Transcript inhibition of COX-1

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
IHD
Chronic forms:
Stable angina pectoris
(Chronic heart failure)
Acute coronary syndromes (ACS):
Unstable angina pectoris
AMI without ST segment elevation
AMI with ST segment elevation
Sudden cardiac death
ACS without ST elevation
(NSTEMI)
(STEMI)
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
• Cardiac Syndrome X
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)
Radiation of Pain at IHD
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
Antithrombotics
Antiaggregatory drugs
Anticoagulants
Thrombolytics
(inh. platelets)
(inh. coagulatory factors) (dissolve thrombus)
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 (aspirin)
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)
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
•
•
•
•
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)
Glyceryl trinitrate (GTN)
• Different application forms
• At sublingual administration pain subsides
in 1-5 minutes
• At peroral administration effect starts in 2040 minutes and lasts 2-6 hours
• Used mainly at acute episodes
• ADR: headache, flushing, palpitations,
ortosthatic disturbances
Long-acting nitrate preparations
• GTN, isosorbide dinitrate, isosorbide mononitrate
(all come in long-acting preparations)
• Prevention of angina pectoris
• KI: acute circulatory failure, cardiogenic shock,
systolic blood pressure below 90 mm Hg, the use
of sildenafil, tadalafil, verdenafil
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)
- 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 slow-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 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
•
•
•
•
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
•
•
•
•
•
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
Trimetazidine
• 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
Ranolazine
• Mechanism of action is not absolutely
known
• Can have some antianginal effects due to
inhibition of late sodium current in heart
cells
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
 Target levels of lipids according to CVS risk (2005)
mmol/l
TOTAL CH
5
NON-HDL-CH
4
LDL-CHOLESTEROL
Patients with high CVS risk
Patients with very high CVS risk
3
 2,5
1,8
TRIACYLGLYCEROLS
2
HDL-CH
1
2011 – important is level of LDL!
Hypolipidemics
1. 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
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
• pravastatine ≤ lovastatine ≤ flluvastatine ≤ simvastatine ≤
atorvastatine ≤ rosuvastatine
• statins  total and coronary mortality
• have pleiotropic effects (endothelium, inflammation,
coagulation,...)
Statins ADR
• Myopathy
 biggest problem, check CK
 th CERIVASTATIN 16 – 80x more frequently =>
deregistration
 higher risk: at combination of statins with drugs increasing
concentration of statins, or myotoxic drugs
 rhabdomyolysis – 5-10 cases / million treated
• drugs inhibiting metabolism of statins (CYP3A4), increase
occurance of statin toxicity, important dose reduction at
combination therapy:
- ERYTHROMYCIN, CYKLOSPORIN, AZOLES
• Neuropathy
- manifested by sensory and sensorimotor disturbances
- association with DM, the main difficulties in the differential
diagnosis of neuropathy
• Rebound effect
- sudden discontinuation of statin therapy can result in
worsening of the underlying disease
- increase of pathological levels of lipids (LDL cholesterol, TG)
- increased incidence of thromboembolic events (AP, MI,)
Combination Therapy with Statins
• Ezetimibe
• Fenofibrate
• ?CEPT inhibitors
• ?PSCK9 inhibitors
Ezetimibe
• drug that lowers plasma cholesterol levels by decreasing
cholesterol absorption in the small intestine
• I: combination with statints at patients where with monotherapy
aren´t reached normal values = dual inhibition
Fibrates
Bind as ligand to PPAR α – receptor activated with peroxisome
proliferator
Increase lipolysis of lipoprotein lipases
Fibrates
ADRs:
NAUSEA, DIARRHEA, NAUSEA
MYOPATHY (MORE FREQUENT AT RENAL DISEASES)
LDL-CH.
TOTALCH.
TG
HDL-CH.




FENOFIBRAT E
 ALSO URIC ACID
CIPROFIBRATE
 FIBRINOGEN
BEZAFIBRATE
IMPROVES GLUCOSE TOLLERANCE
GEMFIBROZIL
 FIBRINOGEN
Therapy of stable AP- improving
prognosis
• Antiplatelet therapy (mainly ASA and clopidogrel)
• Hypolipidemics (statins)
• ACE inhibitors
• Betablockers (at patients after MI)
Therapy of stable APtherapy/prevention of symptoms
•Nitrates
•Betablockers
•Calcium channel blockers
•Others (nicorandil, ivabradine, molsidomine, ranolazine)