
• dysrythmic IHD
• chronic heart failure

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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
• Prinzmetals caused by spasmus, elevation of ST
  segment on ECG

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

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Angina pectoris

• Anginous pain is symptom of IHD
• Not every ischemia is accompanied with pain
  silent ischemia (only at ECG depression of ST
  segment)

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Patologically-anatomical ground

• Coronary atherosclerosis
• Organ damage embolia, vasculitis
• Function impairment spasms, defects in
  relaxation of arteriolas

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Non-pharmacologic approach

• Changes of lifestyle (nicotine, food) ? lowering
  lipids
• Psychosocial factors (excercise, taking care of
  oneself) ? primary and secondary prevention

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Risk factors

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

CAN BE INFLUENCED
CANT BE INFLUENCED
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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 dint decrease mortlity, decreased
  occurrence of MI, increased cerebral bleeding (US
  Physicians Health Study)

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• females even more unclear prospective study
  1991 showed that occurrence of the first MI
  decreased, but overall or cardiovascular
  mortality didnt decrease
• HST postmenopausal women
• Womens Health Initiative Study proved, that
  among women in the first year of using HST, it
  significantly increases risk of coronary event
  occurrence

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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

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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

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Therapy of stable AP

• Antiplatelet drugs
• Nitrates EBM didnt prove benefit
• Calcium channel blockers
• Betablockers
• Others (molsidomin, trimetasidin, ivabradin)

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Antiplatelet drugs (Antiaggregatory drugs)

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

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

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Examples of Antiplatelet Drugs

• Aspirin
• Ticlopidine
• Clopidogrel
• Indobufen
• Dipyridamole

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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

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Ticlopidine

• Inhibition of platelet activation, mediated by
  adenosindiphosphate, starting after several days
• 2 times per day 250 mg
• Risk of leukopenia

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Clopidogrel

• Tienopyridine
• 1 times per day 75 mg
• Good tollerance
• According to CAPRIE lowers atherotrombotic
  complications regardless of their localisation by
  9 more than ASA

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Indobufen

• Dose 2 times per day 200 mg is effective in
  already 2 hours
• Effect is reversible, vanishes till 24 hours
• 10 days before planned surgery we administer
  instead of ASA

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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

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Nitrates

• Lower intensity and also frequency of episodes,
  but according to EBM doesnt influence morbidity
  and mortality

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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

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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)

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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

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Ca2 Channel Blockers (CCB)

• Different chemical structures, with different
  hemodynamic and clinical effects
• According to chemical structure divided to
• - dihydropyridins (amlodipine, felodipine,
  lacidipine, nifedipine, isradipine)
• - phenylalkylamins (verapamil, gallopamil)
• - benzothiazepins (diltiazem)

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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, decrease in
  contractility, electrical irritability and
  conductivity of conducting system of the heart

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separate sodium-calcium exchange channel.
                                                                                                                                                                                                                 
separate sodium-calcium exchange channel.
                                                                                                                                                                                                                 
separate sodium-calcium exchange channel.
                                                                                                                                                                                                                 
 

                                                      
 
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Antianginal effect of CCB

• 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 heart
• contractility and frequency

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Selectivity of CCB
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Nifedipine

• The oldest Ca2CB
• 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

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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

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Verapamil

• Only phenylalkylamine in practice
• Administered to patients, who cant take BB
• KI combination with BB
• AV blocks II., III. degree
• Lowers renal excretion of digoxin

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Diltiazem

• Suitable for monotherapy
• KI combination with BB, AV block
• Retard form 2 times per day

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Beta Blockers

• Decrease oxygen consumption
• Increase fibrilation treshold
• Antiarrhytmic effect
• Stopping of administration cant be abrupt

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KI BB

• Atrial bradycardia
• Bradycardia below 50 per min
• Ischemic disease of lower extremities,
  worsening claudication

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BB

• We try to chose cardioselective drugs
• Importance of ISA is still questionable not
  recommended after overcomed MI

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Representatives

• Metipranol nonselective
• Pindolol nonselective with ISA
• Metoprolol cardioselective
• Atenolol cardioselective
• Carvedilol hybrid (alfa1 also beta)

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Molsidomin

• At its administration no tollerance
• Not suitable for acute episode of AP
• Effective in long-term prevention

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Trimetazidin

• 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

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Ivabradin

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

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Hyperhomocysteinemia

• Marker of increased cardiovaskular risk, no its
  reason
• Preventive taking of niacin has no proven benefit
  
• No pharmacologic proofs, that lowering of
  homocysteinemia is connected with lower risk of
  CVD occurance

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Dyslipidemia

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

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Classification of Lipids
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Pharmacotherapy of dyslipoprotinemias

• Affecting mainly cholesterol
• Statins atorvastatin
• Bile acid-binding resins cholestyramine (bind
  bile acids in the small intestine, reduce CH in
  the liver and increase the catabolism of LDL)
• 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

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Statins
Inhibit enzyme HMGCoA reductase, and so decreases
intracellular synthesis of new cholesterol and
decreases concentration of LDL
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Fibrates
Bind as ligand to PPAR a receptor activated
with peroxisome proliferator Increase lipolysis
of lipoprotein lipases
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State after MI

1. Modification of life-style
2. Antiagreggatory therapy
3. Anticoagulant therapy
4. Betablockers
5. ACEI
6. CCB (calcium channel blockers)
7. Coronary angioplastic

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Unstable AP

1. Anticoagulant therapy
2. Antiaggregatory therapy
3. Nitrates
4. BB
5. Urgent angiography

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Radiation of Pain at IHD