Pharmacology Flashcards
1
Q
what is Primaquine?
A
- It is an oral drug
- Tissue schizonticide & gametocide
- Exact mechanism is unknown (Its metabolite act as an oxidant)
2
Q
what are the therapeutic uses of primaquine?
A
- Radical cure of relapsing malaria
- Terminal prophylaxis of relapsing malaria (given after
leaving the endemic area to ensure that dormant forms are eradicated)
* 3. Prevents transmission of disease to mosquito
(gametocide)
3
Q
what are the adverse effects of primaquine?
A
- Adverse effects
- Haemolytic anemia (in G6PDD)
- Methaemoglobinemia
- Teratogenic
- Resistance could develop
4
Q
what is chloroquine?
A
➢ Mainstay of malaria treatment
➢ Blood schizonticide
➢ Moderately effective gametocidal (in all species except falciparum)
5
Q
what are the therapeutic uses of chloroquine?
A
- Prophylaxis & treatment of chloroquine sensitive malaria
- Amoebic hepatitis and amoebic liver abscess
- Rheumatoid arthritis (anti- inflammatory effect)
6
Q
Describe the pharmacokinetics of chloroquine
A
1) Absorption: Rapidly and completely absorbed after
oral administration
➢2) Distribution:
▪ Has very large volume of distribution
▪ Concentrated in the RBCs liver, spleen, lung, leukocytes and melanin containing tissues
▪ Cross BBB
▪ Cross placenta
➢ 3) Metabolized in the liver & 4) excreted via kidney
7
Q
what are the adverse effects of chloroquine?
A
- Headache – pruritis
- Eye: Corneal opacity - blurred vision and retinopathy
* 3. Hemolytic Anemia: in G6PD-deficient subjects
* 4. C.V.S: quinidine like action → prolong QT interval (hypotension & arrhythmias)
* 5. GIT: Nausea-vomiting and diarrhea
* 6. Resistance
8
Q
what is quinine?
A
➢ Blood schizonticide
➢ Plant in origin
➢ Absorbed well after oral administration
➢ Exact mechanism of action is unknown
➢ Interfere with heme polymerization → death of RBCs
-Used in sever infestation and treatment of chloroquine resistant falciparum
➢ Has no role as prophylaxis (too toxic)
➢ weak muscle relaxant effect (potentiate the action of neuromuscular blockers)
9
Q
what are the adverse effects of quinine?
A
- Quinidine like action → hypotension & arrhythmias
- Eye → blurred vision and blindness
- Cinchonism: tinnitus - headache - dizziness and visual disturbances
- Black water fever & hemolysis (hold medication)
10
Q
what is mefloquine?
A
- Mechanism: Same as quinine but
➢ More effective
➢ Longer acting
➢ Less toxic - Uses: Treatment & prophylaxis of chloroquine
resistant falciparum
11
Q
what is Amodiaquine?
A
*Used in treatment of chloroquine resistant falciparum
12
Q
what are the side effects of amodiaquine?
A
- Aplastic anemia
- Agranulocytosis
13
Q
give examples of 4-aminoquinolines
A
Chloroquine, Quinine, Mefloquine, Amodiaquine
14
Q
what is halofantrine?
A
- Structurally related to 4-aminoquinolines
- Interferes with the degradation of haemoglobin
- Blood schizonticide, active in all types & in multi resistant falciparum
- Prolonged QT interval → sudden cardiac death
limit its use to treatment of chloroquine resistant falciparum
15
Q
what is Artemisinin?
A
➢ Plant in origin
➢ Free radicals resulting from cleavage of the drug
endoperoxide bridge by heme iron in the parasite food vacuole
➢ Interferes with Hb digestion
➢ Bind and damage specific malarial protein
➢ Available oral, rectal, IV
➢ Recommended for ttt of multidrug resistance P.
falciparum
➢ Can cause nausea, vomiting, diarrhea, prolonged QT interval
16
Q
what is atovaquone?
A
- Inhibit mitochondrial electron transport
- No ATP
-Affection of pyrimidine biosynthesis - Usually combined with proguanil
- Combination used to treat chloroquine resistant strain of P. falciparum
- Prevention and treatment of malaria
17
Q
A
- Pyrimethamine - Proguanil - Sulfadoxine
- Fansidar (pyrimethamine + sulfadoxine)
- Blood schizonticides (mainly) –tissue schizonticides- sporontocides
18
Q
what is the mechanism of action of antifolate antimalarial drugs?
A
- Sulfonamides inhibit synthesis of folate by competition with PABA
- Pyrimethamine & proguanil inhibit dihydrofolate reductase → inhibit formation of active folic acid→ inhibit synthesis of DNA& RNA
19
Q
what are the therapeutic uses of antifolate antimalarial drugs?
A
- Treatment of chloroquine resistant falciparum (fansidar plus quinine)
- Chemoprophylaxis in all types
- Toxoplasmosis (pyrimethamine + sulfadiazine)
20
Q
what are the side effects of antifolate antimalarial drugs?
A
- GIT upset – hypersensitivity
* 2. Megaloblastic anemia - haemolytic anemia (in G6PDD)
21
Q
what are Tetracycline, doxycycline and clindamycin?
A
- Inhibit protein synthesis
- Blood schizonticide
- Not used alone
22
Q
how is malaria treated?
A
According to WHO guidelines
* Uncomplicated P. Falciparum
* ACT (Artemisinin Based Combination Therapy)
* Artemisinin or its derivatives plus
* Lumefantrine or amodiaquine or mefloquine or sulfadoxine and proguanil
* For 3 days followed by single dose Primaquine (Gametocide)
- Uncomplicated P. Vivax, Ovale and Malariae
- ACT (Artemisinin Based Combination Therapy ) or
Chloroquine for 3 days - Followed by Primaquine for 14 days (for radical cure)
23
Q
how is chloroquine resistant falciparum treated?
A
*Quinine + sulfadoxine pyrimethamine (or doxycycline)
or
* Atovaquone + proguanil
or
* Mefloquine
24
Q
how is severe malaria treated?
A
*IV or IM Artesunate for 24 hours then complete with ACT
*Or Quinine
25
Describe the prevention of malaria
* Artemisinin
* or
* Chloroquine
* or
* Mefloquine
* or
* Proguanil + Atovaquone
* or
* Doxycycline
26
how is malaria prevented during travel?
Drugs for chemoprophylaxis are given for 2 weeks (chloroquine, mefloquine) or for 2 days (proguanil or doxycycline) before
travel & during the stay
& for 4 weeks after leaving an endemic area
27
what are the types of anemia?
Under production
* Bone marrow suppression
* Problems with Hg synthesis
(Problems with iron {iron deficiency anemia, anemia of chronic inflammation}, problems with globin
synthesis {thalassemia}, problems with protoporphyrin {sideroblastic
anemia})
* Problems with cell division (DNA problems; vit B12 & Folate deficiency)
* Chronic kidney disease
Destruction/blood loss
* Due to intrinsic factors
Haemoglobinopathies
(Thalassemia, sickle cell
anemia) Enzymopathies
(G6PD deficiency)
Membranopathies
(spherocytosis, elliptocytosis)
* Due to extrinsic factors
Immune mediated, Malaria,
DIC, ITP, Rh incompatibilities,
Blood transfusion
28
how is iron deficiency anemia confirmed?
Iron deficiency anemia causes:
--sudden increase in blood formation
--Chronic blood loss
--Increased Demand
--Decreased Absorption
29
what are the indications of iron therapy?
Treatment of Iron-Deficiency Anemia:
(200-400 mg/day
elemental iron)
Prophylactic to prevent Iron-Deficiency Anemia
(30-60 mg/day elemental iron)
30
what is meant by elemental iron
It Is the total amount of iron in the supplement available for absorption.
Each type of iron has a different percentage of
elemental iron
31
how is the required iron dose calculated?
➢ Normally 3-6% (5-10%) of inorganic iron (non-heme iron) is absorbed
➢ In response to low iron stores or increased
iron requirements it reaches up to 25-30%
➢ In iron deficient individuals, about 50-100
mg of iron can be incorporated into
hemoglobin daily
32
Describe oral iron therapy
-Route of choice
-Effective & cheap
Preparations:
1) Ferrous sulfate, gluconate or fumarate (vary in
elemental iron content -12-33%)
2) Polysaccharide-iron complex 150mg, carbonyl iron
-150 mg contain 100% elemental iron
3) Heme iron polypeptide -- more expensive
33
what are the adverse effects of oral iron therapy?
-GIT disturbances: nausea, epigastric pain, constipation
-Black stool
-Black staining of
teeth
34
when should oral iron be taken?
Given after meals to decrease GIT disturbances- Start with small dose then gradually increase.
35
what is the recommended duration of oral iron therapy?
➢ Treatment continued till hemoglobin level is normal
➢ It takes from 7-10 days to increase hemoglobin level by 1g/dl
➢ Then for an extra 2-3 months to replenish
stores
36
what is the follow up procedure of oral iron therapy?
➢ An increase in reticulocytes 5-10 days after the initiation of iron therapy
➢ The hemoglobin concentration increases by
about 1 g/dL (7-10 days)
➢ Until normal values are restored 2-3 months
later, measure serum ferritin
37
what are the types of parenteral iron therapy?
--IMZ – track injection
technique
--IV Infusion
38
what are the adverse effects of parenteral iron therapy?
IM - local pain - tissue
staining
IV: headache, fever, urticaria,
lymphadenopathy &
anaphylactic shock
39
what are the indications of parenteral iron therapy?
- Non-compliance to oral therapy
- Mal-absorption syndrome
- Severe anemia
- Anemia of chronic kidney disease
(especially in patient on dialysis and receiving erythropoietin)
40
What are the indications of using iron therapy in patient with chronic kidney disease on dialysis and erythropoietin?
-↓ erythropoietin → under
production of RBCs
-When this patient is on dialysis and on erythropoietin treatment:
-Increase in blood formation --Chronic blood loss
41
what are the preparations of parenteral iron therapy?
A) Iron dextran (given IM & IV)
B) Iron sucrose complex &
Iron sodium gluconate
complex
C) Newer preparations:
Ferric carboxymaltose,
Ferumoxytol
(given IV)
Iron could be taken IV as a total dose infusion (TDI)
42
what are the advantages of TDI (total dose infusion)
➢ Avoids non-compliance of the patient
➢ Avoids unpleasant effects of IMI
➢ Allows delivery of the entire dose of iron necessary at one time
43
how to calculate the parenteral iron dose?
Dose (mL) = 0.0442 (Desired Hb - Observed Hb)
x BW + (0.26 x BW)
44
how to calculate total iron deficit?
Total iron deficit (mg) = Body weight [kg] x
(Target Hb – Actual Hb) [g/l] x 2.4 + Iron stores
[mg]
45
Describe the symptoms of acute iron toxicity?
Abdominal pain, vomiting,
bloody diarrhea, dyspnea
followed by metabolic acidosis,
cardiovascular collapse,
convulsions, coma & death
46
how is acute iron toxicity treated?
1) Raw egg or milk - bind and precipitate iron as albuminate or caseinate until chelating agent is available
2) Deferoxamine:
-1-2 g IM or IV - chelates iron promoting its excretion in urine.
5g in 100 ml water swallowed or by stomach tube
3) IV infusion of saline, dextrose or bicarbonate --> correct water and electrolyte disturbance
47
how do patients develop chronic iron toxicity?
- Patients receiving many red
cell transfusions
- Patients with hemochromatosis:
- an inherited disorder characterized by increased Fe absorption ---> hemosiderosis
48
describe the treatment of chronic iron toxicity?
1) Venesection (500 ml blood
removes 200 mg iron) - weekly.
2) Iron chelators
- Deferoxamine: (IM or SC)
- Deferasirox: oral iron chelator
3) Large intake of tea - binds iron
49
what is Anemia of Chronic Illness?
- It is a functional iron deficiency anemia
- occurs when there is infection and inflammation with release of cytokines that stimulate hepcidin release from the liver.
-High
50
describe the importance of vitamin B12
➢ Essential for Cell
growth and DNA synthesis
➢ Maintenance of
normal myelin sheath
➢ Normal metabolic
functions of folic acid
51
how is vitamin b12 prepared?
A. Cyanocobalamin
B. Hydroxocobalamin (preparation of
choice)
1. More slowly absorbed
2. More bound to plasma proteins
3. Slowly excreted
4. More sustained rise in serum level
52
uses of vitamin b12
treatment of:
A) Megaloblastic anemia:
1)Pernicious anemia (lifelong treatment by IMI)
2) Megaloblastic anemia due to diphylobothriasis: Treated by VB12 and praziquantel
B) Drug induced megaloblastic anemia: Neomycin, colchicine and antiepileptics reduce absorption of VB12
C) Neurological Conditions:
-Peripheral neuritis in diabetes & retrobulbar neuritis in heavy smokers
53
what are the causes of folic acid deficiency?
1. Inadequate dietary supply or increased demand (e.g. Pregnancy, lactation)
2. Diseases in small intestine
3. Alcoholism
4. Drug-induced folic acid
deficiency
54
what are the therapeutic uses of folic acid?
*- Megaloblastic anemia
* - Malabsorption syndrome
* - In alcoholics and pregnant women
* - Patients with liver disease & with hemolytic anemia
* - Patients on dialysis (as folic acid is removed each time)
* - With anticonvulsant drugs
55
Describe the Treatment of aplastic Anemia (SEA BICE)
1) Supportive treatment
2) Eliminate underlying cause
3) Anabolic agents
4) Bone marrow transplantation
5) Intravenous Anti thymocyte immunoglobulin
6) Corticosteroids (reduce bleeding due to thrombocytopenia)
7) Erythropoietin
56
Describe the uses of erythropoietin
➢ IV or SC
➢ Acts as regulator of erythropoiesis
➢ Used in anemia of chronic renal failure & severe anemia of cancer & AIDS
➢ It decreases the need for
transfusion as it elevates red blood cell level
➢ Hypertension and thrombosis
57
Describe platelet activation
Damage of vessel wall → exposure of collagen in
subendothelium →
platelet adhesion (enhanced by factor VIII and von Willebrand factor) followed by activation→
release reaction (ADP, fibrinogen TXA2
, etc.….).
ADP binds to its receptor on platelets →
exposure of glycoprotein GP IIb/IIIa receptor on platelet membrane.
Fibrinogen binds to the GP IIb/IIIa receptor linking adjacent platelets → aggregation
58
what are the therapeutic uses of antiplatelet drugs?
(mainly in arterial thrombosis)
1. High risk of myocardial infarction (AMI): e.g., previous attack of angina (aspirin).
2. Acute coronary syndrome (aspirin +clopidogrel).
3. Coronary bypasses grafting, angioplasty & stent insertion
(aspirin plus clopidogrel or abciximab).
4. Prosthetic heart valves: ↓thrombo-embolism (dipyridamole plus warfarin).
5. Thrombotic stroke (dipyridamole plus aspirin).
6. Hemodialysis (epoprostenol)
59
Describe the mechanism of action of low dose aspirin
(Acetylsalicylic Acid)
➢ Irreversible inhibition of cyclooxygenase enzyme (COX-1 ) via acetylation.
➢Small dose inhibits thromboxane (TXA2) synthesis in platelets But not prostacyclin
(PGI2) synthesis in endothelium (larger dose).
60
what are the Side effects of low dose aspirin?
-Increased incidence of GIT bleeding (aspirin prolongs
bleeding time)
GIT irritation
Hyperuricemia
Hypersentivity
61
how is clopidogrel given?
-Clopidogrel is given orally and has a slow onset of action (3 - 5 days).
-It is a Prodrug so avoid taking with omeprazole as it inhibits its activation in liver
62
what are the Adverse effects of ADP pathway inhibitors?
Ticlopedine --> neutropenia, bleeding, GIT irritation (rarely used)
Clopidogrel -->
➢Bleeding (prolong bleeding time)
➢G.I.T : nausea, dyspepsia, diarrhea.
➢Prodrug
➢Less neutropenia
63
Describe the mechanism of action of Dipyridamole
Inhibits phosphodiestrase thus increase cAMP
-->
Vasodilator and antiplatelet
64
Dipyridamole uses
➢ Given orally.
➢Week antiplatelet, so usually combined
65
Adverse effects of Dipyridamole
- Headache
- Postural hypotension
- Coronary Steal phenomenon
-GIT irritation
66
what are the side effects of Glycoprotein IIb/ IIIa receptor inhibitors?
bleeding, thrombocytopenia,
arrhythmia
67
Drugs used in Thrombotic Disorders
Anticoagulants
Antiplatelets -->
Prevention and treatment of
thromboembolic
Fibrinolytics= Thrombolytic
--> Fibrin lysis
Acute treatment
68
what is thrombosis?
Pathological condition from inappropriate activation of platelet aggregation
and coagulation cascades
69
what are the types of thrombosis?
Arterial thrombus:
Mainly from platelets in a fibrin mesh, associated with
atherosclerosis and interrupted blood flow resulting in ischemia
--Treated mainly by
antiplatelet and fibrinolytic
Venous thrombus:
Mainly of fibrin tail with white head (platelet)→→→
stasis and detached leads to emboli (DVT and pulmonary
embolism)
--Treated mainly by
anticoagulants
70
Describe the primary and secondary prevention of thrombosis
■ Primary prevention: prevent the initial formation
of blood clots in patients with recognised risk
factors
■ Secondary prevention chronically to treat and
prevent recurrence of thrombi and their
associated complications
71
Describe the parenteral treatment of thrombosis
Indirect thrombin inhibitors:
Heparin, LMWH
Direct thrombin inhibitors:
Bivalirudin, argatroban, desirudin
Inhibitor of factor Xa
(Indirect)
Fondaparinux
72
Describe the oral treatment of thrombosis
Inhibitors of synthesis of
clotting factor II, VII, IX, X
--Warfarin
Direct thrombin inhibitors
--Dabigatran
inhibitor of factor Xa (Direct)
--Rivaroxaban, apixaban, edoxaban
73
Describe the mechanism of heparin action
Indirect Thrombin Inhibitor (indirectly by increasing the activity of the endogenous
anticoagulant “antithrombin III” (1000 folds) on activated clotting factors especially: Factor IIa (Thrombin) - factor
IXa - factor Xa
Heparin binds to both antithrombin III and thrombin to form a complex
❑ Heparin dissociates leaving them
❑ Once dissociated, Heparin is free to bind to another antithrombin
-Slight vasodilator
-Stimulates lipoprotein lipase
74
describe the pharmacokinetics of heparin
– Immediate onset of action after IV injection and short duration (4-6 h).
– 80 % hepatic metabolism, 20 % excreted renally, unchanged.
– Does not cross placenta & is not secreted in milk (high MW)
can be used during
lactation or pregnancy
75
what are the heparin routes of administration?
■ IV
■ SC
■ Never IM may lead to
hematoma
76
Control of heparin therapy
aPTT (activated partial thromboplastin time) should be kept as close as possible
to twice normal value (normal value 30-35 seconds)
77
what are the adverse effects of heparin?
■ Hemorrhage
■ Hair loss
■ Hematoma
■ Hypersensitivity reaction
■ Hyperkalemia (monitor K level if given > 7
days)
■ Osteoporosis (long term use)
■ Thrombocytopenia (regular platelet count is
needed)
78
Reversal of Heparin Action in hemorrhage
■ Discontinuation of the drug
■ Heparin is strongly acidic and isneutralized by i.v. protamine sulfate (a strongly basic protein)
■ It combines with heparin to form a stable complex devoid of anticoagulant
activity
■ 1mg to every 100U heparin,
excessive amount may lead to bleeding
79
what are the types of HIT (heparin induced thrombocytopenia)?
Non immune-HIT
■ Start early (within 2 days)
■ Platelet count >100
000/ul
■ Returns to normal within 5
days despite continued
heparin use (or within 2
days if heparin is stopped).
Immune-HIT
■ Start late
■ Potentially catastrophic thrombosis, blood contain
abnormal low platelet (TOO LOW)
■ 30% develop severe venous and/or arterial thrombosis and bleeding uncommon
■ Replace heparin by argatroban or fondaparinux
80
LMWHs mechanism of action
■They bind to antithrombin increasing its inhibitory effect on factor Xa and to a lesser extent on thrombin (Factor IIa)
81
Describe low molecular weight heparins
■ Have equal efficacy
■ No frequent laboratory monitoring (
suitable for outpatient therapy)
■ Greater bioavailability
■ longer t ½ (sc once/day)
■ Binding to platelets and osteoblasts is reduced with LMWH compared with
Heparin
82
what is Fondaparinux (Indirect Xa inhibitor)?
a synthetic compound that inhibits factor Xa by
accelerating antithrombin no effect on thrombin
83
what are the advantages of Fondaparinux?
– Long t1/2 (sc once/day)
– Low risk of HIT
– Bleeding is the major side effects, not
antagonized by protamine sulfate
– No need for monitoring
84
what is protamine sulfate?
low MW carrying electropositive charge.
Neutralizes heparin (each 1 mg neutralizes ≈ 100 IU heparin).
Partially antagonizes LMWHs but does not antagonize fondaparinux.
Has a slight anticoagulant effect avoid overdose.
85
describe the mechanism of action of direct thrombin inhibitors
■ Directly bind to thrombin independent of antithrombin→ more
inhibition of fibrin bound thrombin
86
How are direct thrombin inhibitors given and what are the side effects?
■ Given intravenous
■ Bleeding is the major side effect
■ Argatroban in HIT in patients with renal insufficiency
87
what is an alternative to heparin?
Bivalirudin is alternative to heparin in patient with normal kidney
function also inhibit platelet activation
88
what is the mechanism of action of warfarin?
Warfarin inhibits the synthesis of biologically active forms of vitamin K-dependent clotting factors II, VII, IX and X
-Inhibition of vitamin K epoxide reductase enzyme g prevention of reactivation of vitamin K. so interference
with hepatic synthesis of vitamin K-dependent clotting factors (II, VII, IX, X)
89
pharmacokinetics of warfarin
■ Well absorbed after oral administration(100%
bioavailability).
■ More than 99 % bound to plasma proteins.
■ Metabolized by liver & excreted by kidney.
■ Delayed onset with long duration of action (up to 6
days).
■ Crosses placenta.
■ Secreted in milk (negligible amounts safe during
lactation)
90
what are the antidotes of warfarin
Fresh frozen plasma.
Vitamin K
91
adverse effects of warfarin
■Hemorrhage.
■Skin necrosis
■Teratogenic
92
disadvantages of warfarin
■ Delayed onset (5-10 days ) requires
overlapping therapy with heparin.
■ Narrow therapeutic index
■ Requires routine monitoring of coagulation.
■ Drug interactions
