Cardiovascular Pharmacology

1. Positive inotropes: cardiac glycosides

2. Antiarrhythmic drugs
3. Vasodilators
4. Drugs acting on blood and blood forming
organs
 Hematinic drugs
 Hemostatics
 Anticoagulants

Takele Beyene AAU-CVMA Dec 2016

Learning objectives of the chapter
• To know specific Drugs used for the treatment
of CV abnormalities: CHF, arrhythmia, anemia,
thrombosis and bleeding disorders.

• To understand MOA, PK, PD, DI, ADRs and

indications of drugs acting at CVS.

Takele Beyene AAU-CVMA Dec 2016

Positive inotropes
CARDIAC GLYCOSIDES

Lecture # 1

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Learning Objectives
The students should:
• Know Sources of cardiac glycosides
• know MOA and indications CG
• Understand Pharmacological actions, ADRs
and toxicity Mgt of CGs

Takele Beyene AAU-CVMA Dec 2016

Sources
• Diverse plants are sources of sugar containing compounds
(glycosides) that also contain a steroid ring and augment the
contractile force of heart muscle:
– cardiotonic glycosides. cardiosteroids, or
“digitalis.”

Takele Beyene AAU-CVMA Dec 2016

 MOA
a) Binding of CG to phosphorylated
extra cytoplasmic α-subunit of Na+/
K+ ATPase

(-) Na+/ K+ ATPase

Suppress the Ca++/Na+

exchanger

(-) Ca++ flow out of the cell

Increase intracellular Ca++

+ve inotopic effect

Increase force of contraction

Takele Beyene AAU-CVMA Dec 2016
MOA
b) Neurohormonal modulation
• Digoxin at lower dose

• Increase vagal tone by direct stimulation of vagal centre

• Reduce plasma NE level by improving impaired

baroreceptor reflexes in heart failure

• May also lower plasma rennin levels

secondary to (-) of sympathetic activity
(-) Na+/K+ ATPase in the kidney

Takele Beyene AAU-CVMA Dec 2016

 Pharmacologic action of CG
• Force of contraction: dose dependent
 Increase myocardial contractility without increase in oxygen
consumption
• Heart rate: do not increase, instead in marked CHF secondary to
improved circulation. This restore the diminished vagal tone and
abolishes sympathetic over activity.
• Blood Vessels: mild direct vasoconstrictor
• Kidney: diuresis in CHF patients secondary to improved
circulation.
• CNS: Higher dose cause activation of CTZ (nausea and
vomiting), mental confusion, disorientation and visual
disturbance.

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PK
 Food delays absorption of digoxin and digitoxin.
 High volume of distribution.
 Digoxin
25% bound to plasma proteins,
primarily excreted unchanged mainly by glomerular
filtration
 frequently used b/c: well absorbed orally, fast onset of action,
intermediate t1/2(1-2 days), dose adjustment is possible in 2-3
days, rapid disappearance of manifestation if discontinued up on
toxicity.
 Digitoxin
 metabolized partly into digoxin
 undergo enterohepatic circulation.
 90% protein bound
 used for maintenance therapy (longer t 1/2 =7days) but
dose adjustment takes weeks and toxic effects persist.
Takele Beyene AAU-CVMA Dec 2016
Adverse Effects

• Toxicity of digitalis are high and low safety margin (TI=1.5-3)

• Cats are more sensitive to digoxin than dogs.

• GIT: Anorexia, nausea, vomiting, abdominal pain due to gastric irritation,

mesesntric vasoconstriction.

• CNS: fatigue, headache, mental confusion, visual disturbances (yellow colored spot)

• Cardiac: most serious and may manifest as ventricular or superventricular

arrhythmias.

• Vagotonic actions can produce bradyarrhythmias, including high-grade heart block.

• Skin rash and gynecomastia may rarely occur

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Therapy of intoxication

 Administration of K+, reduces binding of CG, but may impair AV-

conduction;

 Administration of antiarrhythmic, such as phenytoin or lidocaine,

propranolol when K+ is high

• Atropine for sinus bradycardia,

 Oral administration of colestyramine for binding and preventing

absorption of digitoxin present in the intestines (enterohepatic cycle);

 injection of Digibind, an anti-digoxin antibody fragments (Fab) that bind and

inactivate digitoxin and digoxin.
 Compared with full antibodies, fragments have superior tissue penetrability,
more rapid renal elimination, and lower antigenicity

Takele Beyene AAU-CVMA Dec 2016

 Drug interactions
1. Diuretics:
 Hypokalemia enhances inhibitory action of CG on Na+/K+ATPase.
 Hypercalcemia accelarates overloading of Ca++ stores.
 Hypomagnesaemia is also a risk factor for arrhythmias

2. Propranolol, verapamil, deltiazem and disopramide additively

depress AV node conduction=cause heart block

3. Adrenergic drugs can induce arrhythmias in digitalised patients

4. Erythromycin, omeprazole, and TTC increase absorption of digoxin.

5. Metoclopramide, sucralfate, antiacids, neomycin, sulfasalazine can
reduce degoxin absorption.
6. Quinidine increase plasma level of digoxin=displacement
7. Phenobarbital and other enzyme inducers increase digitoxin
metabolism.
Takele Beyene AAU-CVMA Dec 2016
Indications of CGs:

Chronic CHF;
 Atrial fibrillation or flutter, where inhibition of AV
conduction protects the ventricles from excessive atrial
impulse activity and thereby improves cardiac
performance.
 Occasionally, sinus rhythm is restored.

Takele Beyene AAU-CVMA Dec 2016

 Excercise
3. Digitalis glycosides slows the heart rate in patients with systolic dysfunction as a result
of all of the following except:
A. Direct action of digitalis on the AV- node to slow conduction.
B. Indirect effect of enhanced vagal tone on AV node
C. Enhanced parasympathetic outflow from the CNS through an indirect.
D. Enhanced responsiveness of the SA and AV nodes to NE through an indirect mechanism
E. All are correct
4. An old large German breed dog came to CVMA veterinary clinic with heart
insufficiency. You have diagnosed and seen with a symptom and findings of initial left
ventricular failure. You can give it digitalis and recall that all of the following are the
pharmacological effects of digitalis except:
A. Decrease conduction velocity in the AV-node.
B. Prolongs the functional refractory period of the AV-node
C. Weakens myocardial contractility.
D. Increase the effects of normal vagal activity of the heart
E. Shortens the effective refractory period of the purkinje fibers.
F. All of them are the correct pharmacologic effects
5. Digitalis toxicity manifested by premature ventricular contractions with high K+ ions
may be treated with all of the following EXCEPT:
A. Quinidine B. Lidocaine C. Digitalis specific immune FAB antibody D. Phenytoin
E. All are correct
Takele Beyene AAU-CVMA Dec 2016
Antiarrhythmic Drugs
Lecture # 2

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Dec 2016
Objectives
At the end of this lecture students should:
• Define arrhythmia
• Know cardiac electrophysiology
• Understand the Mechanism of arrhythmia development
• Classify Antiarrhythmic Drugs
• Understand the MOA and specific features of each classes of
AADs

Takele Beyene AAU-CVMA Dec 2016

 Terms
• Arrhythmia- abnormal due to disturbance in
impulse initiation and propagation.

• Failure of impulse initiation may result in slow

heart rates (bradyarrhythmias)

• Tachyarrhythmias (abnormally rapid heart

rhythms

Takele Beyene AAU-CVMA Dec 2016

 Antiarrhythmic Drugs

Cardiac Electrophysiology

The resting membrane potential -80-90 mv

Resting potential is established Na+/K+ ATPase

Na+ does not enter normal resting cardiac cells down its
electrochemical gradient because Na+ channels are closed at –ve
transmembrane potentials

In contrast, a specific type of K+ channel is in an open conformation

at –ve potentials.
K+ current and thus extracellular [K+] is the major determinant of
resting potentials.
Takele Beyene AAU-CVMA Dec 2016
 -The P wave is generated by
atrial depolarization,

-The QRS by ventricular muscle

depolarization, and The T wave
by ventricular repolarization.
-Thus, the PR interval is a
measure of conduction time
from atrium to ventricle, and

-The QRS duration indicates the

time required for all of the
ventricular cells to be activated
(i.e., the intraventricular
conduction time).

-The QT interval reflects the

duration of the ventricular
SA node, AV node, and Purkinje cells display action potential
pacemaker activity (phase 4 depolarization)
Takele Beyene AAU-CVMA Dec 2016
 1 2

Phase 3
Phase 0

Phase 4

Fig. Schematic diagram of the ion permeability changes and transport processes
that occur during an action potential and the diastolic period following it.
Takele Beyene AAU-CVMA Dec 2016
 MECHANISMS OF CARDIAC ARRHYTHMIAS
• Arrhythmia occurs due to disturbance in impulse initiation and propagation.

• Failure of impulse initiation Bradyarrhythmia,

• Failure of impulses to propagate normally from atrium to ventricle results in

dropped beats or "heart block"

• Tachyarrhythmias = abnormally rapid heart rhythms

– common clinical problems that may be treated with antiarrhythmic drugs.

Takele Beyene AAU-CVMA Dec 2016

 MOA OF ANTIARRHYTHMIC DRUGs

 Drugs may slow automatic rhythms by:

1. Increase maximum diastolic potential,

e.g. Adenosine and ACh

2. Decrease phase 4 slope=BBs

3. Increasing threshold potential= Na+ or CCBs

4. Increase action potential duration= K+ CBs

Takele Beyene AAU-CVMA Dec 2016

Classification of Antiarrhythmic Drugs
• Vaughn Williams classification system, four main groups:
• Based on predominant MOA
• Several drugs have effects characteristics of more than one
group.
1. Class I Drugs: Na+ Channel Blockers
2. Class II Drugs: Beta Blockers: Propranolol, acebutalol,
3. Class III Drugs: K+ Channel Blockers: Amiodarone,
sotalol, N-acetyl procainamide(NAPA)
4. Class IV Drugs: Ca2+ Channel Blockers
5. Class v Drugs: Others: Digoxin, adenosine

Takele Beyene AAU-CVMA Dec 2016

Class I Antiarrhythmic Drugs
• block the voltage-gated sodium channel when either in the
open or the inactivated state.

• Inhibition of the sodium channel results in a decrease in the

rate of rise of phase 0 of the cardiac membrane action
potential and a slowing of the conduction velocity.

• suppress both normal Purkinje fiber and His bundle

automaticity in addition to abnormal automaticity resulting
from myocardial damage.

• The Antiarrhythmic agents that belong to class I are divided

into three subgroups with slightly different properties.

Takele Beyene AAU-CVMA Dec 2016

 Class IA drugs
• slow the rate of rise of phase 0 of the
action potential and prolong the
ventricular ERP.

• impair the function of the m/m sodium

channel, thereby decreasing the number
of channels available for membrane
depolarization.

• do not alter the resting m/m potential

• slow conduction velocity.
• directly decrease the slope of phase 4
depolarization in pacemaker cells,
especially those that arise outside of the
sinoatrial node.

• Have equal effects at every resting m/m

potential.
• Anticholinergic effects

Takele Beyene AAU-CVMA Dec 2016

 Class IB drugs
• have a minimal effect on the
rate of depolarization and
phase 4 slope= conduction
velocity.
• are characterized by their
ability to decrease the
duration of action potential
and ERP of Purkinje fibers.
• have a minimal effect on
conduction velocity in
ventricular myocardium and
are without apparent effect
on refractoriness.

Takele Beyene AAU-CVMA Dec 2016

Class IC drugs
• produce a marked
depression in the rate
of rise of the
membrane action
potential

• have minimal or no
effects on the duration
of membrane action
potential and ERP of
ventricular myocardial
cells.

Takele Beyene AAU-CVMA Dec 2016

 Class II Antiarrhythmic Drugs (Beta blockers)
• competitively inhibit- adrenoceptors
• Propranolol and acebutolol have Na+
channel blocking activity= membrane
stabilizing effects at high dose.

• Sotalol has additional class III effects

• They decrease all phase of AP:
– Slope of phase 4
– Phase 0 depolarization
(decrease conduction)
– Phase 3 repolarization
• Increase AV-nodal conduction
time

Takele Beyene AAU-CVMA Dec 2016

Class III Antiarrhythmic Drugs (K+ Channel-blockers

• prolong the membrane

action potential
• no effect on phase 0 of
depolarization

• By increasing the ERP, they

suppress tachyarrhythmias

• have a significant risk of

proarrhythmia
– because of the prolongation
of action potential

Takele Beyene AAU-CVMA Dec 2016

 Class IV Antiarrhythmic Drugs
• block the slow inward Ca++
current in cardiac tissue.
• The administration of class
IV drugs
– slows conduction
velocity and
– increases refractoriness
in the A-V node,
– reducing the ability of
the A-V node to
conduct rapid impulses
to the ventricle.

Takele Beyene AAU-CVMA Dec 2016

 Other antiarrhythmic drugs
Digoxin
 Its effect is via vagotonic actions
 (-) Ca++ current in the AV-node =dec. conduction
 (+) Ach-sensitive K+-channel in the atrium =
Hyperpolarization of resting membrane potential,

 prolongation of ERP in the atria

 sinus bradycardia arrest,
 prongation of AV cond., high grade AV block.
 Used for reentrant arrhythmias.
Takele Beyene AAU-CVMA Dec 2016
Summary of antiarrhythmic drugs

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Takele Beyene AAU-CVMA Dec 2016
 Exercise Questions
NOT Properties of the class IA antiarrhythmic
A. Slow conduction velocity of his-purkinje fiber
B. Decrease the rate of rise and amplitude of phase 0 depolarization
C. Prolong PR and QT intervals
D. Facilitate inward Na+ conductance during rapid depolarization

Which of the following is/ are classified as class IB antiarrhythmic drugs:

A. Lidocaine, phenytoin, mexiletine
B. Lidocaine, phenytoin, quinidine.
C. Lidocaine, tocainide, quinidine
D. Quinidine, disopyramide, procainamide
E. A and B are correct

Class IC antiarrhythmic drugs possess which of the following electrophysiological

properties?
A. Markedly depress phase 0 depolarization
B. Markedly prolong repolarization
C. Enhance Na+ entry during phase 0 depolarization

Takele Beyene AAU-CVMA Dec 2016

VASODILATORS
Lecture # 3

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 Learning Objectives
• To classify the vasodilators systematically

• To know MOA and indications of different

vasodilator drugs

• To Understand PK,PD, ADRs and toxicity

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 Overview
Vasodilators- drugs which causes dilation of blood
vessels.

The distribution of blood within the circulation is a

function of vascular caliber.

The luminal diameter of the arterial vasculature

determines PR

CO and PR are prime determinants of arterial BP.

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Counter-regulatory responses in hypotension

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Classification of Vasodilator Drugs

 Categorized according to the type of vessels

that they dilate as:
afterload reducers or
preload reducers

 Afterload: arterioles (resistance vessels)

 Preload: veins (capacitance vessels)

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Individual Vasodilators
• 1. Arterial Dilators:
Ca2+-antagonists
Dihydralazine
Minoxidil
• 2. Arterial and Venous Dilators:
Organic Nitrates,
ACE-inhibitors,
α1- antagonists,
AT1- antagonists
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Arterial Dilators

Calcium Antagonists (CCBs)

• Drugs include

1. Dihydropyridine derivatives (DHP):

Nifedipine, Felodipine, Nimodipine, Amelodipine .

2. Nondihydropyridine derivatives: Verapamil

and Deltiazem
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Dihydropyridine Derivatives
MOA:
• block voltage sensitive Ca++ channels in vascular smooth m/s cell
m/m

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 MOA…
 induce a relaxation of arterial beds.

not produce –ve inotropic and chrontropic effect.

vasoselective Ca2+ antagonists.

effect on cardiac function is absent at therapeutic
dosage
Because of the dilatation of resistance vessels, Dec BP
 Cardiac afterload is diminished.

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Indications :
Nifedipine : Angina pectoris. Hypertension
Felodipine : hypertension.
Nimodipine: prophylactically after subarachnoidal
hemorrhage to prevent vasospasms due to depolarization by
excess K+ liberated from disintegrating erythrocytes or
blockade of NO by free hemoglobin.
ADRs:
 Flushing, Headaches, Postural dizziness , Palpitation and
tachycardia,
 GERD= due to relaxation of the lower esophageal
sphincter
Takele Beyene AAU-CVMA @2016/17
 Non-dihydropyridine Derivatives:

MOA: the same as dihydroprydines.

Verapamil
Exerts inhibitory effects on arterial smooth muscle, & heart
muscle.
In the heart, Ca2+ inward currents are important in:
impulse generation,
 impulse propagation through the AV- junction, and
electromechanical coupling in the ventricular
cardiomyocytes.
•Thus, produces negative chrono-, dromo-, and inotropic
effects.

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 Indications
 Verapamil
– Antiarrhythmic drug in supraventricular tachyarrhythmias.
– effective in reducing ventricular rate by virtue of inhibiting AV-conduction.
– prophylaxis of angina pectoris attacks
– treatment of hypertension
– Prevent premature delivery due to uterine relaxation.
 ADRs:
–Reflex tachycardia.
–Bradycardia may even develop.
–AV-block and myocardial insufficiency can occur.
–Constipation =relaxation of colon.

Diltiazem
 an activity profile resembling that of verapamil.

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@2016/17
Dihydralazine and Minoxidil
 Dihydralazine
 dilates arterioles but not veins
 used in antihypertensive therapy.
 unsuitable for monotherapy because of compensatory
circulatory reflexes.
MOA: unclear
 Minoxidil
– orally active vasodilator
– dilates arterioles but not veins
MOA:
opening of K+ channels in smooth muscle
membranes
ADR:
Lupus erythematosus with dihydralazine, and
Hirsutism with minoxidil
Takele Beyene AAU-CVMA @2016/17
2. Arterial and Venous Dilators
 Organic Nitrates
ACE-inhibitors,
α1- antagonists,
AT1- antagonists

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Organic Nitrates

• Nitroglycerin and isosorbide dinitrate.

– more pronounced effect in venous than in arterial beds.
 decrease preload and afterload, cardiac work is decreased.
 Prevent coronary spasm.
• MOA: of nitrates, nitrites, and other substances that increase the
concentration of nitric oxide (NO) in smooth muscle cells.

MLCK*= activated myosin

light chain kinase

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 Sodium Nitroprusside
 a powerful parenterally administered
 hypertensive emergencies as well as severe HF
 dilates both arterial and venous vessels

MOA:
 activation of guanylyl cyclase, or via release of NO
 Adm by infusion to achieve controlled hypotension
 Cyanide ions liberated can be inactivated with sodium
thiosulfate.

Advantage: Potency, preload & afterload red., iv infusion, short

half-life, and cost.
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 ACE Inhibitors
 Captopril, enalapril, trandolapril, and fosinopril.
• ACE identified in vascular endothelial cells, epithelial cells of the
proximal tubule and small intestine, male germinal cells, and the
CNS
• The lung vascular endothelium contains the highest
concentration of ACE
 major organ for the production of circulating AT II.
• MOA:
– Decrease AgII level:
• Decrease SNS output,
• Decrease retention of water and sodium,
• increase vasodilation
• Increase bradykinin level

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PK:
– After absorption from GIT enalapril is converted in the liver to
the active metabolite enalaprilat.
– Enalapril has delayed onset.
– T1/2 is increased in animals with RF or severe CHF.
– Clinically used to treat HPTN
DI:
– Hypotension with concurrent use of other vasodilators or
diuretics.
– Hyperkalemia with concurrent use of K-sparing.
ADRs:
– Better safety profile related with others.
– Azotemia- BUN & creatinine monitoring.
– Coughing due to (-) bradykinin degradation.

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α1- Antagonists
– Drugs: Prazosin
– both preload and afterload reducer.
– Is effective orally but tolerance developed rapidly.
– Undergoes significant first pass metabolism
– Rarely used clinically for small animals.

AT1- Antagonists
– Drugs: Losartan, candesartan
– lower high BP.
– not inhibit degradation of kinins
– Cough is not a frequent side-effect.

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Drugs Acting on the Blood and Blood
Forming Organs

Lecture # 4

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Drugs Acting on the Blood and Blood Forming
Organs
1. Hematinic drugs (Antianemics)
 Vitamin B12 (Cyanocobalamin), Folic Acid, Iron cpds, Epoiten Alfa
2. Hemostatics
 Topical=Local hemostatics
Epinephrine and Norepinephrine
 Systemic hemostatics
 Vitamin K
3. Anticoagulants (Reading Assignment)
 Heparin
 Vitamin K antagonists
 Fibrinolytic agents
 Antithrombotics

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Hematinics (Antianemics)
 Drugs or other agent that increases RBC production:
 Hgb synthesis + bone marrow RBC formation

 Erythropoiesis
 stimulated by the hormone erythropoietin
 Disturbance is due to two principal causes:

1. Cell multiplication is inhibited as a result of insufficient DNA synthesis.

• occurs in vit B12 or folic acid deficiencies (macrocytic
hyperchromic anemia).
2. Hemoglobin synthesis is impaired.
• arises in iron deficiency,
• Fe2+ is a constituent of hemoglobin (microcytic hypochromic
anemia).

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Takele Beyene AAU-CVMA @2016/17
 Vitamin B12 (Cyanocobalamin)
– Essential for DNA synthesis.
– Deficiency causes inhibited nuclear maturation and division.
– RBC maturation arrest in the bone marrow leads to megaloblastic or
pernicious anemia.
– produced by bacteria; B12 generated in the colon, however, unavailable
for absorption.
PK:
– Enteral absorption requires intrinsic factor from parietal cells, gastric
acid, pepsin or pancreatic duct cells.
– The complex formed undergoes endocytosis
– Bound to transcobalamin, and transported for storage(liver) or uptake
into tissues.
– not degraded in the body; mainly excreted in bile and undergoes
considerable enterohepatic circulation.
– Only trace amounts are normally lost in the urine and stool.
 It takes years before normal body stores are depleted.
Takele Beyene AAU-CVMA @2016/17
 Causes of vitamin B12 deficiency
– Atrophic gastritis leading to a lack of intrinsic factor=
malabsorption: Ilioectomy, gastroectomy
– Chronic use H2 antagonists: cimetidine
Block acid production
– Damage to mucosal linings and
Degeneration of myelin sheaths with neurological
sequelae will occur

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Folic Acid
• For DNA and RNA synthesis
• Anemia associated with FA is magaloblastic anemia
• Source: green vegetables, yeast, kidney and liver
• Stored in liver
• Causes of deficiency include:
 insufficient intake, malabsorption, increased requirements
during pregnancy.
 Inhibition of DHFR (e.g., by methotrexate, depresses the
formation of the active species, tetrahydro-FA.
• Symptoms of deficiency are:
 megaloblastic anemia and mucosal damage.
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 Oral adm of FA or in folinic acid when deficiency is caused
by
 Liver d+, malabsorption, drugs: DHFR inhibitors, chronic
debilitating d+
 Administration of FA can mask a vit B12 deficiency.
• Vitamin B12 is required for
 methyltetrahydro-FA →tetrahydro-FA= important for DNA
synthesis.
• Inhibition of this reaction due to B12 deficiency can be
compensated by increased FA intake.

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 PK:
IRON Compounds
– Not all iron ingested is equally absorbable.
– Fe3+ is virtually not taken up from the SI
– Fe2+ is markedly better absorbed.
– Within the mucosal cells of the gut, iron is oxidized and either deposited as
ferritin (= protein apoferritin + Fe3+) or passed on to the transport protein,
transferrin
– Amount absorbed does not exceed that needed to balance losses ( “mucosal
block”).
– Small amount of iron is lost by exfoliation of GIT mucosal cells into the
faeces
• Factors facilitating iron absorption
1. Acid; by favoring dissolution and reduction of Fe3+,
2. Reducing substances: ascorbic acid, amino acid containing SH,
3. Meat: probably by increasing HCl secretion.

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Cause of iron deficiency
 chronic blood loss due to gastric/intestinal ulcers or tumors.
 Iron deficiency results in impaired synthesis of hemoglobin and
anemia
 Alkalis (Antacids), Phosphate and TTC form complex with iron

Oral iron Preparations:

Ferrous sulphate, Ferrous gluconate, Ferrous fumarate
 Absorption higher when taken in an empty stomach
 Oral adminstartion is advantageous:
 Impossible to overload the body with iron through an intact mucosa
because of its demand-regulated absorption (mucosal block).

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Parentral iron preparations:
– Fe-dextran, Fe-sorbitol-citric acid complex, Fe-sucrose
complex, Fe-Na gluconate complex.

Parenteral preparations should be only when:

1. Oral iron is not tolerated,
2. There is malabsorption,
3. Severe deficiency with chronic bleeding,
4. Erythropoetin is used to induce rapid erythropoisis.

• Epoetin Alfa
– The synthetic form of the human glycoprotein erythropoietin(EP)
– Indicated in the treatment of anemia associated with chronic renal
failure in dogs & cats.

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Hemostatics

 Topical=Local hemostatics
Lyophilized Concentrates of clotting factors
Epinephrine and Norepinephrine

 Systemic hemostatics
Vitamin K

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 Topical=Local hemostatics
Epinephrine and Norepinephrine
– used as hemostatics by means of their vasoconstrictive effects.
– May be included in topical medications to decrease blood flow to
the tissues.

• Vitamin K
– used as a hemostatic only in patient with Vit-K
deficiency.
– promotes the hepatic-carboxylation of glutamate
residues on the precursors of factors II, VII, IX, and X, as
well as that of other proteins, e.g., protein C, protein S,
or osteocalcin.
Takele Beyene AAU-CVMA @2016/17
• There are several vit- K derivatives of different origins:

 K1 (phytomenadione) from chlorophyllous plants;

 more effective with more rapid restoration of coagulation
factors.
 K2 from gut bacteria; and
 K3 (menadione) synthesized chemically.
 All are hydrophobic and require bile acids for absorption.

Principal indications of Vit- K

For the treatment of

Rodenticides poisoning,
Moldy clover poisoning (dicumarol), and
Sulfa quinoxaline toxicity

Takele Beyene AAU-CVMA @2016/17

Anticoagulants.
1. Thrombin inhibitors:
Heparin
2. Vitamin K Antagonists:
Coumarins & indanediones
3. Fibrinolytic Agents:
urokinase, streptokinase, t-PA
4. Antithrombotics:
antiplatelet agents=NSAIDs-
– Reading Assignment

Takele Beyene AAU-CVMA @2016/17

 1. Thrombin inhibitors
Heparin

• Two types of heparin are used clinically.

Standard (unfractionated) heparin=UFH - animal

extract
Low molecular weight heparin=LMWH -from UFH
• Indirect Thrombin Inhibitors.
Its effect is exerted by their interaction with
antithrombin.
• efficacy varies with chain length.
Takele Beyene AAU-CVMA @2016/17
 LMWH
• Include; Enoxaparin, dalteparin, tinzaparin, ardeparin,
nadroparin, & reviparin

• Produced by chemical depolymerization and extraction of UFH.

• Do not catalyze inhibition of thrombin by antithrombin.

• 2-4 fold greater antifactor Xa activity than AT activity.

• greater BA, longer DA, than UFH and only once daily regimen.

• Has dose-independent clearance PK.

Takele Beyene AAU-CVMA @2016/17

MOA of Heparin

• Its biologic activity is dependant upon the plasma protease

inhibitor antithrombin.

• Antithrombin (AT) inhibits the clotting factor proteases:

thrombin IIa, Ixa & Xa, by forming stable complexes with
them.
 AT (-)cleavage of peptide bond b/n serine & arginine by protease
enzyme=thereby (-)the clotting factor.

• Heparin also catalyzes the inhibition of thrombin by the

heparin cofactor II, a circulating inhibitor.

Takele Beyene AAU-CVMA @2016/17

PK
• Not absorbed after oral administration
• Numerous negative charges, are significant in:
poor membrane penetrability—ineffective when applied
oral route or topically

attraction to +velly charged lysine residues is involved in

complex formation with AT III;

permit binding of heparin to its antidote, protamine.

• IV=immediate anticoagulant effect

• Im injection should be avoided because of
unpredictable absorption rates, local bleeding and
irritation. Takele Beyene AAU-CVMA @2016/17
PD
• Inhibits both in vitro and in vivo clotting factor.

• High dose can interfere with platelets aggregation and thereby prolong
bleeding time.

Protamine(Heparin Antagonist)
• Specific heparin antagonist

• Are basic LMW +velly charged proteins that have a high affinity for the –
velly charged heparin molecules.

• Neutralize heparin actions in case of serious hemorrhage= formation of

innert complex.

• If protamine is given in heparin-induced bleeding, the effect of

heparin is immediately reversed.
Takele Beyene AAU-CVMA @2016/17
2. Vitamin K Antagonists
• Coumarin derivatives & indanediones

• They are oraly active anticoagulants.

• They resemble vitamin K

• Importance in veterinary is due to their toxicity.

• Warfarin is the most reliable member of this group.

Takele Beyene AAU-CVMA @2016/17
 Warfarin
MOA
 block the carboxylation of several glutamate residues in prothrombin
and factors VII, IX, and X as well as the endogenous anticoagulant
proteins C and S.

 The blockade results in incomplete molecules that are biologically

inactive in coagulation.

 This protein carboxylation is physiologically coupled with the oxidative

deactivation of vitamin K.

 The anticoagulant prevents reductive metabolism of the inactive vitamin

K epoxide back to its active hydroquinone form.

 Mutational change of the responsible enzyme, vitamin K epoxide

reductase, can give rise toTakele
genetic resistance to warfarin in humans and
Beyene AAU-CVMA @2016/17
especially in rats.
Vitamin K cycle—metabolic interconversions of vitamin K associated with the synthesis
of vitamin K-dependent clotting factors. Vitamin K1 or K2 is activated by reduction to the
hydroquinone form (KH2). Stepwise oxidation to vitamin K epoxide (KO) is coupled to
prothrombin carboxylation by the enzyme carboxylase. The reactivation of vitamin K
epoxide is the warfarin-sensitive step (warfarin).

Activated hydroquinone VKE-reductase

form vitamin K epoxide

Takele Beyene AAU-CVMA @2016/17

PK
• Its sodium salt form
• has 100% BA.
• >99% of racemic warfarin is bound to plasma albumin,
– small VD
– its long t1/2 (36 hours),
– lack of urinary excretion of unchanged drug.
• Racemic mixture composed of equal amounts of two
enantiomers.
– Levo S-warfarin is 4x more potent than the dextro R-
warfarin.
• Displacement of warfarin results in bleeding.
• Metabolized by P450 isozymes, hydroxylated metabolites are
excreted in the bile.
Takele Beyene AAU-CVMA @2016/17
ADRs
• Hemorrhage
• Rare: diarrhea, SI necrosis, urticaria, skin necrosis, purple toes, and
dermatitis.
CIs
• GIT ulcer, thrombocytopenia, hepatic or renal diseases; recent
surgery, bacterial endocarditis, pregnancy.
• Warfarin can cross the placenta and may cause teratogenicity and
hemorrhage in the fetus.
 Drug interactions:
 Interactions that enhance the risk of hemorrhage
– Decreased metabolism due to (-)CYP2C9.
– Displacement from protein binding
– Antimicrobial agents-elimination bacteria

 Interactions that decrease the effect:

– Inductions of hepatic cyp 450 enzymes
– Reduced absorption caused by binding to cholestyramine.
Takele Beyene AAU-CVMA @2016/17
Clinical indications for anticoagulants
• Prophylactic treatment of thromboembolism
– ineffective against already formed thrombi,
– may prevent further propagation.

• E.g. low dose heparin inhibit free thrombin formation there

by prevent thrombus formation.

Takele Beyene AAU-CVMA @2016/17

3. Fibrinolytics (Thrombolytics)
• Drugs include:
– streptokinase, urokinase, and t-PA=alteplase,
anistreplase, reteplase & tenecteplase.

• Fibrin is formed from fibrinogen through thrombin

(factor IIa)-catalyzed proteolytic removal of two
oligopeptide fragments.

• Individual fibrin molecules polymerize into a fibrin mesh

that can be split into fragments and dissolved by
plasmin.

• Plasmin derives by proteolysis from inactive precursor,

plasminogen. Takele Beyene AAU-CVMA @2016/17
 MOA
plasminogen activators.

• Clot selective fibrinolysis without activating plasminogen to plasmin in the

plasma is the desirable property.
– Older agents (streptokinase, urokinase) are not clot selective.
– Newer thrombolytic agents Takele
bind Beyene
to fibrin and activate fibrinolysis more than
AAU-CVMA @2016/17
fibringenolysis.
 Urokinase

• Endogenous plasminogen activator.

• Human enzyme synthesized by the kidney that

directly converts plasminogen to active plasmin.

• Urokinase is better tolerated than streptokinase.

Takele Beyene AAU-CVMA @2016/17

Streptokinase
• produced by streptococcus, accounts for ADRs

• Streptokinase antibodies present as a result of prior

infections=neutralize streptokinase

• a protein/not an enzyme in itself) synthesized by streptococci

that combines with the proactivator plasminogen.

• This enzymatic complex catalyzes the conversion of inactive

plasminogen to plasmin.

• By itself, it is enzymatically inactive;

– only after binding to a plasminogen molecule does the complex
become effective in converting plasminogen to plasmin.
Takele Beyene AAU-CVMA @2016/17
Tissue plasminogen activators (t-PA).
• binding affinity for fibrin
• fibrin-selective activation of plasminogen.
– Binds to fibrin and activates bound plasminogen
more rapidly than it activates plasminogen in the
circulation
poor plasminogen activator in the absence of fibrin

• Human t-PA is manufactured as alteplase by

means of rDNA technology.
Takele Beyene AAU-CVMA @2016/17
 4. Antithrombotic drugs
Platelet Aggregation
• activated by mechanical and diverse chemical stimuli: TX A2, thrombin,
serotonin, and PAF, act via receptors on the platelet membrane.
Antiplatelet Agents
• Targets identified for platelet inhibitory drugs
– Inhibition of prostaglandin metabolism (aspirin),

– Inhibition of ADP induced platelet aggregation

(clopidogrel), and

– Blockade of GP IIb/IIIa receptors

Takele Beyene on platelets (abciximab).
AAU-CVMA @2016/17
 Aspirin
• Inhibits the synthesis of thromboxane A2 by irreversible
acetylation of the enzyme COX-1.

• Inhibition is permanenet and lasting for the life span of

the platelet.

• Other salicylates and NSAIDs also (-)COX reversibly

– have a shorter duration of inhibitory action.
– Have not been shown antithrombotic efficacy.
– May even antagonise the effect of low-dose aspirin

• The goal of therapy with aspirin is to selectively inhibit

the synthesis of TXA2 and thereby inhibit platelet
aggregation with low dose.
Takele Beyene AAU-CVMA @2016/17
Takele Beyene AAU-CVMA @2016/17
Exercise Questions
1. Which of the following is not correct about DHP derivatives of calcium channel
blockers?
A. Their vasodilator action is exerted by blocking L-type voltage gated Ca++-
channels
B. They induce a relaxation of vascular smooth muscle in both arterial and
venous beds.
C. They do not produce negative inotropic and chrontropic effect.
D. They are regarded as vasoselective Ca2+ antagonists.
E. All are correct
2. Thiocyanate toxicity is a potential adverse effect associated with
A. Nitroglycerin
B. Nitropruside
C. Amirinone
D. Propranolol
3. The rapid heart rate seen after nitroglycerin administration is best explained by:
A. Its ability to release norepinephrine from sympathetic nerve endings.
B. A direct positive chronotropic effect on the myocardium
C. A reflex sympathetic discharge due to a fall in systemic blood pressure.
D. A direct positive ionotropic effect on the myocardium.

Takele Beyene AAU-CVMA @2016/17

Takele Beyene AAU-CVMA @2016/17