Download Cardiovascular system pharmacology

Cardiovascular system pharmacology
*Cardiac stimulants : drugs that increase-heart rate and force of
contraction quickly .they are used mainly in the to treatment of heart block
include :
1- sympathomemitic drugs (adrenergic drugs) as epinephrine , isoprenaline
2- parasympatholytic drugs (anticholinergic drugs) as atropine
3- CNS stimulants as picrotoxine
4- drugs that directly effect on the heart as caffeine , aminophylline
Cardiac tonic :
(1)- Cardiac glycosides are the combination of aglycone & one to four
sugars. the aglycone is chemically similar to bile acids. It is the
pharmacologically active portion of glycosides.The sugar modify the water-&
lipid solubility of the glycosides molecules and thus,affect its potency and
duration of action.
- glycosides are obtained from dried leaves of the foxglove ( digitalis
purpurea) as digitoxin & gitoxin and from digitalis lanta as digoxine.
- pharmacological effects of digitalis:- the most important property of cardiac glycosides is their positive inotropic
effect , that is , their ability to ↑ the force of myocardial contraction .The result
is ↑ed cardiac work at reduced metabolic cost.
- digitalis also have effects on electrophysical properties of the heart (
conductivity , refractory period and automaticity)
- digitalis have extracardiac effects on vascular smooth muscle , neural tissue
and other tissue
Effect of digitalis on the heart :
1-Myocardial contractility :
Digitalis ↑ muscle contraction of cardiac muscle by ↑ing both velocity of
muscle contraction and the maximum force that is developed.
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Cardiovascular system pharmacology
Mechanism of action: digitalis combine reversibly with Na-K ATPase of
cardiac cell membrane , resulting in an inhibition of pump activity . This cause
an ↑ in the intracellular sodium concentration which flavors the transport of Ca
In to the cardiac cell via the Na – Ca exchange mechanism thus increase
intracellular Ca resuIt in ↑ in systolic force of contraction .
Mechanism of action of cardiac glycosides
2- electrophysiologic activity :
- the electrophysiologic effects of digitalis vary in different parts of heart ( atria
,A-V node , ventricules ).
3- heart rate : digitalis has little effect on heart rate in congestive heart
failure, digitalis slow H.R ( negative chromotropic effect , this result from vagal
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Cardiovascular system pharmacology
nerve stimulation .
adverse effects of digitalis
Cardiac glycosides have low margin of safety with lethal dose much closure
to the minimal effective dose (only 5-10 times)
large doses of the drug are associated with the intoxication due to depletion
of serum K+ ions.
Toxic signs produced by digitalis are :
Anroxia , nausea , vomiting , diarrhea , headache , fatigue , neuralgia ,
delirium , changes in vision. Also cardiac adverse effects are detected as
atrial & ventricular extrasystolics , tachycardia , ventricular fibrillation , AV or
SA node depression or block.
Treatment of digitalis toxicity:
1-cardiac glycosides & K+ ions depleting drugs are discontinued.
2-Kcl is administered orally by slow I.V infusion if hypokalemia is present
unless there is AV node. Some times , magnesium deficiency may
accompany hypokalemia so mg++ replacement may be necessary.
3-cholestyramine : binds to cardiac glycosides and has been used to faster
their elimination.
4-a digoxin specific Ab-fragment (FAB) from immunized sheep is nonimmunogenic & is available for treatment of life threatening toxicity.
(2)-adrenergic agonists as adrenaline
(3)-phosphodiestrase inhibitors as amrinone , milrinone.
Anticoagualnts : two types of drugs are employed in preventing blood
coagulation heparin and vit.K antagonists, there mechanism of action is differ,
as do their clinical uses .
A) - heparin and LMWH (Low molecular weight heparin as enoxaparin)
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Cardiovascular system pharmacology
heparin is an injectable rapidly-acting anticoagulant that is often used
acutely to interfere with formation of thrombi .
Heparin normally occurs as a macromolecule complexed with histamine in
mast cells where its physiologic role is unknown . It is extracted for comercial
use from porcine intestine mucosa or bovine lung . It is strongly acidic
because of presence of sulfate and carboxylic acid groups.
Heparin is not given orally because it will be destroyed by stomach acidity, so
it must be given by IV or deep subcutaneous but not I.M because it will be
produce hematoma
LMW heparins have a longer half-life than standard heparin and a single dose
by subcutaneous injection is as effective as IV heparin.
Mode of action:
Heparin acts indirectly by binding to antithrombin III to cause a rapid
anticoagulant effect. The heparin-antithrombin complex is also inhibitory to
activated forms of other clotting factor (IXa , Xa , Xia , XIIa )
 the main side effect of heparin is bleeding . this can usually be
controlled by stopping the drug administration. Since it has a short
duration of action (4-6 hrs) .if necessary , heparin can be neutralized by
IV injection of protamine sulfate.
 Hypersensitivity reaction including asthma,urticaria, lacrimation …etc.
 Transient alopecia
 Reversible thrombocytopenia
 Osteoporosis : in female leads to spontaneous fracture.
Vitamin K antagonist
Coumarins as warfarin & dicumarol .
Warfarin initially used as a rodenticide , now , widely used clinically as an oral
anticoagulant. Warfarin has along half-life ( about 40 hrs) & it can take up to 5
days for the prothrombin time to return to normal after stopping treatment.It is
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Cardiovascular system pharmacology
metabolized by liver to inactive -7-hydroxywarfarin. So drugs that induce
hepatic microsomal enzymes ( as barbiturate ) antagonize the anticoagulant
action of warfarin .Drugs that inhibit its action ( as cimetidine , ethanol ,
metronidazole) .
Mechanism of action :
- warfarin block carboxylation for some clotting factors ( II , VII , IX , X)
which are essential for coagulating process.
- They are biologically inactive unless they are carboxylation by
microsomal enzyme system that utilizes reduced Vit.K as cofactor . Vit.k
is present as an " inactive" form called Vit.K epoxide , it change in to
active form by aid of reductase enzyme
- Coumarins act on reductase enzyme leads to inhibition of Vit.K in to its
active form so inhibit coagulation process.
Side effect :
1- teratogenic effect : the drugs should never be used in pregnancy
because it is teratogenic & can be cause abortion.
2- Bleeding disorders
3- Thrombocytopenia
 warfarin can be reversed by giving a concentrate of clotting factors (or
fresh frozen plasms which contains clotting factors ) , this is the
treatment of choice for rapid reversal. In severe overdose vit.K can be
given by I.V injection but this taken 6-12 hrs to act.
Agents used for treatment of anemia
Anemia is defined as a below-normal plasma hemoglobin concentrations
resulting from a decreased number of red blood cells or an abnormally low
total hemoglobin content per unit of blood volume.
A)- Iron : iron stored in intestinal mucosal cells as ferritin , until needed by the
body.supplementation with ferrous sulphate is required to correct the iron
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Cardiovascular system pharmacology
deficiency. GIT distribances caused by local irritation are the most common
adverse effects caused by iron supplements.
B)- folic acid : folate deficiency may be caused by 1)- increased demand
(pregnancy , lactation ) 2)- poor absorption caused by pathology of small
intestine 3)- treatment with drugs that are dihydrofolate reductase inhibitors
as trimethoprium . A primary result of folic acid deficiency is megaloblastic
anemia caused by diminished synthesis of purines and pyrimidines.this leads
to an ability of erythropoietic tissue to make DNA and proliferate.
C)- Syanocobalamin (B12)
Deficiency of vit B12 can result from 1)- low dietary levels 2)-poor absorption
of the vit B12 due to failure of gastric parietal cells to produce intrinsic factor .
the vitamin can be administered orally or parenterally for treatment of
megaloblastic anemia .There are no known adverse effects of this vitamin
D)- erythropoietin. Is a glycoprotein , normally made in kidney ,that
regulates RBC proliferation and differentiation in bone marrow . humen
erythropoietin produced by recombinant DNA technology.
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