☺ANEMIA☺

• Anemia is a group of diseases charcterized by a decrease in either hemoglobin or volume of RBC, which
results in decreased oxygen carrying capacity of the blood.
• Anemia can result from inadequate RBC production, increased RBC destruction or blood loss.
• Anemia can be temporary or long term, and it can range from mild to severe.
• The most common symptom of all types of anemia is a feeling of fatigue and a lack of energy.
• Other common symptoms may include:

o paleness of skin

o fast or irregular heartbeat

o shortness of breath

o chest pain

o headache

o light-headedness

Causes
1) Anemia caused by blood loss

Causes of anemia due to blood loss include:

• gastrointestinal conditions, such as ulcers, hemorrhoids, cancer, or gastritis

• use of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen

• menstrual bleeding

2) Anemia caused by decreased or faulty red blood cell production

Bone marrow is a soft, spongy tissue found in the center of bones. It is essential for the creation of red blood
cells. Bone marrow produces stem cells, which develop into red blood cells, white blood cells, and platelets.

A number of diseases can affect bone marrow, including leukemia, where too many abnormal white blood
cells are produced. This disrupts normal production of red blood cells.

Other anemias caused by decreased or faulty red blood cells include:

• Sickle cell anemia: Red blood cells are misshapen and break down abnormally quickly. The
crescent-shaped blood cells can also get stuck in smaller blood vessels, causing pain.

• Iron-deficiency anemia: Too few red blood cells are produced because not enough iron is
present in the body. This can be because of a poor diet, menstruation, frequent blood donation, endurance
training, certain digestive conditions, such as Crohn's disease, surgical removal of part of the gut, and some
foods.
 • Bone marrow and stem cell problems: Aplastic anemia, for example, occurs when few or no
stem cells are present. Thalassemia occurs when red blood cells cannot grow and mature properly.

• Vitamin deficiency anemia: Vitamin B-12 and folate are both essential for the production of
red blood cells. If either is deficient, red blood cell production will be too low. Examples include megaloblastic
anemia and pernicious anemia.

3) Anemia caused by the destruction of red blood cells

Red blood cells typically have a life span of 120 days in the bloodstream, but they can be destroyed or removed
beforehand.

Excessive hemolysis (red blood cell breakdown) can occur for many reasons, including:

Infections, certain drugs, for example, some antibiotics, snake or spider venom, toxins produced
through advanced kidney or liver disease, an autoimmune attack, for instance, because of
hemolytic disease, severe hypertension, vascular grafts and prosthetic heart valves, clotting
disorders, enlargement of the spleen

MORPHOLOGICAL CLASSIFICATION
MATURATION AND DEVELOPMENT OF RBC

DIAGNOSIS
Tests might include:
• Complete blood count (CBC), which determines the number, size, volume, and hemoglobin content of
red blood cells
• Blood iron level and your serum ferritin level, the best indicators of your body's total iron stores
• Levels of vitamin B12 and folate, vitamins necessary for red blood cell production
• Special blood tests to detect rare causes of anemia, such as an immune attack on your red blood cells, red
blood cell fragility, and defects of enzymes, hemoglobin, and clotting
• Reticulocyte count, bilirubin, and other blood and urine tests to determine how quickly your blood cells are
being made or if you have a hemolytic anemia, where your red blood cells have a shortened life span

IRON DEFICIENCY ANEMIA

• Iron deficiency anemia is a condition where there are too few red blood cells in the body due to a
shortage of iron.
IRON BALANCE

Iron balance in human beings is uniquely dependent on the body's ability to match the rate of iron
absorption from the proximal small intestine to iron requirements. During childhood, iron absorption
normally exceeds immediate requirements, ensuring a positive balance and the gradual establishment of an
iron store. In the adult, the level of absorption is approximately equal to a relatively fixed rate of loss that is
governed by factors unrelated to iron balance. When requirements are increased, e.g., during periods of rapid
growth and in pregnancy, absorption increases to replace the storage iron that is used up.

Normal iron content of the body is about 3-4 g.

About 3mg of iron is bound to transferrin in plasma, and 1000mg of iron exists as storage iron in the form
of ferritin or hemosiderin. Rest of iron stored in the cytochromes.

Daily recommended dietary allowance for iron is 8mg in adult males and postmenopausal females and 18mg
in menstruating females.

ETIOLOGY
• Inadequate iron intake
Eating too little iron over an extended amount of time can cause a shortage in your body. Foods such
as meat, eggs, and some green leafy vegetables are high in iron. Because iron is essential during times
of rapid growth and development, pregnant women and young children may need even more iron-rich
foods in their diet.
• Pregnancy or blood loss due to menstruation
Heavy menstrual bleeding and blood loss during childbirth are the most common causes of iron
deficiency anemia in women of childbearing age.
• Internal bleeding
Certain medical conditions can cause internal bleeding, which can lead to iron deficiency anemia.
Examples include an ulcer in your stomach, polyps in the colon or intestines, or colon cancer. Regular
use of pain relievers, such as aspirin, can also cause bleeding in the stomach.
• Inability to absorb iron
Certain disorders or surgeries that affect the intestines can also interfere with how your body absorbs
iron. Even if you get enough iron in your diet, celiac disease or intestinal surgery such as gastric
bypass may limit the amount of iron your body can absorb.
• Endometriosis
If a woman has endometriosis she may have heavy blood loss that she can not see because it is hidden
in the abdominal or pelvic area.
PATHOPHYSIOLOGY OF IDA

SIGNS AND SYMPTOMS

SYMPTOMS SIGNS
Decreased exercise tolerance Pale appearance
Fatigue Decreased mental acuity
Dizziness Increased intensity of some cardiac valvular
murmurs
Irritability
Weakness
Palpitation
Vertigo
Shortnesss of breath, chest pain
LABORATORY FINDINGS
o Low serum iron and ferritin levels
o High TIBC (total iron binding capacity)
o In the early stages, size of RBC is normal, hb, hct, and RBC indices remains normal. In the
later stages, hb and hct falls below normaland microcytic anemia develops.
o Low transferrin indicates IDA
TREATMENT
Dietary supplementation and oral iron preparations
o Iron is best absorbed from meat, fish, and poultry.
o Orange juice and other ascorbic acid rich foods can be included with meals to increase
absorption.
o Milk and tea reduce absorption and should be consumed in moderation.
o Ferrous sulfate, succinate, lactate, fumarate, glutamate, and gluconate are absorbed when
given orally.
Oral iron products

Adverse effects -:
o Dark discolouration of feces
o Constipation or diarhea
o Nausea/vomiting
Parenteral iron therapy
Indication for parenteral iron therapy include;
o Intolerance to oral, malabsorption, and nonadherence.
o Patients with significant blood loss who refuse transfusions and cannot take oral iron therapy.
o Patients with IBD and those with gastric bypass/ gastric resection due to poor oral absorption.
o Patients with CKD, especially those undergoing hemolysis and some cancer patients
receiving chemotherapy.
Preparations
o Iron dextran, sodium ferric gluconate, iron sucros, ferumoxytol, ferrous carboxymaltose.

Dose of iron (mg) = whole blood hemoglobin deficit (g/dl) * body weight (kg) * 0.22

o Sodium ferric gluconate is a complex of iron bound to one gluconate and 4 sucrose molecules.
o Adverse effects include- cramps, nausea, vomiting, flushing, hypotension
o Ferumoxytol 510mg IV is used to treat iron deficiency in adults with CKD who are of
dialysis.

TREATMENT ALGORITHM
 VENOUS THROMBOEMBOLISM
• VTE is a potentially fatal disorder which results from clot formation within the venous
circulation and is manifested as deep vein thombosis or pulmonary embolism.
• DVT is rarely fatal but PE can result in death within minutes of symptom onset, before effective
treatment can be given.
• Blood clots can form in: Arms, legs, lungs
1. Venous thromboembolism (VTE) - Blood clot that forms in a vein
2. Deep venous thrombosis (DVT) - Blood clot in a deep vein
3. Pulmonary embolism (PE) - Blood clot in the lungs

EPIDEMIOLOGY
• 900,000 VTE incidences annually
• First VTE occurs in 100/100,000 persons annually
o Approximately 1/3 = PE, 2/3 = DVT alone
o Idiopathic condition in 25-50% patients
• Recurrence rate ~7% at 6 months (despite therapy)
• Death ~6% DVT, ~12% PE within 1-month diagnosis

ETIOLOGY
1. Blood stasis- Blood stasis favors clotting in part through reduced clearance of the elements
responsible for blood clot formation. Contraction of the calf and thigh muscles coupled with
one-way valves in leg veins fascilitate blood flow back to the heart and lungs, and thus
damage to venous valves and periods of prolonged immobility results in venous stasis.
2. Vascular injury- intact vascular endothelial cells separate flowing blood from vessel wall
components responsible for preventing blood loss through clot formation.
3. Hypercoagulability- inherited and acquired conditions and certain drugs, ie estrogen
containing contraception, estrogen replacement therapy, and selective estrogen receptor
modulators increases the risk of VTE.
PATHOPHYSIOLOGY
NORMAL CLOTTING

COAGULATION CASCADE

THROMBUS FORMATION
 • Thrombus orginates in te soleal venous sinuses or valvular sinuses (calf vein).
• It may also orginate in the iliac or femoral vein.
• Renal veins, upper limb veins, right side of heart and in situ thrombosis in the pulomonary
circulation are other sites.
• Thrombus formation and propogation depends on the presence of abnormalities of blood
flow, blood vessel wall, and blood clotting components known collectively as Virchow’s
triad.

RISK FACTORS
a. Recent orthopedic/general surgery
b. Limited physical movement/immobile
c. stroke, heart attack, heart failure, paralyzed
d. Broken bone (leg, hip, pelvis)
e. Cancer
f. Blood circulation problems
g. Personal or family history of blood clots
h. Hormones (birth control, hormone replacement)
i. Obesity
j. > 60 years of age
k. Smoker
l. Implanted vascular access
m. Previous thromboembolism (high risk)
n. Anti-phospholipidsyndrome (high risk)
VTE RISK SCORE
• Assess patient specific risk factors
• Scores categorize the risk of that patient having a VTE
• Evidence-based standardized scoring systems
a. CapriniVTE Risk Score (surgical)
b. Rogers VTE Risk Score (surgical)
c. Padua VTE Prediction Score (non-surgical)
d. KucherVTE Risk Score (non-surgical)
CLINICAL PRESENTATION
•Depends on location of blood clot
•Deep Venous Thrombosis (DVT)
•Pulmonary Embolism (PE)
Symptoms of DVT: Leg or Arm
1. Unilateral swelling
2. Warmth, redness
3. Pain (Worsens when standing or walking)
Symptoms of PE: Lungs
1. Difficulty Breathing
2. Shortness of breath (SOB)
3. Chest pain (Worse with deep breaths)
4. Coughing (May cough up blood or bloody phlegm)
5. Rapid HR
6. Fainting/Dizziness

DIAGNOSIS
• Clinical assessment
• Elevated D-dimer*
• Diagnostic studies

VTE DIAGNOSTIC STUDY

DVT Venography- It is the gold standard for diagnosis of DVT. It is an invasive test
that involves injection of radiopaque contrast dye intoa foot vein.it is an
expensive and cause anaphylaxis and nephrotoxicity.
Compression ultrasound- Most commonly used. It is a non- invasive test that
can visualize clot formation in vein of the legs.
PE Pulmonary angiography- it is gold standard for diagnosis of PE. It is an
invasive test that involves injection of radiopaque contrast dye into pulmonary
artery.
Computerized tomography
Ventilation-perfusion (V/Q) scan- it measures the distribution of blood and
airflow in the lungs. When ther is mismatch between blood and airflow in one
area of the lung, there is high probability that the patient has a PE

TREATMENT
NON-PHARMACOLOGICAL TREATMENT
IVC Filter – Percutaneous insertion of an Inferior vencava filter (IVC) is a minimally invasive
procedure performed using fluoroscopic imaging.
• Implanted in inferior vena cava
• Captures an embolism on its way to heart/lungs
• Allows blood flow around trapped clots
• Option when unable to take anticoagulants:
o Contraindicated
o Previous failure on therapy

PHARMACOLOGICAL TREATMENT

DRUGS ACTING ON COAGULATION CASCADE

Drugs for VTE

➢ Heparin
➢ Low Molecular Weight Heparins (LMWH) • Lovenox®, Fragmin®
➢ Factor XaInhibitors • Arixtra®, Xarelto®, Eliquis®, Savaysa®
➢ Vitamin K Antagonist (VKA) • Coumadin®
➢ Direct Thrombin Inhibitor • Pradaxa®
➢ Thrombolytic therapy
➢ Surgical removal

1. HEPARIN
MOA: acts on multiple sites of the normal coagulation system
- Combines with antithrombinIII to inactivate Factor Xa, which inhibits conversion of
prothrombin to thrombin
Side Effects: bleeding, heparin-induced thrombocytopenia (HIT)
DOSE: adjust to target activated partial thromboplastin time (aPTT) (60-85
sec) per nomogram
• IV: 80 U/kg (or 5000 U) x 1, then 1000 U/Hr
• S/C: 333 U/kg x1, then 250 U/kg Q12H

2. LOW MOLECULAR WEIGHT HEPARIN (LMWH)

MOA: higher activity with anti-factor Xathan anti-thrombin compared to heparin

DOSE:
• Enoxaparin: 1 mg/kg SQ Q12H <or> 1.5 mg/kg SQ Q24H
• Dalteparin: 100 units/kg SQ Q12H <or> 200 mg/kg SQ Q24H
DOSE ADJUST:
• CrCl<30 ml/min
• Anti-factor Xalevel: 0.5-1 units/mL

• Side Effects: bleeding, anemia, diarrhea, nausea, thrombocytopenia

3. FACTOR Xa INHIBITORS
• Injectable -Arixtra® (fondaparinux)
• Oral tablet -Xarelto® (rivaroxaban), Eliquis® (apixaban) ,Savaysa® (edoxaban) ,Future:
betrixaban

MOA: selectively inhibits active binding site for factor Xa on the coagulation cascade
Side Effects: hemorrhage, anemia, thrombocytopenia

• Fondaparinux (Arixtra®)

DOSE:
• 5 mg SQ Q24H (<50 kg)
• 7.5 mg SQ Q24H (50-100 kg)
• 10 mg SQ Q24H (>100 kg)

Caution: • Bleeding risk increased in renal impairment and BW < 50 kg

• Rivaroxaban

DOSE
• 15 mg PO BID x 21 days, then20 mg PO Daily
• CrCl< 30: Avoid use

• Patient Counseling
a. Take with food
 b. Missed dose
o If miss dose and taking BID-may take 2 doses at once! (max 2 tablets in one
day, 30 mg/24 hours)
o If miss dose and taking once daily-take as soon as remember on that day, do
NOT double dose
• Apixaban (Eliqius®)

DOSE
• 10 mg PO BID x 7 days, then 5 mg PO BID

• Patient counseling
a. With or without food
• Edoxaban
DOSE
• 60 mg PO Daily after 5-10 days parenteral anticoagulant
o Decrease dose to 30 mg PO Daily if: CrCL15-50 mL/min, ≤ 60 kg,
or certain P-gpinhibitors

4. VITAMIN K ANTAGONIST (VKA)

• Coumadin® (warfarin)
• Jantoven® (warfarin)
MOA: inhibits vitamin K-dependent clotting factors (factors II, VII, IX, X) and anticoagulant
proteins C and S

DOSE (patient specific):

• Start with 5 mg PO daily (alt: 10 mg load x2 days)
• Adjust to INR 2-3 (goal 2.5) for VTE

• Side Effects: hemorrhage, skin necrosis, systemic atheroemboli, hypersensitivity

5. DIRECT THROMBIN INHIBITOR

MOA: directly inhibits thrombin, which prevents conversion of fibrinogen to
fibrin
DOSE:
• 150 mg PO BID after 5-10 days of parenteral anticoagulation
• Adjust if CrCl< 30 ml/min or acute renal failure
Side Effects: bleeding, GI effects, hypersensitivity
Counseling Points
• Keep in original container
• Bottle is only good for 4 months after opening
• Swallow whole with full glass of water
6. SURGICAL REMOVAL
•Thrombectomy
•Embolectomy
o Reserved for massive PE

SPECIFIC THERAPY ACCORDING TO LOCATION

PE
DVT

TREATMENT STRATEGY-
TREATMENT ALGORITHM
 DRUG INDUCED BLOOD DISORDERS
• The most common drug-induced hematologic disorders include aplastic anemia,
agranulocytosis, megaloblastic anemia, hemolytic anemia, and thrombocytopenia.
• Drug-induced hematologic disorders are generally rare adverse effects associated with drug
therapy.
• The most common drug-induced hematologic disorders include aplastic anemia,
agranulocytosis, megaloblastic anemia, hemolytic anemia, and thrombocytopenia.
• Drug-induced hematologic disorders are generally rare adverse effects associated with drug
therapy.
• The incidence of idiosyncratic drug-induced hematologic disorders varies depending on the
condition and the associated drug.

EPIDEMIOLOGY
• Women are generally more susceptible than men to the hematologic effects of drugs.
• The incidence varies based on geography, which suggests that genetic differences may be
important determinants of susceptibility.
• Drug-induced thrombocytopenia is the most common drug-induced hematologic disorders,
with some reports suggesting that as many as 5% of patients who receive heparin develop
heparin-induced thrombocytopenia.
• Although drug-induced hematologic disorders are less common than other types of adverse
reactions, they are associated with significant morbidity and mortality.
• An epidemiologic study conducted in the United States estimated that 4,490 deaths in 1984
were attributable to blood dyscrasias from all causes.
• Aplastic anemia was the leading cause of death followed by thrombocytopenia,
agranulocytosis, and hemolytic anemia.
• Similar to most other adverse drug reactions, drug-induced hematologic disorders are more
common in elderly adults than in the young; the risk of death also appears to be greater with
increasing age.

ETIOLOGY
DRUGS THAT CAN CAUSE PANCYTOPENIA
• Chloramphenicol,
• Chemotherapy drugs,
• Thiazide diuretics,
• Anti-epileptic drugs,
• Colchicine,
• Azathioprine, and
• Non-steroidal anti-inflammatory drugs (nsaids).

DRUGS THAT CAN CAUSE AGRANULOCYTOSIS

• Antithyroid medications- carbimazole and methimazole (Tapazole)
 • Anti-inflammatory medications- sulfasalazine (Azulfidine), dipyrone (Metamizole),
and nonsteroidal anti-inflammatory drugs (nsaids)
• Antipsychotics, such as clozapine (Clozaril)

DRUGS THAT CAN CAUSE HEMOLYTIC ANEMIA

• Conditions that may lead to hemolytic anemia include inherited blood disorders such
as sickle cell disease or thalassemia, autoimmune disorders, bone marrow failure, or
infections
DRUGS THAT CAN CAUSE NEUTROPENIA
• Carbimazole,
• Clozapine,
• Dapsone,
• Dipyrone,
• Methimazole,
• Penicillin g,
• Procainamide,
• Propylthiouracil,
• Rituximab,
• Sulfasalazine, and
• Ticlopidine.

PATHOPHYSIOLOGY
 The pathophysiology of drug-induced hematologic disorders requires a basic understanding of
hematopoiesis.
The pluripotential hematopoietic stem cells in the bone marrow, which have the ability to self-
reproduce, maintain the blood.
These pluripotential hematopoietic stem cells further differentiate to intermediate precursor cells, which
are also called progenitor cells or colony-forming cells.
Committed to a particular cell line, these intermediate stem cells differentiate into colonies of each type
of blood cell in response to specific colony-stimulating factors.

• Drug-induced hematologic disorders can affect any cell line, including white blood cells (WBCs), red
blood cells (RBCs), and platelets.
• When a drug causes decreases in all three cell lines accompanied by a hypoplastic bone marrow, the
result is drug-induced aplastic anemia.
• The decrease in WBC count alone by a medication is drug-induced agranulocytosis.
• Drugs can affect RBCs by causing a number of different anemias, including drug-induced immune
hemolytic anemia, drug-induced oxidative hemolytic anemia, or drug-induced megaloblastic anemia.
• A drug-induced decrease in platelet count is drug-induced thrombocytopenia.

DRUG-INDUCED APLASTIC ANEMIA

Aplastic anemia is a rare, serious disease of unclear etiology. It was first described by Ehrlich in 1888
Aplastic anemia can be divided into two broad categories,

• Inherited
• Acquired.
• Inherited aplastic anemias are a set of inherited diseases that result in bone marrow failure, fatty
infiltration of the marrow, and loss of circulating blood cells.
• The most common of these disorders are Fanconi’s anemia, dyskeratosis congenita, and Blackfan
Diamond anemia.
• Acquired aplastic anemia is the focus of this section because it is the type of aplastic anemia that results
from drugs, radiation, viruses, or chemical exposure, and it accounts for most cases of aplastic anemia.
• Acquired, drug-induced aplastic anemia is an idiosyncratic reaction, with unpredictable severity and
time to recovery.
• It has been estimated that 50% of aplastic anemia cases are acquired in nature, but a definitive causative
agent cannot be identified in most cases.
• The mortality rate associated with acquired aplastic anemia varies by series but averages about 50%

CLINICAL FEATURES
• Pancytopenia (anemia, neutropenia, and thrombocytopenia)
• Neutropenia typically presents first followed by thrombocytopenia. Anemia develops slowly
because of the longer life span of RBCs.
• Hypocellular bone marrow
• No gross evidence of increased peripheral blood cell destruction.
• Symptoms of anemia include pallor, fatigue, and weakness; fever, chills, pharyngitis, or other
signs of infection can characterize neutropenia. Thrombocytopenia, manifested by easy
bruisability, petechiae, and bleeding.
PATHOPHYSIOLOGY
The cause of drug-induced aplastic anemia is damage to the pluripotential hematopoietic stem cells
before their differentiation to committed stem cells.
This damage effectively reduces the normal levels of circulating erythrocytes, neutrophils, and platelets.
There are three major etiologies of acquired aplastic anemia:
1. Direct toxicity,
2. Metabolite-driven toxicity, and
3. Immune-mediated mechanisms.
• Cytotoxic chemotherapy and radiation therapy are known to induce varying degrees of bone
marrow suppression or failure. The antineoplastic agents exemplify the dose-dependent mechanism
for the development of aplastic anemia. Certain chemicals or agents may also induce direct injury to
hematopoietic cells. Chloramphenicol, an antimicrobial agent, is such an agent, causing bone
marrow suppression that is dose dependent and reversible.
• Genetic variation leads to variability in the presence of these reactive metabolites and explains the
idiosyncratic nature of these sorts of drug reactions.
• Idiosyncratic drug-induced aplastic anemia secondary to direct toxicity can be characterized by
dose independence, a latent period before the onset of anemia, and continued marrow injury after
drug discontinuation. The idiosyncratic mechanism is believed to result from abnormal metabolism
of chloramphenicol.
• Other drugs thought to induce aplastic anemia through toxic metabolites
include phenytoin and carbamazepine
• Of the three potential mechanisms, the most common cause of drug-induced aplastic anemia is the
development of an immune reaction.
It is proposed that exposure to an inciting antigen (drug) activates cells and cytokines of the immune
system, leading to the death of stem cells.

DIAGNOSIS
• Bone marrow examination shows an absence or marked reduction of hematopoietic stem cells
and an increase in fat cells.
• The diagnosis of aplastic anemia can be made by the presence of two of the following criteria:
1. A WBC count of 3,500 cells/mm3 (3.5 × 109/L) or less,
2. A platelet count of 55,000 cells/mm3 (55 × 109/L) or less, or
3. A hemoglobin value of 10 g/dl (100 g/L; 6.2 mmol/L)
4. Reticulocyte count of 30,000 cells/mm3 (30 × 109/L) or less.
• Depending on the blood counts, aplastic anemia can be categorized as moderate, severe, and
very severe aplastic anemia.
Moderate aplastic anemia (MAA):
Two of the following three criteria—
1. Neutrophils less than 1,500 cells/mm3 (1.5 × 109/L),
2. Platelets less than 50,000 cells/mm3 (50 × 109/L), and
3. Hemoglobin less than 10 g/dl (6.2 mmol/L)
Severe aplastic anemia (SAA):
Two of the following three criteria—
1. Neutrophils less than 500 cells/mm3 (0.5 × 109/L),
2. Platelets less than 20,000 cells/mm3 (20 × 109/L),
 3. Reticulocytes less than 1%
Very severe aplastic anemia (VSAA):
SAA with a neutrophil count less than 200 cells/mm3 (0.2 × 109/L)

• lists drugs that have been associated with drug-induced aplastic anemia.
➢ Acetazolamide
➢ Furosemide
➢ Carbamazepine
➢ NSAID
➢ Phenytoin
➢ Sulphonamides
➢ Methimazole
➢ captopril

TREATMENT: DRUG-INDUCED APLASTIC ANEMIA

Treatment should be based on the severity of disease, with the goal of therapy being to improve
peripheral blood counts, limit the requirement for transfusions, and minimize the risk for infections.
As with all cases of drug-induced hematologic disorders,
• Remove the suspected offending agent
• Appropriate supportive
• Transfusion support with erythrocytes and platelets, as well as appropriate antimicrobial
prophylaxis or treatment during neutropenic periods.
• The use of prophylactic antibiotic and antifungal agents when neutrophil counts are below 500
cells/mm3 (0.5 × 109/l).
• If patients experience febrile neutropenia, broad-spectrum IV antibiotics should be started immediately.
• For patients who have been heavily transfused, iron chelation therapy with agents such as deferoxamine
or DEFERASIROX may be necessary to avoid the serious consequences of iron overload.
• For patients with disease requiring treatment, the two major treatment options for patients with drug-
induced aplastic anemia are allogeneic HSCT and immunosuppressive therapy.
• For patients younger than the age of 40 years, the treatment of choice is allogeneic HSCT from an HLA-
matched sibling donor. For young patients who do not have an available HLA-matched sibling,
allogeneic HSCT from an unrelated donor may be considered but is usually reserved for those who fail
to respond to upfront immunosuppressive therapy.
• For patients older than the age of 40 years and for those who are not candidates for allogeneic HSCT,
the preferred first-line therapy is immunosuppressive therapy.
• The current standard immunosuppressive regimen for the treatment of acquired aplastic anemia is
combination therapy with antithymocyte globulin (ATG) and cyclosporine.
• Cyclosporine plays an important role in immunosuppressive therapy for aplastic anemia.
Although cyclosporine monotherapy has been used to treat moderate aplastic anemia, it is more often
used in combination with ATG. The addition of cyclosporine to ATG therapy has been shown to
increase response rate, improve failure-free survival, and reduce the number of immunosuppressive
courses needed. Cyclosporine inhibits interleukin-2 production and release and subsequent activation of
resting T cells.
• DOSE - 4 to 6 mg/kg per day to 10 to 12 mg/kg per day, initial dose of 5 mg/kg per day in two divided
doses.
• Glucocorticoids
• Hemopoetic stem cell transplantation
• Granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor.
 DRUG-INDUCED AGRANULOCYTOSIS
• Agranulocytosis is defined as a reduction in the number of mature myeloid cells in the blood
(granulocytes and immature granulocytes [bands]) to a total count of 500 cells/mm 3 (0.5 × 109/L) or
less.
• Older patients are thought to be at greater risk for to drug-induced agranulocytosis, probably because of
increased medication use.
• Drug-induced agranulocytosis also occurs more frequently in women than in men.

CLINICAL FEATURES
• Sore throat,
• Fever,
• Bronchitis
• Sinusitis
• lethargy
• Malaise,
• Weakness, and
• Chills.
ETIOLOGY
The cause of drug-induced agranulocytosis is not fully understood, but two mechanisms—
1. Direct toxicity and
2. Immune-mediated toxicity
DIRECT TOXICITY
➢ Direct toxicity to myeloid cells, particularly neutrophils, medications such as
chlorpramazine, procainamide, clozapine, dapsone,sulfonamides, carbamazepine, phenytoin,
indomethacin, and diclofenac.
➢ The toxicity may be due to either the parent drug or a toxic metabolite or byproduct. Agranulocytosis
associated with direct toxicity is usually associated with a slower decline in neutrophils, with a more
insidious presentation of symptoms.
IMMUNE-MEDIATED SUBSET OF AGRANULOCYTOSIS,
Three proposed mechanisms of toxicity.
➢ The hapten mechanism involves the drug or its metabolite binding to the membrane of neutrophils or
myeloid precursors. After binding, antibodies are induced that destroy the cell. This is thought to be the
mechanism of agranulocytosis induced by aminopyrine, penicillin, and gold compounds.
➢ In the immune-complex mechanism, antibodies form complexes with the causative drug, and the
immune complex adheres to the target cell, leading to cell destruction.
➢ Finally, in the autoimmune mechanism, the drug triggers the production of autoantibodies that react with
neutrophils. In this reaction, the causative drug is not directly involved with the serologic reaction. This
is the mechanism of toxicity associated with levamisole.
Nearly all classes of drugs have been associated with some incidence of acute neutropenia or
agranulocytosis, although the risk is exceedingly small. For some drugs, though, the risk may be higher.
These agents include antithyroid medications, ticlopidine, clozapine, sulfasalazine, trimethoprim–
sulfamethoxazole, and β-lactam antibiotics.
In the case of penicillin-induced agranulocytosis, the patient can often begin taking penicillin again,
at a lower dosage, after the neutropenia has resolved without any relapse of drug-induced
agranulocytosis. Because of the rapid onset of symptoms and the dose-related phenomenon, a second
mechanism could possibly be involved with penicillin-induced agranulocytosis.
 Antithyroid medications, such as Propylthiouracil and Methimazole, have been reported to cause
agranulocytosis.
Ticlopidine is an antiplatelet agent indicated for the treatment of cerebrovascular disease and the
prevention of reocclusion associated with stent placement. Agranulocytosis most commonly occurs
within 1 to 3 months from the initiation of ticlopidine. Removal of the drug is the best treatment option,
with counts usually returning to normal within 2 to 4 weeks.
The Phenothiazine class of drugs is known to cause drug-induced agranulocytosis by the innocent
bystander mechanism. The onset of phenothiazine-induced agranulocytosis is about 2 to 15 weeks after
the initiation of therapy, with a peak onset between 3 and 4 weeks. The mechanism by which
phenothiazines cause drug-induced agranulocytosis is by affecting cells in the cell cycle phase that
manufactures enzymes needed for DNA synthesis (G1 phase) or the phase in which cells are resting and
not committed to cell division (G0 phase).
The iron chelator Deferapirone has been associated with a significant risk of neutropenia (8.5%) and
agranulocytosis (0.5. The mechanism of toxicity is largely unknown.
Clozapine, an antipsychotic agent, is associated with a significantly higher risk of agranulocytosis
compared with other antipsychotic medications Because of the frequency and seriousness of clozapine-
induced agranulocytosis and because of its reversible nature if detected early in therapy, clozapine is
currently only available through a limited distribution program that requires strict monitoring of WBC
count.

TREATMENT: DRUG-INDUCED AGRANULOCYTOSIS

The primary treatment of drug-induced agranulocytosis is the
➢ Removal of the offending drug.
➢ After discontinuation of the drug, most cases of neutropenia resolve over time, and only symptomatic
treatment (e.g., antimicrobials for infection treatment and prophylaxis) and appropriate vigilant hygiene
practices are necessary.
➢ Sargramostim (granulocyte-macrophage colony-stimulating factor [gm-csf]) [ ] and Filgrastim
(granulocyte colony-stimulating factor [g-csf]) [ ]have been shown to shorten the
duration of neutropenia, length of antibiotic therapy.

DRUG-INDUCED HEMOLYTIC ANEMIA

• After their release from the bone marrow, normal RBCs survive for about 120 days before they are
removed by phagocytic cells of the spleen and liver.
• The process of premature RBC destruction is referred to as hemolysis, which can occur because of either
defective RBCs or abnormal changes in the intravascular environment.
• The incidence of drug induced hemolytic anemia is estimated to be about one in 1 to 2 million individuals,
although a clear incidence has been difficult to ascertain because of difficulty in establishing a clear
diagnosis and relationship to a specific agent.
CAUSES
o Immune- may operate much like the process that leads to immune-mediated agranulocytosis, or they
can suppress regulator cells, which can lead to the production of autoantibodies.
o Metabolic - involves the induction of hemolysis by metabolic abnormalities in the RBCs.
SIGNS
o Intravascular hemolysis, the lysis of RBCs in the circulation, can result from trauma, complement
fixation to the RBC, or exogenous toxic factors.
o Extravascular hemolysis refers to the ingestion of RBCs by macrophages in the spleen and liver, a
process that requires the presence of surface abnormalities on RBCs, such as bound immunoglobulin.
SYMPTOMS
Fatigue, Malaise, Pallor, And Shortness of Breath

Drug-Induced Immune Hemolytic Anemia

• In immune hemolytic anemia, IgG or immunoglobulin M (IgM) (or both) binds to antigens on the
surface of RBCs and initiates their destruction through the complement and mononuclear phagocytic
systems.
• Drug-induced immune hemolytic anemias involve the formation of antibodies directed against RBCs.
• Antibodies associated with drug-induced immune hemolytic anemia are of two main types.
o Drug-independent antibodies are those that are found even in the absence of the drug. These are
true RBC antibodies and can be the cause of true autoimmune hemolytic anemia.
o Drug-dependent antibodies are those that will only react in the presence of drug, and are the
more common form of antibodies causing drug-induced immune hemolytic anemia.

DIAGNOSIS
A laboratory test called the Direct Coombs Test (or direct antiglobulin test [DAT]), which identifies
foreign immunoglobulins either in the patient’s serum or on the RBCs themselves, is the best means to
diagnose drug-induced immune hemolytic anemia.
The Coombs test begins with the antiglobulin serum, which is produced by injecting rabbits with
preparations of human complement, crystallizable fragment (of immunoglobulin) (Fc), or
immunoglobulins. The rabbits produce antibodies against human immunoglobulins and complement.
The direct Coombs test involves combining the patient’s RBCs with the antiglobulin serum. If the
patient’s RBCs are coated with antibody or complement (as a result of a drug-induced process), the
antibodies in the serum (produced by the rabbit) will attach to the Fc regions of the autoimmune
globulins on separate RBCs, creating a lattice formation called agglutination. This agglutination is
considered positive for the presence of IgG or complement on the cell surfaces.

MECHANISMS
HAPTEN MECHANISM
“Hapten mechanism” or “drug adsorption” mechanism, In this mechanism, patients make an antibody
against a stable complex of the drug with some soluble noncellular molecule or protein. When the drug
is administered again, an immune complex of drug–antidrug forms and attaches nonspecifically to
RBCs, activating complement and leading to cell destruction.
Eg of drugs showing this mechanism- Penicillin, Cephalosporin derivatives - cefotetan and ceftriaxone,
minocycline tolbutamide and streptomycin.
INNOCENT BYSTANDER MECHANISM
In this mechanism, drugs bind to an antibody, usually IgM, to form an immune complex. This immune
complex then attaches to the RBC membrane, activating complement and leading to intravascular
hemolysis. As soon as complement is activated, the complex can detach and move on to other RBCs.
RBCs are essentially victims, or “innocent bystanders,” of the immunologic reaction.
PRODUCTION OF TRUE RBC AUTOANTIBODIES
The first drug associated with this type of reaction was methyldopa. The offending drug may bind to
immature RBCs, altering the membrane antigens and inducing autoantibodies. Other drugs
include fludarabine and cladribine.
NONIMMUNOLOGIC PROTEIN ADSORPTION (NIPA) TO RBC MEMBRANES.
In this “membrane modification mechanism,” drugs can change the RBC membrane so that proteins
attach to the cell, leading to a positive antiglobulin test result.
Eg- β-lactamase inhibitors, cisplatin and oxaliplatin.

Drug-Induced Oxidative Hemolytic Anemia

A hereditary condition, drug-induced oxidative hemolytic anemia, most often accompanies a glucose-
6-phosphate dehydrogenase (G6PD) enzyme deficiency, but it can occur because of other enzyme
defects (reduced nicotinamide adenine dinucleotide phosphate [NADPH] methemoglobin reductase or
reduced glutathione peroxidase). Eg- Dapsone (an oxidizing agent) was transferred from the breast milk
of the mother.
TREATMENT: DRUG-INDUCED HEMOLYTIC ANEMIA
Drug-Induced Immune Hemolytic Anemia
o Immediate removal of the offending agent
o Supportive care
o In severe cases, glucocorticoids can be helpful
o Chimeric anti-cd20 monoclonal antibody rituximab and igg treatments have been used.
Drug-Induced Oxidative Hemolytic Anemia
o Removal of the offending drug
o Patients with these enzyme deficiencies should be advised to avoid medications capable of
inducing the hemolysis.

DRUG-INDUCED MEGALOBLASTIC ANEMIA

• In drug-induced megaloblastic anemia, the development of RBC precursors called megaloblasts in the
bone marrow is abnormal.
• Deficiencies in either vitamin B12 or folate are responsible for the impaired proliferation and maturation
of hematopoietic cells, resulting in cell arrest and subsequent sequestration.
• Examination of peripheral blood shows an increase in the mean corpuscular hemoglobin concentration.
These megaloblastic changes are caused by the direct or indirect effects of the drug on DNA synthesis.
• Because of their pharmacologic action on DNA replication, the antimetabolite class of
chemotherapeutic agents is most frequently associated with drug-induced megaloblastic anemia.
Drugs inducing megloblastic anemia

• Methotrexate, cotrimoxazole, phenytoin, and the barbiturates, primidone, and phenobarbital

TREATMENT: DRUG-INDUCED MEGALOBLASTIC ANEMIA

• Drug-induced megaloblastic anemia results from cotrimoxazole, a trial course of folinic acid, 5 to
10 mg up to four times a day, can correct the anemia.
• Folic acid supplementation of 1 mg every day often corrects the drug-induced megaloblastic anemia
produced by either phenytoin or phenobarbital.

DRUG-INDUCED THROMBOCYTOPENIA
• Thrombocytopenia is usually defined as a platelet count below 100,000 cells/mm3 (100 × 109/L) or
greater than 50% reduction from baseline values.
Drugs causing thrombocytopenia

• Quinine, Quinidine, Gold Salts, Sulfonamide Antibiotics, Rifampin, Glycoprotein (GP) Iib/Iiia
(Gpiib/Iiia) Receptor Antagonists, and Heparin.

MECHANISM
Drug-induced thrombocytopenia can result from
o immune-mediated mechanisms
o nonimmune-mediated mechanism.
Nonimmune-mediated, such as direct-toxicity-type reactions, are associated with medications that cause
bone marrow suppression. This results in suppressed thrombopoiesis and a decreased number of
megakaryocytes. This type of reaction is commonly associated with chemotherapeutic agents.
Immune-mediated - The offending drug binds covalently to certain platelet GPs. Antibodies are
generated that bind to these drug-bound GP epitopes. After the binding of antibodies to the platelet
surface, lysis occurs through complement activation or through clearance from the circulation by
macrophages.
Drug-dependent antibody mechanism- Quinine, anticonvulsants, and nonsteroidal antiinflammatory
medications are thought to induce thrombocytopenia through the drug-dependent antibody mechanism.
In this type of reaction, it is thought that antibodies exist within the patient’s circulation that recognize
an epitope on the platelet GP, but this recognition is too weak to result in antibody binding to the platelet
surface. However, the drug contains structural elements that are noncovalently complementary to
regions of the antibody and the GPs on the platelet surface.
Heparin-induced thrombocytopenia type II
o Less common but more severe and can be associated with more complications.
o About 1% to 5% of patients receiving unfractionated heparin (ufh) and up to 0.8% of patients receiving
low-molecular-weight heparin (lmwh) can develop hit.
o Thrombocytopenia and thrombosis can develop with low-dose heparin, heparin-coated catheters, or
even heparin flushes.
o Highest risk groups include patients receiving heparin for thrombosis prophylaxis after peripheral
vascular surgery, cardiac surgery, and orthopedic surgery.
o Hit is caused by the development of antibodies against platelet factor-4 (pf-4) and heparin complexes.
Mwh bind less well to pf-4 than ufh, and therefore antibody formation is less common.
o Thrombosis is one of the major complications of hit and can occur in up to 20% to 50% of patients with
hit.

TREATMENT: Drug-Induced Thrombocytopenia

o Removal of the offending drug and
o Symptomatic treatment.
o Corticosteroids are sometimes helpful when clinicians are initially trying to distinguish between
drug-induced thrombocytopenia and idiopathic thrombocytopenic purpura (itp).

TREATMENT FOR HIT

The main goal of management is to reduce the risk of thrombosis or thrombosis-associated
complications in patients who have already developed a clot.
All forms of heparin must be discontinued, including heparin flushes, and alternative anticoagulation
must begin immediately.
The direct thrombin inhibitors are the alternative anticoagulants most commonly used. Three
direct thrombin inhibitors are currently available:
o Lepirudin, Argatroban, And Bivalirudin.
Lepirudin,
o The first drug that was approved for the treatment of HIT,
o It is a recombinant analogue of hirudin, a natural anticoagulant found in leeches.
o Lepirudin is renally eliminated and requires dosage adjustment in those patients with kidney
dysfunction.
Argatroban
o IV thrombin inhibitor indicated for the management of HIT.
o It is metabolized in the liver and can be used in patients with end-stage renal disease.
o Dosage adjustment is needed for patients with significant hepatic impairment.
Bivalirudin
o The most recently approved direct thrombin inhibitor
o Parenteral bivalent analogue of hirudin.
o It requires dosage adjustment only in severe renal failure.
Fondaparinux
o An anticoagulant pentasaccharide that inhibits factor Xa.
 EPILEPSY
• Epilepsy is a disorder that is best viewed as a symptom of disturbed electrical activity in the
brain, which may be caused by a wide variety of etiologies
• Seizures that are prolonged or repetitive can be life-threatening
• Patients with epilepsy also may display neurodevelopmental delay, memory problems, and/or
cognitive impairment.
• Epilepsy is a chronic disorder characterized by recurrent unprovoked seizures
EPIDEMIOLOGY

• Each year, 120 per 100,000 people in the United States come to medical attention because of a
newly recognized seizure.
• At least 8% of the general population will have at least one seizure in a lifetime. However, it is
common to have a seizure and not have epilepsy
• The rate of recurrence of a first unprovoked seizure within 5 years ranges between 23% and
80%
ETIOLOGY

• Seizures occur because a group of cortical neurons discharge abnormally in synchrony.

Anything that disrupts the normal homeostasis of neurons and their stability can trigger
hyperexcitability and seizures.
• Patients with mental retardation, cerebral palsy, head injury, or strokes are at an increased risk
for seizures and epilepsy.
• Idiopathic etiology is the term used for suspected primary generalized seizures, whereas
cryptogenic etiology is used if no obvious cause is found for partial-onset seizures.
• The incidence of idiopathic epilepsy is higher in children
• Hyperventilation can precipitate absence seizures.
• Sleep, sleep deprivation, sensory stimuli, and emotional stress increase the frequency of
seizures.
• Hormonal changes occurring around the time of menses, puberty, or pregnancy have also been
associated with the onset of or an increased frequency of seizure
PATHOPHYSIOLOGY

• Firing is reflected on EEG as a sharp wave or spike.

• Initially, a small number of neurons fire abnormally. Normal membrane conductances and
inhibitory synaptic currents break down, and excess excitability spreads, either locally to
produce a focal seizure or more widely to produce a generalized seizure
• There are multiple mechanisms that might contribute to synchronous hyperexcitability
including:
• alterations in the distribution, number, type and biophysical properties of ion channels in the
neuronal membranes;
• biochemical modifications of receptors;
• modulation of second messaging systems and gene expression; (4) changes in extracellular ion
concentrations;
• alterations in neurotransmitter uptake and metabolism in glial cells; and (6) modifications in
the ratio and function of inhibitory circuits.
• In addition local neurotransmitter imbalances could be a potential mechanism for focal
epileptogenesis
 • transitory imbalances between the main neurotransmitters, glutamate (excitatory) and γ-
aminobutyric-acid (GABA) (inhibitory), and neuromodulators (e.g., acetylcholine,
norepinephrine, and serotonin) might play a role in precipitating seizures in susceptible patient
• classification
I. Partial seizures (seizures begin locally)
A. Simple (without impairment of consciousness)
1. With motor symptoms
2. With special sensory or somatosensory symptoms
3. With psychic symptoms
B. Complex (with impairment of consciousness)
1. Simple partial onset followed by impairment of consciousness—with or without automatisms
2. Impaired consciousness at onset—with or without automatisms
C. Secondarily generalized (partial onset evolving to generalized tonic-clonic seizures)
II. Generalized seizures (bilaterally symmetrical and without local onset)
A. Absence
B. Myoclonic
C. Clonic
D. Tonic
E. Tonic-clonic
F. Atonic
G. Infantile spasms
III. Unclassified seizures
IV. Status epilepticus
CLINICAL PRESENTATION

• divided into two main pathophysiologic groups—partial seizures and generalized seizure
• Partial seizures with an alteration of consciousness are described as complex partial (CP)
• A partial seizure that becomes generalized is referred to as a secondarily generalized seizure.
• Generalized absence seizures are manifested by a sudden onset, interruption of ongoing
activities, a blank stare, and possibly a brief upward rotation of the eyes.
• Brief shock-like muscular contractions of the face, trunk, and extremities are known as
myoclonic jerks.
• A sudden loss of muscle tone is known as an atonic seizure.
DIAGNOSIS
Laboratory Tests
• There are currently no diagnostic laboratory tests for epilepsy.
• In some cases, particularly following GTC (or perhaps CP) seizures, serum prolactin levels can
be transiently elevated.
• Other Diagnostic Tests
■ EEG is very useful in the diagnosis of various seizure disorders.
■ An epileptiform EEG is found in only approximately 50% of the patients who have epilepsy.
■ A prolactin serum level obtained within 10 to 20 minutes of a tonic-clonic seizure can be
useful in differentiating seizure activity from pseudoseizure activity but not from syncope.
■ Although magnetic resonance imaging (MRI) is very useful (especially imaging of the
temporal lobes), a computed tomography (CT) scan typically is not helpful except in the initial
evaluation for a brain tumor or cerebral bleeding.
PHARMACOTHERAPY
NONPHARMACOLOGIC THERAPY
• Nonpharmacologic therapy for epilepsy includes diet, surgery, and vagus nerve stimulation
(VNS).
• A vagal nerve stimulator is an implanted medical device that is FDA approved for use as an
adjunctive therapy in reducing the frequency of seizures in adults and adolescents older than
12 years of age with partial-onset seizures that are refractory to AEDs.
• It is also used off-label in the treatment of generalized epilepsy.
• VNS changes the cerebrospinal fluid (CSF) concentration of inhibitory and stimulatory
neurotransmitters and activates specific areas of the brain that generate or regulate cortical
seizure activity through increased blood flow
• The VNS device is relatively safe.
• The most common side effect associated with stimulation is hoarseness, voice alteration,
increased cough, pharyngitis, dyspnea, dyspepsia, and nausea. Serious adverse effects reported
include infection, nerve paralysis, hypoesthesia, facial paresis, left vocal cord paralysis, left
facial paralysis, left recurrent laryngeal nerve injury, urinary retention, and low-grade fever
• Surgery is the treatment of choice in selected patients with refractory focal epilepsy
• The ketogenic diet was devised. It is high in fat and low in carbohydrates and protein and thus
leads to acidosis and ketosis
• Most of the calories are provided in the form of heavy cream and butter, and no sugar is allowed
PHARMACOLOGICAL TREATMENT

(1) Carbamazepine
• Mechanism of Action The exact mechanism by which carbamazepine suppresses
seizure spread is obscure, although it is believed to act primarily through inhibition of
voltage gated sodium channels
• 400 mg/day Because of the auto- and heteroinduction of carbamazepine metabolism, it
is necessary to administer the drug two to four times per day
• Neurosensory side effects (e.g., diplopia, blurred vision, nystagmus, ataxia,
unsteadiness, dizziness, and headache)
• Leukopenia is the most common hematologic side effect
• Carbamazepine should be considered a firstline therapy for patients with newly
diagnosed partial seizures and for patients with primary generalized convulsive
seizures
(2) Ethosuximide
• Mechanism of Action The exact mechanism of action of ethosuximide remains elusive,
however, it is believed to exert its main action through inhibition of T-type calcium
channels
• 500 mg/day, Ethosuximide is still a first-line treatment for absence seizures.
• The most frequently reported side effects are nausea and vomiting
(3) Felbamate
 • Mechanism of Action At therapeutic doses felbamate appears to act by blocking N-
methyl-D-aspartate (NMDA) synaptic responses and by modulating GABAA
receptors. At higher doses it may modulate sodium channels and inhibit high-voltage
activated calcium channels
• 1,200 mg/day, reserved for patients not responding to other AEDs.
• approved for treating atonic seizures in patients with the Lennox Gastaut syndrome and
is effective in treating patients with partial seizures.
• side effects with felbamate prior to marketing were anorexia, weight loss, insomnia,
nausea, and headache, aplastic anemia and acute liver failure
(4) Gabapentin
• Mechanism of Action Gabapentin was designed to be a GABA agonist but does not
react at the GABA receptor, alter GABA uptake, or interfere with GABA
transaminase. Gabapentin appears to bind to an amino acid carrier protein and appears
to act at a unique receptor. Gabapentin inhibits high-voltage activated calcium
channels
• 900 mg/day, second-line agent for patients with partial seizures who have failed initial
treatment.
• Fatigue, somnolence, dizziness, and ataxia are the most frequently reported side
effects. Aggressive behavior has been reported in children
(5) Lamotrigine
• Mechanism of Action A primary mechanism of action for lamotrigine appears to be
inhibition of voltage dependent sodium channels, calcium channels
• 25 mg every other day if on VPA; 25–50 mg/day if not on VPA. Valproic acid
substantially inhibits the metabolism of lamotrigine
• Lamotrigine is useful as both adjunctive treatment in patients with partial seizures and
as monotherapy.
• The most frequently reported side effects of lamotrigine include diplopia, drowsiness,
ataxia, and headache.75 Adverse effects are more common when lamotrigine is given
in combination with other AEDs (e.g., diplopia when given concomitantly with
carbamazepine or tremor with valproic acid)
(6) Levetiracetam
• Mechanism of Action : S-enantiomer pyrrolidone derivative, reduction in high-voltage
activated calcium ion (Ca2+) currents and delayed-rectifier potassium ion (K+)
currents
• 500–1,000 mg/day, levetiracetam is indicated for patients with partial seizures who
have failed initial therapy.
• Adverse effects appear to be modest, with sedation, fatigue, and coordination
difficulties being the most common CNS effects.
(7) Oxcarbazepine
• Mechanism of Action Oxcarbazepine, which is structurally related to carbamazepine,
is a prodrug that is rapidly converted to a 10-monohydrate derivative (MHD)
• 300–600 mg/day, Oxcarbazepine is indicated for use as monotherapy or adjunctive
therapy in the treatment of partial seizures in adults and as monotherapy and adjunctive
therapy in the treatment of partial seizures in patients as young as 4 years of age with
epilepsy. It is also a potential first-line drug for patients with primary generalized
convulsive seizures
• adverse events were dizziness, nausea, headache, diarrhea, vomiting, upper respiratory
tract infections, constipation, dyspepsia, ataxia, and nervousness. In comparative trials,
oxcarbazepine generally caused fewer side effects than phenytoin, valproic acid, or
 carbamazepine. Dizziness may be more common in elderly patients than in young
adults
(8) Phenobarbital
• Mechanism of Action Phenobarbital may elevate seizure threshold by interacting with
GABA receptors to facilitate intrinsic chloride channel function, was well as by
blocking high voltage-activated calcium channels
• 1–3 mg/kg/day (10–20 mg/kg LD), Phenobarbital is the drug of choice for neonatal
seizure
• CNS side effects are the primary factors limiting the use of phenobarbital. Tolerance
usually develops to initial complaints of fatigue, drowsiness, sedation, and depression
(9) Phenytoin
• Mechanism of Action The primary mechanism of action of phenytoin is believed to be
caused by its ability to inhibit voltage-dependent sodium channels
• PO: 3–5 mg/kg (200–400 mg) (15–20 mg/kg LD), Phenytoin has long been a first-line
AED for primary generalized convulsive and partial seizures
• CNS depressant effects can result in lethargy, fatigue, incoordination, blurred vision,
higher cortical dysfunction, and drowsiness
(10) Pregabalin
• Mechanism of Action Pregabalin’s mechanism of action is unknown, however, it is
proposed that the binding of the drug to the subunit of the voltage-gated calcium
channel may be responsible for a large part of its activity. This binding results in a
decrease in the release of several excitatory neurotransmitters including glutamate,
noradrenaline, substance P, and calcitonin gene-related peptide
• 150 mg/day, Pregabalin is a second-line agent for patients with partial seizures who
have failed initial treatment. Pregabalin is also useful in the treatment of chronic
neuropathic pain and generalized anxiety disorder
• Dizziness, somnolence, ataxia, blurred vision, and weight gain are the most frequently
reported side effects
(11) Tiagabine
• Mechanism of Action Tiagabine is a potent and specific inhibitor of GABA uptake
into glial and other neuronal elements. Thus, tiagabine enhances the action of GABA
by decreasing its removal from the synaptic space
• 4–8 mg/day,Tiagabine is considered a second-line therapy for patients with partial
seizures who have failed initial therapy
• The most frequently reported adverse effects of tiagabine are dizziness, asthenia,
nervousness, tremor, diarrhea, and depression.
(12) Topiramate
• Mechanism of Action Topiramate is a sulfamate-substituted monosaccharide that has
multiple modes of action involving voltage-dependent sodium channels, GABA
receptor subunits, high voltage calcium channels, and kainate/AMPA subunits.The
drug also inhibits the enzyme carbonic anhydrase
• 25–50 mg/day,Topiramate is a first-line AED for patients with partial seizures. The
drug is also approved for the treatment of tonic-clonic seizures in primary generalized
epilepsy
• The main adverse events of topiramate are ataxia, impaired concentration, memory
difficulties, attentional deficits, confusion, dizziness, fatigue, paresthesia, somnolence,
and “thinking abnormally,” which rarely has included psychosis
(13) Valproic Acid/Divalproex Sodium
• Pharmacology and Mechanism of Action Initially it was believed that valproic acid
increased GABA by inhibiting its degradation or by activating its synthesis.
 • 15 mg/kg (500–1,000 mg),Valproic acid is first-line therapy for primary generalized
seizures such as myoclonic, atonic, and absence seizures. It can be used as both
monotherapy and adjunctive therapy for partial seizures, and it can be very useful in
patients with mixed seizure disorders
• The most frequently reported side effects are gastrointestinal complaints including
nausea, vomiting, and anorexia, as well as weight gain. Pancreatitis is rare
(14) Zonisamide
• Pharmacology and Mechanism of Action Zonisamide, a synthetic 1,2-
benzisoxazole derivative classified as a sulfonamide, inhibition of slow sodium
channels, by blockade of T-type Ca2+ channels, and possibly by inhibition of
glutamate release
• 100–200 mg/day,Zonisamide is currently approved for the adjunctive treatment of
partial seizures.
• The most common adverse effects of zonisamide include somnolence, dizziness,
anorexia, headache, nausea, agitation, word-finding difficulties, and irritability.
Adverse effects may be more common during rapid dose escalation.
 PARKINSONISM
PD is considered a chronic, progressive neurodegenerative movement disorder. PD is a disorder of the
extrapyramidal system.
Presence of tremor at rest, rigidity, bradykinesia and postural instability are considered to be hallmark
of the disease.
EPIDEMIOLOGY
• Upto 1 million individuals in the US have PD.
• The approx annual incidence of PD is age- dependent and ranges from 120 per 1,00,000 persons in
9th decade.
• Usual age at the time of diagnosis ranges between 55- 80 years.
• Higher in males.
ETIOLOGY
• True etiology is unknown.
• At cellular level, degeneration of dopiminargic neurons projecting from the substantia nigra pars
compacta to striatum are a hallmark of PD.
• Neurons in autonomic ganglia, enteric nervous system, limbic system, olfactory bulb, spinal cord,
and neocortex are affected.
Genetic Factors
• Specific genetic mutations that can cause Parkinson's disease. But these are uncommon except in
rare cases with many family members affected by Parkinson's disease.
• Certain gene variations appear to increase the risk of Parkinson's disease but with a relatively
small risk of Parkinson's disease for each of these genetic markers.

Environmental triggers

• Exposure to certain toxins or environmental factors may increase the risk of later Parkinson's
disease, but the risk is relatively small.

➢ The presence of Lewy bodies. Clumps of specific substances within brain cells are
microscopic markers of Parkinson's disease. These are called Lewy bodies.
➢ Alpha-synuclein is found within Lewy bodies. Although many substances are found within
Lewy bodies, an important one is the natural and widespread protein called alpha-synuclein (a-
synuclein). It's found in all Lewy bodies in a clumped form that cells can't break down. This is
currently an important focus among Parkinson's disease.

RISK FACTORS

Risk factors for Parkinson's disease include:

• Age. Young adults rarely experience Parkinson's disease. It ordinarily begins in middle or late
life, and the risk increases with age. People usually develop the disease around age 60 or older.
• Heredity. Having a close relative with Parkinson's disease increases the chances that you'll
develop the disease. However, your risks are still small unless you have many relatives in your
family with Parkinson's disease.
• Sex. Men are more likely to develop Parkinson's disease than are women.
 • Exposure to toxins. Ongoing exposure to herbicides and pesticides may slightly increase your
risk of Parkinson's disease.
SYMPTOMS
PRIMARY MOTOR SYMPTOMS

• Tremor. A tremor, or shaking, usually begins in a limb, often your hand or fingers. You may a
rub your thumb and forefinger back-and-forth, known as a pill-rolling tremor. Your hand may
tremor when it's at rest.
• Slowed movement (bradykinesia). Over time, Parkinson's disease may slow your movement,
making simple tasks difficult and time-consuming. Your steps may become shorter when you
walk. It may be difficult to get out of a chair. You may drag your feet as you try to walk.
• Rigid muscles. Muscle stiffness may occur in any part of your body. The stiff muscles can be
painful and limit your range of motion.
• Impaired posture and balance. Your posture may become stooped, or you may have balance
problems as a result of Parkinson's disease.

SECONDARY MOTOR SYMPTOMS

• Shuffling gait- rhythm of walking

• Micrographia- abnormally small or cramped handwriting
• A mask like expression
• Dystonia – painfull muscle cramps
• Stooped posture – a tendency to lean forward
• Akathisia – tendency to keep moving
• Sexual dysfunction
• Speech changes. You may speak softly, quickly, slur or hesitate before talking. Your speech
may be more of a monotone rather than with the usual inflections.
• Writing changes. It may become hard to write, and your writing may appear small

NON-MOTOR SYMPTOMS

• Mood
• Behavior
• Impaired sense of smell
• Vision problems
• Oily skin
• Weight loss
PATHOPHYSIOLOGY
➢ Free radicals and deficit in energy metabolism
➢ Programmed cell death
➢ Genetic factors
➢ Environmental factors
➢ Protein aggregation
➢ Aging
➢ Drug induced parkinsonism

Free radical and deficit in energy metabolism

o Most common cellular free radicals are hydroxyl radical, superoxide radicle, and nitric
oxide. Other molecules such as hydrogen peroxide and peroxynitrite are not free radicals
through various chemical reactions.
o Dopamine is a relatively unstable molecule which undergoes auto- oxidation metabolism in
the nigrostriatal tract system thereby producing reactive oxygen species.

Programmed cell death

o Dopaminergic degeneration in the substantia nigra may cause PD.
o Caspases are a family of protease enzymes playing essential roles in apoptosis, pyroptosis,
and necroptosis and inflammation.
Environmental and genetic factors
Environmental factors Genetic factors
Pesticide exposure GBA
Prior head injury STK39
Beta blocker use LRRK2
Agricultural occupation INPP5F

Protein aggregration
o Presence of lewy bodies, cytoplasmic filamentous aggregates composed of protein alpha
synuclein.
o In the premotor stage of PD, Lewy bodies are found in the medulla oblongata, locus
coeruleus, raphe nuclei, olfactory bulb. This provides anatomic correlates to observations that
mood (anxiety, depression) and peripheral symptoms (constipation, impaired olfaction) are
present in premotor stage of PD.
o In advanced stages, lewy pathology spreads to the cortex, and correlates with cognitive and
additional behavior changes.
o Synaptic organization of the basal ganglia involves a variety of other neurotransmitters and
neuromodulators, including Ach, adenosine, enkephalins, glutamate, GAB, serotonin, and
substance P.
DIAGNOSIS
TREATMENT
Nonpharmacologic Therapy
Surgical Therapy
In DBS surgery, a battery-powered neurostimulator is implanted subcutaneously below the clavicle
and provides constant electrical stimulation, via electrode wires, to the targeted brain structure.
Thalamic DBS is very effective for suppressing tremor (specifically arm tremor), but it does not
significantly improve the other parkinsonian features (bradykinesia, rigidity, motor fluctuations, or
dyskinesia’s)
DBS procedures require routine adjustment of the electrical stimulation parameters (e.g., voltage,
frequency, and pulse width) to achieve optimal control while minimizing side effects.
The electrical stimulation parameters (or “electrical dosage”) are adjusted via a programmable
handheld device to meet each patient’s needs.
Pharmacologic Therapy
ANTICHOLINERGIC MEDICATIONS
• Because dopamine provides negative feedback to acetylcholine neurons in the striatum, the
degeneration of nigrostriatal dopamine neurons also results in a relative increase of striatal
cholinergic interneuron activity.
• This increased cholinergic activity is believed to contribute to the tremor of PD. So by using
anticholinergic medications, the cholinergic effects can be blocked and hence tremor can be
reduced.
AMANTADINE
• Used for managing symptoms of tremor, rigidity, and bradykinesia, it is most often used for
management of L-dopa– induced dyskinesia.
• Dose- 300 mg/day in divided doses and extended-release formulations are also available
• MOA- enhancement of dopamine release from presynaptic terminals and inhibition of
glutamatergic N-methyl-d-aspartate (NMDA) receptors are implicated. The antidyskinetic
properties of amantadine are presumed to be mediated by antiglutamate properties which, in the
setting of dyskinesias, appears to dominate over dopaminergic properties.
CARBIDOPA/L-DOPA
• Immediate precursor of dopamine and, in combination with a peripherally acting L-amino acid
decarboxylase inhibitor (carbidopa or benserazide), remains the most effective drug for the
symptomatic treatment of PD.
• Carbidopa- 75 mg/day is required to sufficiently inhibit the peripheral activity of L-amino acid
decarboxylase
MONOAMINE OXIDASE B INHIBITORS
• Three selective MAO-B inhibitors (rasagiline, safinamide, selegiline) are available for
management of PD.
• MOA- The selective inhibition of MAO-B in the brain interferes with the degradation of dopamine
and results in prolonged dopaminergic activity. Rasagiline and selegiline contain a propargylamine
moiety, which is essential for conferring irreversible (“suicide”) inhibition of MAO-B, in contrast
to safinamide, which is a reversible MAO-B inhibitor.
• Dose- Selegiline, also known as L-deprenyl is typically administered 5 mg twice daily.
Rasagiline is a second-generation, irreversible, selective MAO-B inhibitor administered at 0.5 or 1
mg once daily.
Safinamide is a reversible, selective MAO-B inhibitor administered at 50 or 100 mg once daily.
CATECHOL-O-METHYLTRANSFERASE INHIBITORS
• Entacapone and tolcapone, have been developed to extend the effects of L-dopa and are indicated
for managing “wearing off” End-of-dose “wearing off” prior to the next dose of medication is a
common type of response fluctuation. This phenomenon is related to the increasing loss of
neuronal storage capability for dopamine as well as the short half-life of L-dopa
• Tolcapone inhibits both peripheral and central COMT, but its use is limited by reports of fatal
hepatotoxicity, such that strict monitoring of hepatic function, especially during the first 6 months
of therapy, is required
DOPAMINE AGONISTS
• Dopamine agonists fall into two pharmacologic subtypes: ergot-derived agonists (bromocriptine)
and the nonergot agonists (apomorphine, pramipexole, ropinirole, and rotigotine).
• Apomorphine is an aporphine alkaloid originally derived from morphine, but lacks narcotic
properties.
• Dose- Pramipexole is initiated at a dose of 0.125 mg three times a day and increased every 5 to 7
days, as tolerated, to a maximum of 1.5 mg three times a day.
TREATMENT ALGORITHM
 STROKE
Definition and classification
• Stroke is defined as abrupt onset of a focal neurological deficit lasting more than 24 hours. It is also called
cerebrovascular accident (CVA) or apoplexy.
• An acute stroke refers to the first 24-hour- period of a stroke.
• Focal neurological deficit lasting less than 24 hours (usually 5–20 minutes) known as transient ischaemic
attack (TIA) is relevant but beyond the scope of this discussion paper.
• Stroke is classified on the basis of its aetiology as either ischaemic (87%) or haemorrhagic (13%).
• Ischaemic stroke is produced by occlusion of a cerebral artery [thrombotic or atherosclerotic (50%),
embolic (25%) and microartery occlusion, “lacunar stroke”, (25%)].
• Haemorrhagic stroke is caused mainly by spontaneous rupture of blood vessels or aneurysms or secondary
to trauma.

Epidemiology
• Stroke remains the second leading cause of death at the global level and in the European region.
• Of the 56 million deaths that occur every year worldwide, 10.8% are due to stroke.
• Eighty-five per cent of these stroke deaths among all ages occur in developing countries.
• Women have a higher lifetime risk of stroke than men: roughly one in five women (20% - 21%) and one in
six men (14% - 17%) will suffer a stroke in their lifetime, according to a 2006 study.

Ischaemic stroke
• Neurological symptoms and signs of an ischaemic stroke usually appear suddenly, but less frequently, they
occur in a progressive manner (stroke-in-progress).
• The typical presentation is the sudden onset of hemiparesis in an older person.
• Symptoms and signs vary depending on the location of the occlusion and the extent of the collateral flow.
• Atherosclerotic ischaemic stroke is more common in the elderly, and occurs without warning in more than
80% of cases.
The pathophysiology is similar to that of ischaemic heart disease;

• An atherosclerotic plaque in a cerebral artery ulcerates triggering the aggregation of platelets and
coagulation of fibrin to produce the thrombus that occludes the artery.
• Fewer than 20% of cases do not evolve to ulceration, but progress to cause gradual obstruction of flow and
may manifest as TIAs.
• In hypertension-induced arteriosclerosis, small penetrating arteries of the deep white matter of the brain are
affected producing small infarctions known as “lacunar infarcts”.
• In around 40% of elderly stroke patients no clear origin of the infarction can be found.
• Embolic ischaemic stroke is more frequent in patients with atrial fibrillation (80%), myocardial
infarction, prosthetic valves, rheumatic heart disease and larger artery atheroma (artery-artery embolus).
• Most emboli are of atherosclerotic origin, and may partially or temporally obstruct cerebral arteries
causing TIAs. Embolisms tend to be multifocal and may produce small haemorrhages around the
obstruction.
• The occlusion of a cerebral artery causes decreased blood flow and ischaemia.
• If it lasts only few seconds or a minute, recovery is immediate and complete.
• Depending on the severity of the ischemia, infarction (cellular death) will occur within minutes, causing
irreversible damage even after blood flow is restored.
• This is called the “core” of the infarct. Surrounding the core is tissue that is affected functionally due to
diminished circulation but may recover if blood flow is restored.
• This is called the “ischaemic penumbra” of a stroke. Most people will have an ischaemic penumbra
amenable to treatment for 3 hours, but many patients may have it up to 12 hours.
• This is known as the ‘therapeutic window’ available for thrombolysis.
• Thus proper identification of treatable patients is crucial for the efficacy of the interventions.

Haemorrhagic stroke
• There are two types: one resulting from intracerebral haemorrhage secondary to hypertension, cerebral
amyloid angiopathy, or degenerative arterial disease; and the other secondary to subarachnoid
haemorrhages caused by rupture of an aneurysm.
• In the United States, 8–10 million people (3% prevalence) might have an aneurysm, and bleeding occurs in
only 30 000 people per year.
• Other causes are uncommon, and sometimes, no source for the haemorrhage can be found. The main risk
factors are advanced age, heavy alcohol consumption and hypertension.
• Cocaine abuse is an important cause of cerebral haemorrhage in young people.
• Most intracerebral haemorrhagic strokes develop over 30–90 min.
• Symptoms will depend on the location and extent of the haemorrhage. Focal neurological symptoms,
vomiting and drowsiness are common.
• Headache may be present, but stiff neck and seizures are uncommon. Large haemorrhages may cause
stupor or coma.
• Most sub-arachnoid haemorrhages appear suddenly with intense headache, vomiting and neurological
deficit and altered consciousness may occur in about 50% of patients.
• Prodromal neurological symptoms, such as paralysis of a limb, difficulty in speaking, visual impairment or
sudden unexplained headache, appear before a haemorrhage from an enlarging aneurysm causing pressure
on the surrounding tissue or as a result of a leak of blood into the subarachnoid space.
CLINICAL PRESENTATION
• Weakness on one side of body
• Inability to speak
• Loss of vision
• Vertigo
• Neurologic dysfunction and specific deficits
• Hemiparesis
• Aphasia (inability to communicate)
• Dysarthria (slurred speech due to weakness of muscles)

DIAGNOSIS
• Test for hypercoagulable states
➢ Protein C deficiency
➢ Antiphospholipid antibody
• CT scan of the head
• MRI of the head
• Carotid doppler
• ECG
• Transthoracic echocardiography
• Transesophageal echocardiography

PHARMACOTHERAPY
A – ANTIPLATELETS AND ANTICOAGULANTS
 B – BLOOD PRESSURE LOWERING AGENTS
C – CHOLESTEROL LOWERING, CESSATION OF SMOKING
D – DIET
E – EXERCISE

ISCHEMIC STROKE

ANTIPLATELET AGENTS
ALTEPLASE
• Early pharmacologic reperfusion with IV alteplase improve functional ability after ischemic stroke as
compared to no intervention.
• MOA- it is a serine protease which assist fibrin in conversion of plasminogen to plasmin. It binds to fibrin
in a thrombus and inhibits fibrinolysis.
• Dose- 0.9 mg/kg total dose given as 10% as a bolus over 1 minute, remaining 90% over 1 hour, and
maximum dose of 90 mg
• Side effects- nausea, vomiting, bleeding, orolingual angioedema, cholesterol embolization
• Endovascular intervention is not a contraindication to alteplase and patients eligible for alteplase should
receive pharmacologic treatment in addition to mechanical thrombectomy.
ASPIRIN

• MOA- irreversibly acetylates cox 1, blocking thromboxane A2 synthesis, and inhibiting platelet activation
and aggregation
Aspirin inhibits prostacyclin (PGI2) activity in the smooth muscle of vascular walls. PGI2 inhibits platelet
aggregation, and the vascular endothelium can synthesize PGI2 such that the platelet anti aggregating
effect is maintained.
• Dose- initial: 160-325 mg within 48 hrs of stroke; then 75-100mg QD
• Side effects -GI ulceration, increased BP, heartburn, hypersensitivity, tinnitus,
• Discontinue 7-10 days before surgery
• Onset of antiplatelet action- less than 60 minutes
• Administer aspirin at least 2 hours before an NSAID or to wait at least 4 hours after an NSAID dose.
CLOPIDOGREL

• Clopidogrel has a unique platelet anti-aggregatory effect.

• MOA- it is an inhibitor of the ADP pathway of platelet aggregation through purinergic receptor P2Y, G-
protein coupled 12 (P2Y12) receptor inhibition and inhibits known stimuli to platelet aggregation.
• Clopidogrel is a prodrug and requires activation by CYP4502C19 in order to achieve its antiplatelet effect.
• Side effects- excessive tiredness, bleeding, stomach upset, diarrhoea, constipation, rarely very serious
blood disorders.
• Dose- 75mg
TICAGRELOR

• Ticagrelor is a direct-acting ADP P2Y12 receptor inhibitor.

• Dose- a loading dose of 180 mg then 90 mg twice daily for 90 days or aspirin 300 mg loading dose with
100 mg daily 90 days
UNFRACTIONATED HEPARIN

• Use of urgent anticoagulation (e.g., unfractionated heparin or low-molecular-weight heparin) is not

routinely recommended in the early phase of acute ischemic stroke treatment.
• Use and benefit of immediate anticoagulation for non-stroke indications (eg, prophylaxis for venous
thromboembolism) should be weighed against the risk of intracranial haemorrhagic conversion in acute
ischemic stroke patients.
BLOOD PRESSURE MANAGEMENT

• It is more common for patients with ischemic stroke to present with elevated or normal blood pressure, so
hypotension and hypovolemia, if present, should be corrected to maintain systemic perfusion and end
organ function.
• When treating hypertension in acute ischemic stroke it is typical to use intravenous drugs with faster time
to onset and ability to titrate to patient response.
• Labetalol can be used as an intravenous bolus dose or as a continuous infusion and calcium channel
antagonist infusions, such as nicardipine and clevidipine, are often first-line agents.

CHOLESTEROL LOWERING, CESSATION OF SMOKING

• Statin therapy is recommended for all ischemic stroke patients, regardless of baseline cholesterol, to reduce
stroke recurrence.
• The statins reduce the risk of stroke by approximately 30% in patients with coronary artery disease and
elevated plasma lipids.
• It is now recommended that patients age 75 or younger experiencing ischemic stroke of presumed
atherosclerotic origin be treated with high-intensity statin therapy for secondary stroke prevention with a
target of achieving a 50% or greater reduction in low-density lipoprotein (LDL) cholesterol.

HEMORRHAGIC STROKE

BLOOD PRESSURE MANAGEMENT

• Hypertension in patients with hemorrhagic stroke increases the risk of hematoma expansion.
• For patients with ICH presenting with a systolic blood pressure above 220 mmHg, aggressive lowering of
blood pressure with continuous intravenous infusion medications is reasonable.

ANTICOAGULATION REVERSAL
• When ICH occurs in a patient on anticoagulants, the use of reversal agents to correct the medication-
induced coagulopathy should be considered.
• For patients on warfarin with elevated INR, reversal with vitamin K, typically intravenously, in
combination with a four-factor prothrombin complex concentrate is recommended.
• Fresh frozen plasma can be used in place of a prothrombin complex concentrate, if necessary, but is not
preferred.
 ALZHEIMER’S DISEASE
• Alzheimer’s disease (AD) is the most common form of dementing illnessis
• It is a gradually progressive dementia affecting cognition, behavior, and functional status. The
exact pathophysiologic mechanisms underlying AD are not entirely known, and no cure
exists.Although drugs may reduce AD symptoms for a time, the disease is eventually fatal

EPIDEMIOLOGY
• AD is the most common cause of dementia. AD unassociated with any other pathology accounts
for 50% to 60% of cases of latelife cognitive dysfunction. The incidence increases to 80% if
AD in conjunction with other pathologic lesions is considered.
• Approximately 4.5 million Americans have AD.3 By the year 2050, 1 in 5 people will be older
than age 65 years, and the number of AD patients is projected to be 13.2 million
• Most cases present in persons older than age 65 years, but approximately 5% of cases occur in
persons younger than age 65 years.
• Onset can be as early as age 40 years, resulting in the arbitrary age classifications of early onset
(ages 40 to 64 years) and late-onset (ages 65 years and older)

ETIOLOGY
• The exact etiology of AD is unknown; however, several genetic and environmental causes have
been explored as potential causes of AD.
• The majority and most aggressive early onset cases are attributed to mutations of a gene located
on chromosome 14, which produces a protein called presenilin 1.7 A structurally similar
protein, presenilin 2, is produced by a gene on chromosome 1. Both presenilin 1 and presenilin
2 encode for membrane proteins that may be involved in amyloid precursor protein (APP)
processing.
• late-onset AD is thought to be primarily linked to the apolipoprotein E (apo E) genotype
• AD occurs at an early age in some individuals, and AD is associated with vascular risk factors
such as obesity, diabetes, and hypertension.
• Genetic variation at the angiotensin-converting enzyme locus may influence the risk for AD
• Angiotensinconverting enzyme has also been demonstrated to inhibit βAP aggregation and
plaque formation in vitro
• Alterations to chromosomes 1, 14, and 21 are associated with early onset AD, whereas the
presence of apo E4 alleles increases risk of developing late-onset AD
• A number of environmental factors are associated with an increased risk of AD, including age,
decreased reserve capacity of the brain (reduced brain size, low educational level, and reduced
mental and physical activity in late life), head injury, and risk factors for vascular disease
(hypercholesterolemia, hypertension, atherosclerosis, coronary heart disease, smoking, obesity,
and diabetes)

PATHOPHYSIOLOGY
• The signature lesions in AD are neuritic plaques and neurofibrillary tangles (NFTs) located in
the cortical areas and medial temporal lobe structures of the brain. Various theories are:

a) AMYLOID CASCADE HYPOTHESIS: Neuritic plaques (also termed amyloid or senile

plaques) are extracellular lesions found in the brain and cerebral vasculature. Plaques from
AD brains largely consist of a protein called βAP. βAP is produced via processing of a
larger protein, APP
• βAP gave rise to plaques, plaques induced neurodegeneration, and this neuronal loss resulted
in the clinical dementia syndrome typical of AD

b) NEUROFIBRILLARY TANGLES As βAP was being identified in plaques, other

researchers showed that NFTs are commonly found in the cells of the hippocampus and
cerebral cortex in persons with AD and are composed of abnormally hyperphosphorylated
tau protein.
• Tau protein provides structural support to microtubules, the cell’s transportation and skeletal
support system.
• When tau filaments undergo abnormal phosphorylation at a specific site, they cannot bind
effectively to microtubules, and the microtubules collapse.
• Without an intact system of microtubules, the cell cannot function properly and eventually dies.
• The density of the NFTs correlates well with the severity of the dementia, because they are a
hallmark of neuronal death.
• NFTs are found in other dementing illnesses besides AD.

c) INFLAMMATORY MEDIATORS : brain amyloid deposition associates with local

inflammatory and immunologic alterations
• This inflammatory response may represent an attempt to clear amyloid deposition. However, it
is also associated with release of cytokines, nitric oxide, and other radical species, and
complement factors that can both injure neurons and promote ongoing inflammation
• Indeed, levels of multiple cytokines and chemokines are elevated in AD brains, and certain
proinflammatory gene polymorphisms are reported to be associated with AD

d) THE CHOLINERGIC HYPOTHESIS : Multiple neuronal pathways are destroyed in AD

• In late AD, the number of cholinergic neurons is reduced, and there is loss of nicotinic receptors
in the hippocampus and cortex.
• Presynaptic nicotinic receptors control the release of acetylcholine, as well as other
neurotransmitters important for memory and mood, including glutamate, serotonin, and
norepinephrine
• cholinergic cell loss appears to be a secondary consequence of Alzheimer’s pathology, not the
disease-producing event
• cholinergic neurons are only one of many neuronal pathways destroyed in AD.

e) OTHER NEUROTRANSMITTER ABNORMALITIES: , serotonergic neurons of the raphe

nuclei and noradrenergic cells of the locus ceruleus are lost
• monoamine oxidase type B activity is increased. Monoamine oxidase type B is found
predominantly in the brain and in platelets, and is responsible for metabolizing dopamine
• abnormalities appear in glutamate pathways of the cortex and limbic structures
• Glutamate is the major excitatory neurotransmitter in the cortex and hippocampus.
• If glutamate is allowed to remain in the synapse for extended periods of time, it can destroy
nerve cells.
• Toxic effects are thought to be mediated through increased intracellular calcium and
accumulation of intracellular free radicals.
• Dysregulated glutamate activity is thought to be one of the primary mediators of neuronal injury
after stroke or acute brain injury.
 f) BRAIN VASCULAR DISEASE AND HIGH CHOLESTEROL : Cardiovascular risk factors
that are also risk factors for dementia include hypertension, elevated low-density lipoprotein
cholesterol, low high-density lipoprotein cholesterol, and, particularly, diabetes.
• Brain vascular disease may augment the cognitive impairment
• Dysfunctional blood vessels may impair nutrient delivery to neurons and reduce clearance of
βAP from the brain.
• In addition, vascular disease may accelerate amyloid deposition and increase amyloid toxicity
to neurons
• Diabetes may increase the risk of dementia through factors related to “metabolic syndrome”
• Apo E is a lipoprotein that is synthesized in the liver, central nervous system, and cerebrospinal
fluid and is responsible for transporting cholesterol in the blood through the brain. It is carried
by low-density lipoprotein into neurons and binds to NFTs.
• Apo E4 is associated with increasing deposition of βAP and is thought to act as an accelerating
modulator in the course of vascular dementia.
• The elevated cholesterol levels in brain neurons may alter membrane functioning and result in
the cascade leading to plaque formation and AD

g) OTHER MECHANISMS: accumulation of free radicals in the brain of AD patients

• vitamin E and vitamin C, may prevent AD
• Estrogen is thought to be involved in promoting neuronal growth, and in preventing oxidative
damage, which would benefit cells exposed to βAP
• Estrogen may also increase NMDA receptor numbers in brain areas involved in recording new
memories and prevent cell damage by acting as an antioxidant
CLINICAL PRESENTATION

• Cognitive
■ Memory loss (poor recall and losing items)
■ Aphasia (circumlocution and anomia)
■ Apraxia
■ Agnosia
■ Disorientation (impaired perception of time and unable to recognize familiar people)
■ Impaired executive function
• Noncognitive
■ Depression, psychotic symptoms (hallucinations and delusions)
■ Behavioral disturbances (physical and verbal aggression, motor hyperactivity,
uncooperativeness, wandering, repetitive mannerisms and activities, and combativeness)
• Functional
■ Inability to care for self (dressing, bathing, toileting, and eating)
DIAGNOSIS

• Laboratory Tests
■ Rule out vitamin B12 and folate deficiency
■ Rule out hypothyroidism with thyroid function tests
■ Blood cell counts, serum electrolytes, liver function tests
• Other Diagnostic Tests
■ CT or MRI scans may aid diagnosis
• AD is through direct examination of brain tissue at autopsy or biopsy. Several criteria have
been developed for the detection and diagnosis of dementia, including the Diagnostic and
Statistical Manual of Mental Disorders, 4th ed. Text Revision (DSM-IV-TR) criteria
 • defective retention memory (amnesia) will implicate bimesiotemporal dysfunction.
• Evidence of parietal cortical dysfunction (visuospatial dysfunction),
• dorsolateral prefrontal dysfunction (executive dysfunction), or
• lateral temporal dysfunction (language dysfunction)

TREATMENT
NONPHARMACOLOGIC THERAPY
• Behavioral and psychiatric symptoms are among the most challenging and distressing
symptoms of the disease and may be the determining factor in a family’s decision to seek
institutional care.
• Symptoms such as sleep disturbances, wandering, urinary incontinence, agitation, and
aggression in patients with dementia are best managed using behavioral interventions
• Personal discomfort may also trigger behaviors, so it is important to monitor for pain, hunger,
thirst, constipation, full bladder, fatigue, infections and skin irritation, comfortable temperature,
fears, and frustrations

PHARMACOLOGICAL TREATMENT
In mild-moderate disease, consider therapy with a cholinesterase inhibitor.
• Donepezil, or • Rivastigmine, or • Galantamine
• Titrate to recommended maintenance dose as tolerated.
In moderate to severe disease, consider adding antiglutamatergic therapy.
• Memantine • Titrate to recommended maintenance dose as tolerated.
• Alternatively, consider memantine or cholinesterase inhibitor therapy alone.
• Behavioral symptoms may require additional pharmacologic approaches.

1. Antiglutamatergic Therapy
• Memantine is the only NMDA antagonist currently available. Memantine blocks glutamatergic
neurotransmission by antagonizing NMDA receptors.
• Glutamate is an excitatory neurotransmitter in the brain implicated in long-term potentiation,
a neuronal mechanism important for learning and memory.
• By blocking NMDA receptors, excitotoxic reactions, which ultimately lead to cell death, may
be prevented
• It is currently indicated for use in AD patients with moderate to severe illness
• adverse events associated with memantine include constipation, confusion, dizziness,
headache, hallucinations, coughing, and hypertension
• Memantine is likely to be used as monotherapy and also in combination with cholinesterase
inhibitors
• Dose: initiated at 5 mg once a day and increased weekly by 5 mg a day to the effective dose of
10 mg twice daily.
• It may be given with or without food. Dosing of 10 mg daily is recommended in patients with
severe renal impairment.

2. Cholinesterase Inhibitors
• Newer cholinesterase inhibitors donepezil, rivastigmine, and galantamine
• Donepezil specifically and reversibly inhibits acetylcholinesterase.
• Rivastigmine inhibits both butyrylcholinesterase and acetylcholinesterase.
 • Galantamine is a selective, competitive, reversible acetylcholinesterase inhibitor and also
enhances the action of acetylcholine on nicotinic receptors
• The most frequent adverse events associated with these agents are mild to moderate
gastrointestinal symptoms (nausea, vomiting, and diarrhea
• Other cholinergic side effects are generally dose-related and include urinary incontinence,
dizziness, headache, syncope, bradycardia, muscle weakness, salivation, and sweating. Gradual
dose titration over several months can improve tolerability
• Abrupt discontinuation can lead to worsening cognition and behavior in some patients
• Donepezil 5 mg daily at bedtime
• Rivastigmine 1.5 mg twice a day , 4.6 mg/day (patch)
• Galantamine : 4 mg twice a day
Other Potential Treatment Approaches
3. Estrogen : Estrogen replacement has been studied extensively for the treatment and
prevention for AD
4. Antiinflammatory Agents: Epidemiologic studies suggest a protective effect against AD
in patients who have taken NSAID.
• Indomethacin, prednisone, and diclofenac/misoprostol administration have had no
cognitive benefit in AD patients
• gastritis and the possibility of gastrointestinal bleeds, NSAIDs and prednisone are
not recommended for general use in the treatment or prevention of AD at the
present time
• Rofecoxib has been compared to naproxen and placebo with no demonstrated
cognitive benefit after 1 year
5. Lipid-Lowering Agents: 3-hydroxy3-methylglutaryl-coenzyme A-reductase inhibitors
6. Vitamin E Based on pathophysiologic theories involving oxidative stress and the
accumulation of free radicals in AD, Vitamin E is often recommended as adjunctive
treatment for AD patient
• Side effects observed with vitamin E administration include impaired hemostasis,
fatigue, nausea, diarrhea, and abdominal pain. For example, vitamin E can cause
thinning of the blood if it is taken with other medications such as aspirin, ibuprofen,
and/or naproxen
7. Ginkgo Biloba : Ginkgo is one of the most popular dietary supplements used in AD.
• Hypothesized mechanisms of action in AD include increasing blood flow,
decreasing the viscosity of blood, antagonizing platelet activating factor receptors,
increasing tolerance to anoxia, inhibiting monoamine oxidase, antiinfective
properties, and preventing the damage of membranes caused by free radicals.
• Ginkgo biloba may also inhibit catecholamine-O-methyl transferase
• Side effects reported in studies involving EGb 761 are rare and usually mild, and
may include nausea, vomiting, diarrhea, headaches, dizziness, palpitations,
restlessness, and weakness
8. Huperzine A: Huperzine A is an alkaloid isolated from the Chinese club moss, Huperzia
serrata. It reversibly inhibits acetylcholinesterase and is administered orally in doses of 50
to 200 mcg two to four times daily. Clinical studies suggest that huperzine A may be
promising for symptomatic treatment of Alzheimer’s disease
Antipsychotics Psychosis:
Haloperidol : starting dose(sd)-0.25mg , maintenance dose in dementia(md)-1–3 mg/day
Olanzapine : starting dose-2.5 mg, maintenance dose in dementia 5–10 mg/day
Quetiapine starting dose-25 mg, maintenance dose in dementia 100–300 mg/day
Risperidone starting dose-0.25 mg, maintenance dose in dementia 0.75–2 mg/day
Ziprasidone starting dose-20 mg, maintenance dose in dementia 40–160 mg/day
Target symptoms: hallucinations, delusions, suspiciousness Disruptive behaviors: agitation, aggression
Antidepressants
Citalopram: sd-10mg, md- 10–20mg/kg
Escitalopram : sd-5mg, md- 20–40 mg/kg
Fluoxetine : sd-5mg, md- 10–40 mg/kg
Paroxetine: sd-10mg, md- 10–40 mg/kg
Sertraline : sd-25mg,md- 75–100 mg/kg
Venlafaxine : sd-25mg, md- 75–225 mg/kg
Trazodone : sd-25mg, md- 75–150 mg/kg
Target symptoms: Depression, poor appetite, insomnia, hopelessness, anhedonia, withdrawal, suicidal
thoughts, agitation, anxiety
Anticonvulsants
Carbamazepine: sd-100mg, md- 200–600 mg/kg
Valproic Acid: sd-125mg, md- 500–1,000mg/kg
Target syndrome: Agitation or aggression