CLINICAL PHARMACOLOGY OF ANTIANGINAL DRUGS. CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC DRUGS

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CLINICAL PHARMACOLOGY OF ANTIANGINAL DRUGS.
CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC DRUGS
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ISCHEMIC HEART DISEASE

• There are 35 risk factors for development of IHD
• 3 most important ones are
• big triple
• hypercholesterolaemia
• arterial hypertension
• smoking
• 95 of patients with IHD are observed to have
  aterosclerotic changes in coronary arteries

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Antianginal (coronary active) drugs

• a group of drugs which using different
  mechanisms even out irregularities between
  myocardium need in oxygen and its blood supply
  by coronary arteries
• clinically it is manifested by removal or
  prevention of stenocardia attacks (improvement of
  disease current) and increasing of patients
  tolerance to physical load

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ANTIANGINAL (CORONARY ACTIVE) DRUGS

• ?. Nitrates and sidnonims which are close to the
  first ones
• ??. Bets-adrenoblockers
• ???. Antagonists of calcium ions
• ??. Activators of potassium channels
• Inhibitors of ATE
• Antiaggregants and anticoagulants
• Drugs with metabolic influence on miocardium

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NITRATES

• nitroglycerin
• isosorbid dinitrate
• isosorbid-5-mononitrate

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MECHANISM OF ACTION OF NITRATES

• Interaction with sulfhydryl (SH-) groups
  (nitrate receptors) inside cells of vascular
  smooth muscles
• Stimulation of formation of endothelial factor of
  relaxation of vessels (?RF) nitrogen oxide (NO)
  
• Decreasing of ionized ??2 contents
• Relaxation, dilation of vessels, including
  coronary vessels

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MECHANISM OF ACTION OF NITRATES

• Decreasing of tone of venules decreasing of
  preloading (income of blood into heart during
  diastole) decreasing of work of left ventricle
  and heart output
• Decreasing of tone of arterioles decreasing of
  afterloading (decreasing of arterial pressure,
  end diastolic pressure in left ventricle and its
  volume, decreasing of tension of myocardium wall
• decreasing of heart need in oxygen
• improvement of blood float in ischemic zone of
  myocardium redistribution of coronary blood
  circulation with increasing of perfusion of
  subendocardial areas
• dilation of large coronary vessels if they are
  in spasm or narrowed with aterosclerotic mass
• development of anastomoses between arteries in
  myocardium (in case of prolonged administration)

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NITROGLYCERINE

• Tablets (under the tongue)
• 1 alcohol or oil solution (under the tongue)
• aerosol
• Latent period - 2-3 min
• Duration of action - 20-30 min
• ampoules 1 solution intravenously dropply
  0,01 solution
• prolonged forms of nitroglycerine trinitrolong,
  sustak, nitrong, ointment, plaster

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NitroglycerineUnique transdermal system in a
form of plaster
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SIDE EFFECTS OF NITROGLYCERINE

• bursting, pulsating headache
• decreasing of arterial pressure
• (heartbeat, dizziness, collapse)
• skin redness, feeling of fever

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Contraindications for nitroglycerine use

• Close-angled form of glaucoma
• increasing of intracranial pressure, insult
• acute myocardium infarction (in case of presence
  of hypotonia and collapse)

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PROLONGED FORMS OF NITROGLYCERINE

• Trinitrolong polymer films (0,001 g or 0,002 g
  of nitroglycerine) action develops immediately,
  lasts for 3-5 hours
• Sustac Susta?-mite (contains 0,0026 g of
  nitroglycerine) and Sustac-forte (0,0064 g of
  nitroglycerine)
• beginning of action after 10 min,
• maximal action after 1 hour,
• duration of action 4-5 hours
• Nitrong microcapsule form of nitroglycerine of
  prolonged action
• latent period 30-60 min,
• maximal effect - after 3-4 hours,
• action duration - 6-8 hours

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Iso Mak Retard 20mgIso Mak Retard 40mg Isomak
Retard 60mg(isosorbid dinitrate)
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IsoketIsosorbid dinitrate
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SIDE EFFECTS OF NITRATES

• bursting, pulsating headache
• decreasing of arterial pressure
• (heartbeat, dizziness, collapse)
• skin redness, feeling of fever
• development of tolerance
• nitrate dependence
• syndrome of cancellation

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Other nitrates

• Nitrosorbid isosorbid dinitrate
• latent period 30-50 min,
• duration of action 4-6 hours and more
• With sublingual administration of the drug latent
  period grows short to 3-5 min
• buccal form (Dinitrolslrbilong)
• tablets of prolonged action (Isoket-retard)
• ointment
• aerosol
• drugs for intravenous introduction
• Isosorbid-5-mononitrate
• - pharmacologically active metabolite of
  isosorbid dinitrate
• duration of action - from 6 till 24 hours

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SYDNONIMS

• Molsydomin corvaton - sydnopharm
• is metabolized in liver forming a substance
  SIN-1a which contains free N? group (doesnt
  need previous interaction with SH-groups)
• nitrogen oxide stimulates guanilatecyclase that
  activates synthesis of cGMP
• cGMP causes dilation of vessels
• 2 mg of molsydomin 0,5 mg of nitroglycerine

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Molsydomin

• latent period - 20 min (5-10 min if
  administered sublingually), action duration - 6
  hours.
• can be used for prophylaxis and releasing
  stenocardia attacks in patients with glaucoma
  (doesnt increase intraoccular
  pressure)
• indicated for patients who make breaks in using
  nitrates to decrease tolerance towards them
• doesnt lead to development of tolerance (doesnt
  need previous combining with sulfhydryl groups)
• absence of cancellation syndrome

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BETA-ADRENOBLOCKERS

• Mechanism of action during stenocardia
• blockade of b1-adrenoreceptors of heart
  decreasing of power and frequency of heart
  contractions and as follows cardiac need in
  oxygen
• decreasing of thrombocyte aggregation and
  prevention of thrombus formation
• increasing of diastole duration improvement of
  coronary vessels saturation with blood
  improvement of perfusion of ischemic areas of
  myocardium
• Decreasing of calcium ions accumulation
  releasing of cardiac muscle tension, improvement
  of metabolic processes, increasing of ATP
  synthesis
• in case of acute myocardium infarction
  increasing of blood supply of ischemic areas of
  heart, decreasing of size of infarction seat,
  prevention of development of cardiac arrhythmias

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Anaprilin ß1- ß 2 adrenoblocker
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Vasocardin 100 mgMethoprolol tartrate
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Nadolol ( ß1, ß 2- adrenoblocker )
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CALCIUM IONS ANTAGONISTS

• 1. Derivatives of difenilalkilamin (verapamil)
• 2. Derivatives of benzothiazepine (dylthiazem)
• 3. Derivatives of dyhydropyridine (nifedipin,
  amlodipin, nimodipin)
• Drugs of 1 and 2 groups dominantly influence on
  heart (depress automatism of sinus node,
  conductivity through conductive heart system),
  show antiarrhythmic, antiangina and hypotensive
  action.
• Derivatives of dyhydropyridine (group of
  nifedipin) decrease blood pressure and cause
  dilation of coronary vessels, cause reflective
  tachycardia

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Nifedipin - corinfar - fenigidin - adalate

• Doesnt depress conductivity in myocardium,
• has a weak antiarrhythmic action
• Maximal concentration of the drug in blood
  occurs after 45-60 min after administration
  orally and after 2-3 min if administered
  sublingually
• Effect lasts for 4-6 hours

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Antagonists of calcium ions derivatives of
dyhydropyridine of ?? generation (amlodipin,
isradipin, nicardipin)

• almost dont cause tachycardia
• are indicated for prolonged treatment of patients
  with stabile stenocardia
• arent indicated in case of non stabile
  stenocardia (long lasting latent period)
•  

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Usage of calcium ions antagonists
Illness
Drugs
Hypertension
Verapamil
Dylthiazem
Nifedipin
Felodipin
Amlodipin
Stenocardia
Dylthiazem
Nifedipin
Amlodipin
Verapamil
Supraventricular tachy-arrhythmia
Verapamil
Dylthiazem
Possible combination with ß-blockers
Dylthiazem
Nifedipin
Amlodipin
Felodipin
-recommended drug


--should be used carefully
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Nifedipin (??2 ions antagonist of
dyhydropyrydine series)
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Nifedipin (??2 ions antagonist of
dyhydropyrydine series)
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Nifedipin (??2 ions antagonist of
dyhydropyrydine series)
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ACTIVATORS OF POTASSIUM CANALS

• NICORANDIL
• activates ??2-depending potassium canals
• causes relaxation of smooth muscles of vessels
• coronary, arteriolar and venous vasodilation
  
• improvement of blood supply of myocardium,
  decreasing of pre- and afterloads of heart,
  decreasing of myocardial need in oxygen,
  separation of ischemic damage zone

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Acetylsalicylic acid

• 80-100 mg per day as antiaggregative drug,
  decreases risk of development of acute myocardium
  infarction and decreases mortality of patients
  with IHD
• In many world countries it is also used a basis
  treatment drug of IHD which can be used for years

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ACUTE MYOCARDIUM INFARCTION

• one of the main reasons of disablement and
  mortality of people of employed age in many world
  countries, including Ukraine
• men suffer from MI almost 5 times more often than
  women
• Mortality of patients with MI during first two
  hours starting from the beginning of the process
  makes around 50 of all mortal cases connected
  with MI
• the most often death causes acute
  cardiac-vascular insufficiency (angina pectoris,
  lung edema, cardiogenic shock), heart rupture,
  heavy cardiac arrhythmia
• other complications of MI thrombosis and
  emboli, acute and chronic heart aneurisms,
  Dreslers syndrome, chronic cardiac insufficiency

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TREATMENT OF MYOCARDIUM INFARCTION

• three stages
• Immediate treatment decreasing pain and
  treatment of stop of heart beats
• Early treatment separation of zone of
  infarction seat and prevention of early life
  threatening complications (cardiac arrhythmias,
  acute cardiac insufficiency)
• Further treatment prevention and therapy of
  late complications of MI, prophylaxis of
  recurrent MI and death of the patients

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TREATMENT OF ACUTE MYOCARDIUM INFARCTION

• Releasing of pain and
• prophylaxis of cardiogenic shock
• nitroglycerin (1 tablet under the tongue every
  7-10 min.)
• Neuroleptanalgesia (fentanil with droperidol),
  morphine, omnopon, promedol (in combination with
  atropine, dimedrol, aminasine)
• nitrous oxide in combination with neuroleptics
• in case of remaining pain non narcotic
  analgesics in combination with antihistamine and
  neuroleptic drugs
• to increase arterial pressure during cardiogenic
  shock intravenously dropply dopamine (drugs of
  choice), noradrenalin, mesaton
• sometimes glucocorticosteroids are used

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TREATMENT OF ACUTE MIOCARDIUM INFARCTION

• Size limitation
• of infarction seat
• Intravenous dropply introduction of
• 0,01 nitroglycerin solution
• Administration of b-adrenoblockers

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TREATMENT OF ACUTE MYOCARDIUM INFARCTION

• Treatment and prophylaxis of heart arrhythmias
• Treatment of ventricular arrhythmias i.v.
  slowly 0,2 solution of xycain, novocainamid
  intramuscularly
• Prophylaxis of ventricular extrasystolia and
  tachycardia magnesium sulfate (intravenous
  dropping introduction of 4-5 solution),
• ?-adrenoblockers
• Arrhythmias of atrial origin heart glycosides,
  antagonists of calcium ions
• Bradycardia - isadrin, atropine sulfate, alupent
  (i.v.)

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TREATMENT OF ACUTE MYOCARDIUM INFARCTION

• CORRECTION OF BLOOD CLOTTING
• thrombolytic drugs
• streptokinase (1,5 mln OD), urokinase (2 mln
  OD), aktilise recombinant tissue activator of
  plasminogen (100 mg) intravenous
• after performing of thrombolytic therapy
  intravenous introduction of heparin, at first 10
  000 OD, after 1000 OD per hour during 24-48
  hours
• anticoagulants of indirect action
• acetylsalicylic acid
• (80-100-300 mg per day)

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TREATMENT OF ACUTE MYOCARDIUM INFARCTION

• Treatment of heart insufficiency
• i.v. furosemid (40-120 mg) i.v. dropply
  nitroglycerine (12-20 hours), morphine
• i.v. dropply dopamin and dobutamin
• heart glycosides in tachysystolic form of
  scintillating arrhythmia or fluttering of atria
  with moderate left-ventricular insufficiency
• General measures
• oxygen inhalation
• correction of acid-base balance

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ANTIARRHYTHMIC DRUGS CLASS Mechanism
of Action Drug name IA NaChannel
blocker Disopyramide, procainamide,
quinidine IB NaChannel blocker Lidocaine,
mexiletine, tocainide IC NaChannel
blocker Flecainide, propafenone II ?
Adrenoreceptor blocker Esmolol, metoprolol,
pindolol, propranolol III KChannel
blocker Amiodarone, bretylium, sotalol IV Ca
Channel blocker Diltiazem, verapamil Other
antiarrhythmic drugs Adenosine, digoxin