Transcript Document

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
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
• 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
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.
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
Non-pharmacologic approach
Changes of lifestyle (nicotine, food) →
lowering lipids
Psychosocial factors (excercise, taking care
of oneself) → primary and secondary
prevention
Risk factors
-
Hyperlipoproteinemia
Hypertension
Diabetes mellitus
Smoking
Obesity
Family disposition
Male gender
Age
CAN BE INFLUENCED
CAN´T BE
INFLUENCED
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)
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, it
significantly increases risk of coronary event
occurrence
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
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
Therapy of stable AP
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Antiplatelet drugs
Nitrates – EBM didn´t prove benefit
Calcium channel blockers
Betablockers
Others (molsidomin, trimetasidin,
ivabradin)
Antiplatelet drugs
(Antiaggregatory drugs)
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 (ASA, indobufen)
2. Inhibition of TXA A2 formation through increasing level
of cAMP in thorbocyte
- inhibition of fosfodiesterase (dipyridamole)
- stimulation of adenylatcyclase (prostacyclin)
1. 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)
Examples of Antiplatelet Drugs
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Aspirin
Ticlopidine
Clopidogrel
Indobufen
Dipyridamole
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
Ticlopidine
• Inhibition of platelet activation, mediated
by adenosindiphosphate, starting after
several days
• 2 times per day 250 mg
• Risk of leukopenia
Clopidogrel
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Tienopyridine
1 times per day 75 mg
Good tollerance
According to CAPRIE lowers
atherotrombotic complications
regardless of their localisation by 9%
more than ASA
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
Lower intensity and also frequency of
episodes, but according to EBM doesn´t
influence morbidity and mortality
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
• 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
• 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
2+
Ca 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)
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
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
Selectivity of CCB
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
• 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
• 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
• Suitable for monotherapy
• KI combination with BB, AV block
• Retard form 2 times per day
Beta Blockers
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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
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Metipranol – nonselective
Pindolol – nonselective with ISA
Metoprolol – cardioselective
Atenolol – cardioselective
Carvedilol – hybrid (alfa1 also beta)
Molsidomin
• At its administration no tollerance
• Not suitable for acute episode of AP
• Effective in long-term prevention
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
Ivabradin
• Is blocker of sinus node, in which it
blocks If flow
• Causes atrial bradycardia
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
Dyslipidemia
Is disorder of plasmatic protein metabolism
Can have different manifestation.
Disorder can have genetic or dietetic reason,
or other disease.
Classification of Lipids
Pharmacotherapy of
dyslipoprotinemias
1. Affecting mainly cholesterol
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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
2. Affecting cholesterol and TAG
- fibrates – fenofibrate
- derivates of nicotinic acid – lower synthesis of
VLDL in liver and so also formation of LDL
Statins
Inhibit enzyme HMGCoA reductase, and so
decreases intracellular synthesis of new cholesterol
and decreases concentration of LDL
Fibrates
Bind as ligand to PPAR α – receptor activated with
peroxisome proliferator
Increase lipolysis of lipoprotein lipases
State after MI
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Modification of life-style
Antiagreggatory therapy
Anticoagulant therapy
Betablockers
ACEI
CCB (calcium channel blockers)
Coronary angioplastic
Unstable AP
1.
2.
3.
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5.
Anticoagulant therapy
Antiaggregatory therapy
Nitrates
BB
Urgent angiography
Radiation of Pain at IHD