32 - AIIMS november 2008 pharmacology mcqs

37.THALIDOMIDE IS NOT USED IN?
A. HIV RELATED NEUROPATHY
B. ERYTHEMA NODOSUM LEPROSUM
C. APHTHOUS ULCER
D. BECHETS DS

38. DRUGS USED FOR DETRUSOR INSTABILITY ARE ALL EXCEPT?
A. FLAVOXATE
B. SOLIFENACIN
C. DULOXETINE
D.TIAPERETIDE

39.WHICH IS NOT AN ALKYLATING AGENT?
A.CYCLOPHOSPHAMIDE
B. BUSULPHAN
C.5FU
D.MELPHALAN

40.IFOSFAMIDE BELONGS TO WHICH CLASS?
A. ALKYLATING AGENT
B. ANTI METABOLITE
C. TAXANES
D. ANTIBIOTICS

41.DOC FOR REFRACTORY HISTIOCYTOSIS?
A. CLADARABINE
B. FLUDARABINE
C. CYTOSINE ARABINOSIDE
D.HIGH DOSE METHOTREXATE

42.TNF ALPHA INHIBITORS ARE CONTRAINDICATED IN?
A. SLE
B. SERONEGATIVE SPONDYLOARTHRITIS
C. PSORIATIC ARTHRITIS
D. RHEUMATOID ARTHRITIS



43. TRUE ABOUT ALPHA SUBUNIT OF G PROTEIN?
A. HAS GTPase ACTIVITY
B.
C.
D.

44.HERCEPTIN?


45.TRUE ABOUT ACARBOSE ARE A/E?
A. CONTROLS BOTH PRE AND POST PRANDIAL HYPERGLYCEMIA
B. IT DECREASES FIBRINOGEN LEVEL
C. ITS AN ALPHA GLUCOSIDASE INHIBITOR
D.IT DELAYS PROGRESSION OF DIABETES

46.A FEMALE HAS HYPOPIGMENTED LEISON ON CENTRE OF FOREHEAD.DRUG RESPONSIBLE IS?
A. HYDROQUINONE
B. ETHER METABOLITE OF HYDROQUINONE
C. PARA TETRA BUTYL CATECHOL
D. PARA TETRA BUTYL PHENOL

47.DOSE OF WHICH CEPHALOSPORIN IS NOT REDUCED IN RENAL INSUFFICIENCY?
A. CEFIXIME
B. CEFOPERAZONE
C. CEFIPIME


48. TRUE ABOUT ACE INHIBITORS?
A. HALF LIFE OF ENLAPRIL IS MORE THAN LISINOPRIL
B. INHIBIT CONVERSION OF ANGIOTENSINOGEN TO ANGIOTENSIN I
C. FIRST DOSE HYPOTENSION IS NOT SEEN IF PREVIOUS TREATMENT WITH DIURETICS IS STOPPED


49.WHICH OF THE FOLLOWING DOES NOT CONTRIBUTE TO DIGOXIN TOXICITY?
A. HYPERKALEMIA
B. HYPERCALCEMIA
C. RENAL FAILURE
D. HYPOMAGNESEMIA

50.WHICH DRUG USED INTREATMENT OF OSTEOPOROSIS CAUSES BOTH BONE FORMATION AND DECREASED BONE RESORPTION?
A.BISPHOSPHONATE
B STRONTIUN RANOXALATE
C. TERAPEPTIDE
D. CALCITONIN

51.WHICH OF THE FOLLOWING DRUGS CAN BE USED IN RENAL FAILURE?
A.LORAZEPAM
B.METRONIDAZOLE
C.THEOPHYLLNE
D. ACETAMINOPHEN


52.A GIRL ON SULPHONAMIDES DEVELOPED ABDOMINAL PAIN AND PRESENTED TO EMERGENCY WITH SEIZURE.WHAT IS THE PROBABLE CAUSE?
A. ACUTE INTERMITTENT PORPHYRIA
B. CONGENITAL ERYTHROPOIETIC PORPHYRIA
C. INF MONONCLEOSIS
D. KAWASAKIS DS

to view all the 200 mcqs of AIIMS november 2008 click here

31 - pharmacology cases mcqs - 1

Cases 1 :

One of your clinic patients is being treated with spironolactone.

Which of the following statements best describes a property of this drug?

a. Contraindicated in heart failure, especially if severe

b. Inhibits Na+ reabsorption in the proximal renal tubule of the nephron

c. Interferes with aldosterone synthesis

d. Is a rational choice for a patient with an adrenal cortical tumor

e. Is more efficacious than hydrochlorothiazide in all patients who receive the

drug

The answer is d. (Brunton, pp 759–762; Craig, pp 247–248; Katzung,

pp 250–252.)

Spironolactone is a potassium-sparing diuretic. Its active

metabolite displaces aldosterone from aldosterone receptors in the collecting

ducts. The drug is ineffective in the absence of aldosterone. (Recall that

aldosterone normally causes renal Na+ retention and K+ loss. The effects of

aldosterone are qualitatively the opposite: Na+ loss, K+ retention.)

Owing to the ability of spironolactone to counteract the effects of

aldosterone, it is particularly suited for patients with primary or secondary

hyperaldosteronism (e.g., adrenal cortical tumor or hepatic dysfunction, as

might occur with long-term/high-dose alcohol consumption, respectively).

There is abundant data that the drug is beneficial in heart failure and probably

reduces morbidity in severe heart failure.

In addition to the potential for causing hyperkalemia (especially if

combined with oral potassium supplements, which should not be done)

and hyponatremia (overall risk is low), spironolactone may cause several

other side effects. CNS side effects include lethargy, headache, drowsiness,

and mental confusion. Other side effects that are fairly common arise from

the drug’s androgen receptor–blocking actions: gynecomastia (in men and

women) and erectile dysfunction. It may also cause seborrhea, acne, and

coarsening of body hair. (Paradoxically, the drug can cause hirsutism in

some patients, but it is also used to manage hirsutism in others.)

30 - PGI december 2003 pharmacology mcqs

note : questions can have multiple answers .

1q: side effects of timolol maleate ?

1. asthma
2. depression
3. tachycardia
4. hypotension
5. hypertension

answer: a , b , d .

2q: methotrexate acts by ?

1. inhibition of dihydrofolate reductase
2. aldose dehydrogenase
3. glutathione reductase
4. inhibition of sterol synthesis

answer: a .

3q: true about carvedilol ?

1. alpha 1 blocker
2. beta 1 blocker
3. beta 2 blocker
4. antioxidant
5. used in hypertension

answer: a , b , c , d , e .

4q: prophylaxis of migraine ?

1. flunarizine
2. cinarizine
3. beta blockers
4. sodium valproate
5. carbamazepine

answer: a , c , d .

5q: which of the following are prodrugs ?

1. mercaptopurine
2. dipivefrine
3. enalapril
4. phenytoin
5. linezolid

answer: a , b , c .

6q: first pass metabolism is seen in ?

1. lignocaine
2. propranolol
3. salbutamol
4. dypyridamol
5. erythromycin

answer: a , b , c .

7q: true about quinidine

1. it increases the effective refractory period
2. used in hypertension
3. causes paradoxical tachycardia
4. it decreases absolute refractory period
5. cinchonism is seen

answer: a , c , e .

8q: regarding ritonavir in AIDS patient which of the following are true ?

1. interacts with terfenadine
2. gastrointestinal symptoms are seen
3. contraindicated in renal failure
4. it is NNRTI
5. should not be used in AIDS patient with bleeding disorder

answer: a , b .

9q: anti hypertensive drug beneficial or neutral role in lipid metabolism ?

1. prazocin
2. propranolol
3. furosemide
4. losartan
5. chlorthiazide

answer: a , d . prazocin and losartan .

10q: neurochemical mechanism of analgesia

1. VR-1
2. Nicotinic cholinergic
3. Nocistatin pattern
4. Nociceptin pattern
5. Anandomide

Answer: a, b , d , e .

11q: side effects of phenytoin are ?

1. gum hypertrophy
2. alopecia
3. subungual exostosis
4. onycholysis
5. acne rosacea

answer: a .

12q: ototoxicity of aminoglycosides is increased with concurrent use of which of the following drugs ?

1. cisplatin
2. furosemide
3. vancomycin
4. vincristin
5. erythromycin

answer: a , b , c , e .

13q: treatment of pencillinase producing neisseria gonorrhea is/are ?

1. amoxicillin
2. ciprofloxacin
3. cefotaxime
4. azithromycin
5. doxycycline

answer: b , c .

14q: true about lispro-insulin ?

1. action is faster and short in duration than regular insulin
2. it is given 15 minutes prior to meal
3. source is lamb
4. action is faster and long in duration than regular insulin

answer: a , b .

15q: true about pseudocholine esterase ?

1. present in neuromuscular junction
2. level is increased in pregnancy
3. succinyl choline is metabolized
4. organophosphorous inhibits it

answer: c .

16q: alkylating agents are ?

1. vincristin
2. actinomycin-D
3. chlorambucil
4. 5-FU
5. Cyclophosphamide

Answer: c , e .

29 - ezetimibe

Ezetimibe is an anti-hyperlipidemic medication which is used to lower cholesterol levels. It acts by decreasing cholesterol absorption in the intestine. It may be used alone when other cholesterol-lowering medications are not tolerated, or together with statins (e.g. ezetimibe/simvastatin, marketed as Vytorin and Inegy) when cholesterol levels are unable to be controlled on statins alone. It is marketed by Schering-Plough and Merck under the trade names Ezetrol, Zetia and Ezemibe. Ezetimibe was originally discovered by a team of four Schering-Plough research chemists: Drs. Stuart B. Rosenblum, Duane A. Burnett, John W. Clader and Brian A. McKittrick.

Ezetimibe localises at the brush border of the small intestine, where it inhibits the absorption of cholesterol from the diet. Specifically, it appears to bind to a critical mediator of cholesterol absorption, the Niemann-Pick C1-Like 1 (NPC1L1) protein on the gastrointestinal tract epithelial cells as well as in hepatocytes. In addition to this direct effect, decreased cholesterol absorption leads to an increase in LDL-cholesterol uptake into cells, thus decreasing levels in the blood plasma.

Ezetimibe is indicated as an adjunct to dietary measures in the management of:

• Hypercholesterolaemia
• Homozygous sitosterolemia (phytosterolemia)

On 9 June 2006, U.S. regulators approved the use of ezetimibe in combination with fenofibrate to treat mixed hyperlipidaemia.

Common adverse drug reactions (greater than or equal to 1% of patients) associated with ezetimibe therapy include: headache and/or diarrhea. Infrequent adverse effects (0.1–1% of patients) include: myalgia and/or raised liver function test (ALT/AST) results. Rarely (less than 0.1% of patients), hypersensitivity reactions (rash, angioedema) or myopathy may occur.

Ezetimibe is available as 10 mg tablets in most markets. A combination preparation ezetimibe/simvastatin, which combines ezetimibe with a statin, is also available.

On January 14, 2008, it was reported in the New York Times that a clinical trial (ENHANCE trial) of Zetia that was designed to show that the drug could reduce the growth of fatty plaques in arteries instead resulted in growth of plaques. However, the growth noted was less than it would have been had the patients been on placebo alone. Merck and Schering-Plough completed the clinical trial in April 2006 and had initially planned to release the findings no later than March 2007. The companies missed several self-imposed deadlines, and in December 2007, finally agreed to publish the results "soon" after the delays were publicized in news reports.

It should be recognized that the ENHANCE trial was not a clinical-outcome trial, but merely an imaging study. Formally, the American College of Cardiology (ACC) maintains that Zetia may be a reasonable option for patients who cannot tolerate a statin or cannot be controlled on a high dose statin. Results from the trial have provoked three large clinical-outcome trials. The results from these trials will be presented in the next three to four years. However, a March 30th, 2008 meeting of the ACC resulted in negative press for drugs like Zetia as Yale University Cardiologist Harlan Krumholz and concurring colleagues called into question the efficacy of such drugs. Krumholz' statements maintained that such pharmaceuticals should not be the first or even second option for prescribing doctors. Definitive conclusions of the efficacy and safety of Zetia can be made such a time when the results of more substantial and comprehensive trials are released, such as the upcoming IMPROVE-IT Trial which has an enrollment of 18000 patients and will report results in 2012.

28 - cephalosporins - 1st,2nd,3rd and 4th generations

1^st generation parenteral cephalosporins :

1. cephalothin
2. cefazoline

1^st generation oral cephalosporins

1. cephalexin
2. cephradine
3. cefadroxil

2^nd generation parenteral cephalosporins

1. cefuroxime
2. cefoxitin

2^nd generation oral cephalosporins

1. cefaclor
2. cefuroximeaxetil

3^rd generation parenteral cephalosporins

1. cefotaxime
2. cetizoxime
3. cefoperazone
4. ceftriaxone
5. ceftazidime

3^rd generation oral cephalosporins

1. cefixime
2. cefpodoximeproxetil
3. cefdinir
4. ceftibuten

4^th generation parenteral cephalosporins

1. cefepime
2. cefpirome

27 - Dopamine agonists, antagonists and depleters

Dopamine agonists :

1. dopamine
2. bromocriptine
3. apomorphine

dopamine is an inhibitor of prolactin release , so these drugs cause a decrease in the plasma level of prolactin and hence are used in the treatment of galactorrhea .

Dopamine antagonists :

1. metoclopramide
2. chlorpromazine
3. haloperidol

these drugs cause an increase in the plasma level of prolactin .

Dopamine depleters

1. reserpine
2. methyldopa

26 - pseudotumor cerebri causing drugs

1. hypervitaminosis A

2. oral contraceptive pills

3. tetracyclines

4. glucocorticoids ( withdrawal )

5. amiodarone

6. mineralocorticoids ( withdrawal )

try this stupid mnemonic : HOT Glucose And Minerals – treat pseudotumor cerebri.

25 - gynaecomastia causing drugs with mechanism of action

Various drugs are implicated in gynecomastia and can be classified into the following categories:

• Estrogens or drugs with estrogen like activity such as diethylstilbestrol, digitalis, phytoestrogens, and estrogen-contaminated food and estrogen-containing cosmetics

• Drugs that enhance estrogen synthesis such as gonadotropins, clomiphene, phenytoin, and exogenous testosterone

• Drugs that inhibit testosterone synthesis or action such as ketoconazole, metronidazole, alkylating agents, cisplatin, spironolactone, cimetidine, flutamide, finasteride, and etomidate

• Drugs that act by unknown mechanisms such as isonicotinic acid hydrazide, methyldopa, busulfan, tricyclic antidepressants, diazepam, penicillamine, omeprazole, phenothiazines, calcium channel blockers, ACE inhibitors, alcohol, marijuana, and heroin

• Drugs in the same class do not all cause gynecomastia to the same extent

24 - Hemolysis causing drugs in G6PD deficiency

1. Dapsone

2. Cotrimoxazole

3. Sulfonamides

4. Aspirin

5. Anti-malarials eg: primaquine

6. Nitrofurantoin

7. phenacetin

8. probenecid

9. chloramphenicol

try this stupid mnemonic : Deepa Caught Selling Aspirin At Primetime Night. Phone Probe Closed .

please visit this page for a very detailed list of drugs which carry a definite risk , possible risk and doubtful risk of hemolysis in glucose 6 phosphate dehydrogenase deficient patients .

23 - prodrugs and active forms

MCQ: all of the following are prodrugs except ?

a. lisinopril

b. enalapril

c. levodopa

d. sulindac

answer: a . lisinopril .

PRODRUGS AND ACTIVE FORMS

1. LEVODOPA ------------------- dopamine

2. ENALAPRIL ------------------- enalaprilat

3. SULINDAC --------------------- sulfide metabolite

4. BECAMPICILLIN –---------- ampicillin

5. SULFASALAZINE –---------- 5 – aminosalicyclic acid

6. PREDNISONE ----------------- prednisolone

7. ZIDOVUDINE ----------------- zidovudine triphosphate

8. CYCLOPHOSPHAMIDE --- aldophosphamide

22 - theophylline - drug interactions

THEOPHYLLINE -- DRUG INTERACTIONS

1. drugs which inhibit theophylline metabolism and increase its plasma level :

1. allopurinol
2. cimetidine
3. ciprofloxacin
4. erythromycin
5. OCP

2. drugs which induce theophylline metabolism and decrease its plasma level are :

1. phenytoin
2. phenobarbitone
3. charcoal broiled meat meal
4. rifampicin
5. smoking

3. theophylline enhances the effect of the following drugs:

1. hypoglycemics
2. furosemide
3. digitalis
4. oral anticoagulants
5. sympathomimetics

4. theophylline decreases the effect of :

1. lithium
2. phenytoin

21 - antacids - drug interactions

Examples of antacids (brand names may vary in different countries).

• Aluminium hydroxide (Amphojel, AlternaGEL)
• Magnesium hydroxide (Phillips’ Milk of Magnesia)
• Aluminum hydroxide with magnesium hydroxide (Maalox, Mylanta)
• Aluminum carbonate gel (Basaljel)
• Calcium carbonate (Alcalak, TUMS, Quick-Eze, Rennie, Titralac, Rolaids)
• Sodium bicarbonate (Bicarbonate of soda, Alka-Seltzer)
• Hydrotalcite (Mg₆Al₂(CO₃)(OH)₁₆ · 4(H₂O); Talcid)
• Bismuth subsalicylate (Pepto-Bismol)
• Magaldrate with Simethicone (Pepsil)

1.Sparfloxacin is a broad-spectrum oral fluoroquinolone antimicrobial agent with a long elimination half-life. Concurrent treatment with antacids has demonstrated a reduction in the oral absorption of many quinolones.

2.Antacids may reduce zinc and iron absorption due to the inhibition of gastric acid secretion.

3.Possible effects of antacids and acid-lowering drugs on the pH of the proximal small intestine. Both cimetidine and an antacid containing aluminum and magnesium hydroxide reduced folate absorption from a liquid formula meal. Although the effects of these drugs on reducing folic acid absorption were relatively small, such reductions could become clinically significant in chronic antacid or H2 receptor antagonist use or intensive antacid or H2 receptor antagonist use by individuals eating diets that are marginal in folate content.

4.The effect of small doses of four commercially available aluminum-containing antacids on calcium and phosphorus metabolism was investigated in adult males in 20 studies. During the use of these doses of antacids, urinary and fecal calcium increased significantly during a low calcium intake averaging 252 mg/day, and the calcium balances became distinctly more negative. There was a reversal of the normal pattern of phosphorus excretions, namely, the fecal phosphorus was high and the urinary phosphorus was low. During a normal calcium intake of 800 mg/day, these doses of antacids did not result in significant changes of the calcium excretions or balance. In three patients who received large therapeutic doses of antacids, 240 to 450 ml/day, the changes of calcium and phosphorus metabolism were intensified.

5.Following all doses of antacid, a significant increase in 24 h urinary excretion of aluminium was seen. The estimated absorption of aluminium was 8 and 50 times higher when antacids were taken with orange juice or with citric acid, respectively, than when taken with water. Thus, measurable quantities of aluminium are absorbed from single oral doses of antacids. The absorption is substantially enhanced by concomitant ingestion of citric acid.

6.Two infants presented with growth failure and were found to have generalized osteomalacia (rickets) due to phosphate depletion from prolonged administration of an aluminum-containing antacid given for the symptoms of colic. One of the infants developed bilateral proptosis due to craniosynostosis related to the underlying metabolic bone disease. The chronic use of aluminum-containing antacids in infants has potential risk for the growing skeleton and is not innocuous. Therefore, antacid therapy should be used in low doses and very cautiously, with routine monitoring of serum calcium and phosphorus in children taking medications which reduce gastrointestinal phosphate absorption.

7.antacids reduce the absorption of tetracyclines from the gut .

20 - gynaecomastia causing drugs

MCQ: gynecomastia is caused by

1. rifampicin
2. spironolactone
3. thiazide
4. propranolol

answer: b . spironolactone .

DRUGS CAUSING GYNAECOMASTIA

1. spironolactone
2. ketoconazole
3. estrogens
4. testosterone
5. digitalis
6. clomiphene
7. phenytoin
8. griseofulvin
9. calcium channel antagonists
10. reserpine
11. isoniazid
12. methyldopa
13. ethionamide

for last seven drugs try this mnemonic : PG CRIME . for the first six drugs try TC DESK .

19 - drugs causing interstitial nephritis

1. MCQ: drug induced interstitial nephritis is caused by ?

2. methicillin
3. cloxacillin
4. azlocillin
5. piperacillin

answer: a . methicillin .

drugs causing interstitial nephritis :

1. pencillins especially methicillin

2. cephalosporins

3. ciprofloxacins

4. NSAIDS

5. sulfonamides

6. thiazides

7. furosemide

8. rifampicin

9. phenindone

18 - hypolipidemic drugs - mechanism of action

There are mainly four type of hypolipidemic drugs , they are

1. statins : they act by inhibiting the enzyme HMG CoA reductase which is the rate limiting step of cholesterol synthesis .

examples of statins are : lovastatin, mevastatin, simvastatin , rosuvastatin .

2. fibric acid derivatives : these drugs act by activating the lipoprotein lipase .

examples are : gemfibrozil , clofibrate .

3. bile acid resins : these drugs act by interrupting the enterohepatic recycling of bile acids .

examples of bile acid resins are : cholestyramine and cholestipol .

4. nicotinic acid : this drug acts by unclear mechanisms but it is believed that it acts by inhibition of lipolysis .

17 - natalizumab

Natalizumab is a humanized monoclonal antibody against the cellular adhesion molecule α4-integrin. Natalizumab is used in the treatment of multiple sclerosis and Crohn's disease. It is co-marketed by Biogen Idec and Élan as Tysabri, and was previously named Antegren. Natalizumab is administered by intravenous infusion every 28 days. The drug is believed to work by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood-brain barrier. Natalizumab has proven effective in treating the symptoms of both diseases, preventing relapse, vision loss, cognitive decline and significantly improving quality of life in people with multiple sclerosis, as well as increasing rates of remission and preventing relapse in Crohn's disease.

Natalizumab was approved in 2004 by the United States Food and Drug Administration. It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of the rare neurological condition progressive multifocal leukoencephalopathy when administered in combination with interferon beta-1a, another immunosuppressive drug often used in the treatment of multiple sclerosis. After a review of safety information and no further deaths, the drug was returned to the US market in 2006 under a special prescription program. In the European Union, it has been approved only for the treatment of multiple sclerosis.

Indications

Natalizumab is FDA-approved for the treatment of multiple sclerosis and Crohn's disease and approved for treatment of multiple sclerosis in Europe.

Multiple sclerosis

Natalizumab was evaluated in two randomized, double-blind, placebo-controlled trials in people with multiple sclerosis. Both studies enrolled individuals with MS who experienced at least one clinical relapse during the prior year and had a Kurtzke EDSS score between 0 and 5. In these trials natalizumab was shown to reduce relapses in individuals with MS by 68% vs. placebo, a margin far greater than had been seen for other approved MS therapies.^[2] Natalizumab also slowed the progression of disability in patients with relapsing MS. In combination with interferon beta-1a (IB1A), relapsing and disability progression were reduced more than IB1A alone. Other benefits of natalizumab use by patients with relapsing MS included reduced visual loss,a significant increase in the proportion of disease-free individuals, significantly improved assessments of health-related quality of life in relapsing individuals, reduced cognitive decline of a portion of individuals with MS, reduced hospitalizations and steroid use, and prevention of the formation of new lesions.^[2][10] Approximately 6% of individuals receiving natalizumab have been found to develop persistent antibodies to the drug, which reduces its efficacy^[11][12][4] and produce reactions during the infusion of the drug, as well as hypersensitivity.^[4] Natalizumab is approved in the United States and the European Union. It is indicated as monotherapy (not combined with other drugs) for the treatment of highly active relapsing remitting MS in spite of prior treatments. Natalizumab offers a limited improvement in efficacy compared to other treatments for MS, but due to the lack of information about long-term use, as well as potentially fatal adverse events, reservations have been expressed over the use of the drug outside of comparative research with existing medications.

Crohn's disease

Several randomized controlled trials have demonstrated that natalizumab is effective in increasing rates of remission^[13] and maintaining symptom-free status^[14] in patients with Crohn's disease. Natalizumab may be appropriate in patients who do not respond to medications that block tumor necrosis factor-alpha such as infliximab,^[15] with some evidence to support combination treatment of Crohn's disease with natalizuma and infliximab may be helpful in inducing remission.^[16] Treatment of adolescent patients with natalizumab demonstrates an effectiveness similar to that of adult patients.^[17]

In January 2008, the FDA approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's disease,^[18] though it has not been approved for this use in the European Union due to concerns over its risk/benefit ratio.^[19]

Adverse effects

Common adverse effects include fatigue and allergic reactions with a low risk of anaphylaxis,^[20] headache, nausea, colds and exacerbation of Crohn's disease in a minority of patients with the condition.^[16] Adolescents with Crohn's disease experience headache, fever and exacerbation of Crohn's disease.^[17] Natalizumab is contraindicated for people with known hypersensitivity to the drug or its components and in patients with a history of PML (see interactions).

Postmarketing surveillance in early 2008 revealed that 0.1% of people taking natalizumab experience clinically significant liver injury, leading to the FDA, EMEA and manufacturers recommending that the medication be discontinued in patients with jaundice or other evidence of significant liver damage.^[21][22][23] This rate is comparable to other immune-suppressing drugs.^[24] Evidence of hepatotoxicity in the form of elevated blood levels of bilirubin and liver enzymes can appear as soon as six days after an initial dose; reactions are unpredictable and may appear even if the patient does not react to previous treatment.^[25] Such signs reoccur upon rechallenge in some patients, indicating that damage is not coincidental.^[25] In the absence of any blockage these liver function tests are predictors of severe liver injury with possible sequelae of liver transplantation or death.^[25]

Natalizumab has also been linked to melanoma, though the association is unclear.^[26] The long-term effects of the drug are unknown^[27] and concern has been expressed over the risks of infection and cancer.^[4]

Mechanism of action

Natalizumab is a humanized monoclonal antibody against alpha-4 (α4) integrin, the first drug developed in the class of selective adhesion molecule inhibitors. α4-integrin is required for white blood cells to move into organs; natalizumab's mechanism of action is believed to be the inhibition these immune cells from crossing blood vessel walls to reach affected organs.^[28]

In multiple sclerosis

The symptom-causing lesions of MS are believed to be caused when inflammatory cells such as T-lymphocytes pass through the blood-brain barrier through interaction with receptors on the endothelial cells. Natalizumab appears to reduce the transmission of immune cells into the central nervous system by interfering with the α4β1-integrin receptor molecules on the surfaces of cells. The affect appears to occur on endothelial cells expressing the VCAM-1 gene, and in parenchymal cells expressing the osteopontin gene. In animals used to model MS and test therapies, repeated administration of natalizumab reduced migration of leukocytes into the brain's parenchyma, and also reduced lesioning, though it is uncertain if this is clinically significant for humans.^[29]

Individuals with MS dosed with natalizumab demonstrated increased CD34-expressing cells, with research suggesting a peak in expression after 72 hours.^[30]

In Crohn's disease

The interaction of the α4β7 integrin and the addressin (also known as MADCAM1) endothelial cell receptor is believed to contribute to the chronic bowel inflammation that causes Crohn's disease. Addressin is primarily expressed in the endothelium of venules in the small intestine and are critical in guiding T-lymphocytes to lymphatic tissues in Peyer's patches. In CD patients, sites of active inflammation of the bowel in CD patients have increased expression of addressin, suggesting a connection between the inflammation and the receptor. Natalizumab may block interaction between the α4β7 integrin and addressin at sites of inflammation. Animal models have found higher levels of VCAM-1 expression in mice with irritable bowel syndrome and the VCAM-1 gene may also play a part in CD but its role is not yet clear.^[29]

Interactions

Natalizumab appears to interact with other immune-modulating drugs to cause progressive multifocal leukoencephalopathy (PML), an often-fatal opportunistic viral infection. In 2005, two people taking natalizumab in combination with interferon beta-1a developed PML. One died, and the other recovered with disabling sequelae.^[31][32] A third fatal case initially attributed to an astrocytoma was reported in a patient being treated for Crohn's disease.^[33] Though the patient was being treated with natalizumab in combination with azathioprine, corticosteroids and infliximab, indications of PML infection appeared only after natalizumab monotherapy was re-introduced.^[33] No deaths have been linked to natalizumab when it was not combined with other immune-modulating drugs^[34] and other rates of opportunistic infections are not increased in patients taking natalizumab^[35] possibly due to the drug’s mechanism of action.^[36] Other than a prior history of PML, there is no known method to identify patients at risk of developing PML.^[37] Natalizumab's label indicates that it is contraindicated for immunosuppressed individuals or those with a history of PML.^[29] Due to the uncertain risk of PML, natalizumab is only available through a restricted distribution program.^[29] As of 2008, no other cases of PML associated with natalizumab have been reported.^[37]

Though the small number of cases precludes conclusion on the ability of natalizumab alone to induce PML, its black box warning states that the drug has only been linked to PML when combined with other immune-modulating drugs and natalizumab is contraindicated for use with other immunomodulators.^[29] Corticosteroids may produce immunosuppression, and the Tysabri prescribing information recommends that people taking corticosteroids for the treatment of Crohn's disease have their doses reduced before starting natalizumab treatment.^[29] The risk of developing PML was later estimated to be 1 in 1,000 (0.1%) over 18 months^[11][35][38] though the longer term risks of PML are unknown.^[11]

Legal status

Natalizumab was originally approved for treatment of multiple sclerosis in 2004, through the FDA's accelerated Fast Track program, due to the drug's efficacy in one-year clinical trials. In February 2005, four months after its approval, natalizumab was withdrawn voluntarily by the manufacturer after two cases of progressive multifocal leukoencephalopathy. Groups representing individuals with MS lobbied to have the drug returned to the US market^[39] and in June, 2006, after recommendation by an advisory committee and a review of two years of safety and efficacy data, the FDA re-approved natalizumab for patients with all relapsing forms of MS (relapse-remitting, secondary-progressive, and progressive-relapsing) as a first-line or second-line therapy.^[40][41] Patients taking natalizumab must enter into a registry for monitoring.^[39] Natalizumab is the only drug after alosetron withdrawn for safety reasons that returns to the US market.

In April, 2006 the Committee for Medicinal Products for Human Use recommended authorizing natalizumab to treat relapsing-remitting MS, and several weeks later the European Medicines Agency approved natalizumab in the European Union for highly-active relapsing remitting MS.^[1]

Health Canada added natalizumab to Schedule F of the Food and Drug Regulations on April 3rd, 2008 as a prescription drug requiring oversight from a physician.

16 - daclizumab

Daclizumab (Zenapax) is a therapeutic humanized monoclonal antibody to the alpha subunit of the IL-2 receptor of T cells. It is used to prevent rejection in organ transplantation, especially in kidney transplants.

It is given in multiple doses, the first 1 hour before the transplant operation and 5 further doses given at two week intervals after the transplant. These saturate the receptors and prevent T cell activation and thus prevent formation of antibodies against the transplant.

Like the similar drug basiliximab, daclizumab reduces the incidence and severity of acute rejection in kidney transplantation without increasing the incidence of opportunistic infections.

Daclizumab usage may also be indicated in place of a calcineurin-inhibitor (ciclosporin or tacrolimus) during the early phase after kidney transplantation, when the kidney is recovering and vulnerable to calcineurin-inhibitor toxicity. This has been shown to be beneficial in non-heart beating donor kidney transplantation.

In the United Kingdom, the National Institute for Health and Clinical Excellence has recommended its use be considered for all kidney transplant recipients.

In 2006 it began a Phase II clinical trial that finished in 2007 as a possible Multiple Sclerosis treatment. Participants were nine patients with multiple sclerosis not controlled with interferon. Daclizumab was effective in reducing lesions and improving clinical scores.

Daclizumab has also been used to slow the progression of autoimmune diseases, particularly that of birdshot chorioretinopathy.

15 - osteoporosis causing drugs

1. drugs causing osteoporosis are :

a- vitamin K

b- lithium

c- dilantin

d- heparin

e- etidronate

answer : b , c , d . lithium, dilantin and heparin . dilantin is the other name of the anti-epileptic drug phenytoin . etidronate is used in the treatment of osteoporosis .

à the drugs that cause osteoporosis are : ( GHALACTose)

1. glucocorticoids, GnRH antagonists
2. heparin
3. anticonvulsants, aluminium,
4. lithium
5. alcohol excess intake
6. cyclosporine, cytotoxic drugs
7. thyroxine excess

14 - enoxaparin ( levonox ) ( lupenox )

How does it work?

Enoxaparin is a medicine known as a low molecular weight heparin. It is an anti-clotting or anticoagulant medicine, and works by interfering with the body's natural blood clotting mechanism. Blood clotting involves a complex series of pathways. Enoxaparin inactivates a compound in this pathway called thrombin, which plays an important role in blood clot formation. Therefore, enoxaparin prevents the formation of blood clots (thrombosis) in the body. Blood clots within the body can be dangerous as they can travel in the blood vessels and potentially block off blood supply to the heart, lungs or brain. Enoxaparin is given by injection under the skin, and is used to prevent clots forming in the blood. This can occur in various conditions where the normal blood circulation is disturbed. Surgery, particularly abdominal surgery, produces a risk of thrombosis, as does a heart attack and poorly controlled angina (unstable angina). Clots can also occur when people are bed-ridden for long periods of time. Enoxaparin is given to prevent thrombosis in these groups of people. In addition, enoxaparin is used to prevent blood clotting when it is filtered through a kidney dialysis machine. Enoxaparin is also used to treat blood clots which have formed in the veins of the leg (deep vein thrombosis), as these may otherwise detach and travel in the circulation to the lungs causing a pulmonary embolism.

What is it used for?

 Angina not well controlled by medical treatment

 Blood clot lodged in a vein of the leg

 Heart attack

 Prevention of blood clot formation in the veins after surgery

 Prevention of blood clot formation in the veins in people bedridden due to illness

 Prevention of blood clots during haemodialysis

Warning!

 This medicine is not recommended for use in children as no dose has been established.

 It is recommended that blood tests to monitor the levels of platelets in the blood are performed prior to and during treatment with this medicine.

 Blood potassium levels should be measured before starting treatment and at regular intervals throughout, particularly if treatment lasts longer than 7 days.

Use with caution in

 Decreased liver function

 Diabetes affecting the eyes

 History of reduced platelet count (thrombocytopenia) caused by heparin treatment

 People who have previously had a peptic ulcer

 People who have recently had a stroke

 People who have recently had eye surgery

 People who have recently had surgery of the brain or spinal cord (neurosurgery)

 People with problems stopping bleeding

 Severe uncontrolled high blood pressure

 Severely decreased kidney function

Not to be used in

 Active peptic ulcer

 Bacterial infection of the heart valves and the lining surrounding the heart (bacterial endocarditis)

 Major bleeding disorders such as haemophilia

 People with an increased risk of bleeding (haemorrhage)

 Reduced platelet count in the blood

 Stroke associated with internal bleeding of the brain

This medicine should not be used if you are allergic to one or any of its ingredients. Please inform your doctor or pharmacist if you have previously experienced such an allergy. If you feel you have experienced an allergic reaction, stop using this medicine and inform your doctor or pharmacist immediately.

Pregnancy and Breastfeeding

Certain medicines should not be used during pregnancy or breastfeeding. However, other medicines may be safely used in pregnancy or breastfeeding providing the benefits to the mother outweigh the risks to the unborn baby. Always inform your doctor if you are pregnant or planning a pregnancy, before using any medicine.

 This medicine is not recommended for use in pregnancy unless considered essential by your doctor. Seek medical advice from your doctor.

 It is not known whether this medicine passes into breast milk. Mothers who need to take this medicine should not breastfeed. Seek medical advice from your doctor.

Side effects

Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Because a side effect is stated here, it does not mean that all people using this medicine will experience that or any side effect.

 Allergy to active ingredients (hypersensitivity)

 Alteration in results of liver function tests

 Bleeding (haemorrhage)

 High blood potassium level (hyperkalaemia)

 Thinning of the bones (osteoporosis) with long term use

 Decrease in the number of platelets in the blood (thrombocytopenia)

 Presence of blood clots in the spinal cord (intra-spinal haematoma)

 Blood clots which form a solid swelling at the injection site (haematoma)

 Pain and irritation at the injection site

 Death of skin cells (necrosis) at the site of injection

The side effects listed above may not include all of the side effects reported by the drug's manufacturer. For more information about any other possible risks associated with this medicine, please read the information provided with the medicine or consult your doctor or pharmacist.

13 - low molecular weight heparins

In medicine, low-molecular-weight heparin (LMWH) is a class of medication used as an anticoagulant in diseases that feature thrombosis, as well as for prophylaxis in situations that lead to a high risk of thrombosis.^[1]

Heparin is a naturally-occurring polysaccharide that inhibits coagulation, the process whereby thrombosis occurs (see Heparin: Mechanisms of action). Natural heparin consists of molecular chains of varying lengths, or molecular weights. Chains of molecular weight from 5000 to over 40,000 Daltons, making up polydisperse pharmaceutical-grade heparin.^[2]

Heparin derived from natural sources, mainly porcine intestine or bovine lung, can be administered therapeutically to prevent thrombosis (see anticoagulation). However, the effects of natural, or unfractionated heparin can be difficult to predict. After a standard dose of unfractionated heparin, coagulation parameters must be monitored very closely to prevent over- or under-anticoagulation.

Low-molecular-weight heparins (LMWHs), in contrast, consist of only short chains of polysaccharide. LMWHs are defined as heparin salts having an average molecular weight of less than 8000 Da and for which at least 60% of all chains have a molecular weight less than 8000 Da. These are obtained by various methods of fractionation or depolymerisation of polymeric heparin. They have a potency of greater than 70 units/mg of anti-factor Xa activity and a ratio of anti-factor Xa activity to anti-thrombin activity of >1.5.^[3]

Low-molecular-weight heparin products

The anhydromannose in IdoA(2S)-anhydromannose can be reduced to an anhydromannitol

Various methods of heparin depolymerisation are used in the manufacture of low-molecular-weight heparin.^[4] These are listed below:

• Oxidative depolymerisation with hydrogen peroxide. Used in the manufacture of ardeparin (Normiflo®)
• Deaminative cleavage with isoamyl nitrite. Used in the manufacture of certoparin (Sandoparin®)
• Alkaline beta-eliminative cleavage of the benzyl ester of heparin. Used in the manufacture of enoxaparin (Lovenox® and Clexane®)
• Oxidative depolymerisation with Cu²⁺ and hydrogen peroxide. Used in the manufacture of parnaparin (Fluxum®)
• Beta-eliminative cleavage by the heparinase enzyme. Used in the manufacture of tinzaparin (Innohep® and Logiparin®)
• Deaminative cleavage with nitrous acid. Used in the manufacture of dalteparin (Fragmin®), reviparin (Clivarin®) and nadroparin (Fraxiparin®)

Deaminative cleavage with nitrous acid results in the formation of an unnatural anhydromannose residue at the reducing terminal of the oligosaccharides produced. This can subsequently be converted to anhydromannitol using a suitable reducing agent as shown to the left.

UA(2S)-GlcNS(6S)

Likewise both chemical and enzymatic beta-elimination result in the formation of an unnatural unsaturated uronate residue(UA) at the non-reducing terminal, as shown to the left.

Differences between low molecular weight heparin products

Comparisons between LMWHs prepared by similar processes vary. For example, a comparison of Dalteparin and Nadroparin suggests they are more similar than products produced by different processes. However comparison of enoxaparin and tinzaparin shows they are very different from each other with respect to chemical, physical, and biological properties.

As might be expected, products prepared by distinctly-different processes are dissimilar in physical, chemical, and biological properties.

see references.^{[5][6][7][8][9][10]}.

Differences from unfractionated heparin

Its differences with unfractioned heparin include:

• Average molecular weight: heparin is about 20000 Da and LMWH is about 3000 Da
• Once-daily dosing, rather than a continuous infusion of unfractionated heparin
• No need for monitoring of the APTT coagulation parameter
• Possibly a smaller risk of bleeding
• Smaller risk of osteoporosis in long-term use
• Smaller risk of heparin-induced thrombocytopenia, a feared side-effect of heparin.
• The anticoagulant effects of heparin are typically reversible with protamine sulfate, while the effect on LMWH is limited
• Has less of an effect on thrombin compared to heparin, but maintains the same effect on Factor Xa.

Clinical uses

Because it can be given subcutaneously and does not require APTT monitoring, LMWH permits outpatient treatment of conditions such as deep vein thrombosis or pulmonary embolism that previously mandated inpatient hospitalization for unfractionated heparin administration

The use of LMWH needs to be monitored closely in patients at extremes of weight or in-patients with renal dysfunction. An anti-factor Xa activity may be useful for monitoring anticoagulation. Given its renal clearance, LMWH may not be feasible in patients that have end-stage renal disease.

Use in venothromboembolic disease associated with cancer

The CLOT study, published in 2003, showed that, in patients with malignancy and acute venous thromboembolism, dalteparin was more effective than coumarin in reducing the risk of recurrent embolic events.^[11]

References

1. ^ Weitz JI (1997). "Low-molecular-weight heparins". N Engl J Med 337 (10): 688-98. PMID 9278467.
2. ^ Linhardt, R.J. Gunay, N. S. (1999). "Production and chemical processing of low molecular weight heparins". Sem. Thromb. Hem. 25 (3): 5-16.
3. ^ European Pharmacopedia Commission (1991). "{{{title}}}". Pharmeuropa 3: 161-165.
4. ^ Linhardt, R.J. Gunay, N. S. (1999). "Production and chemical processing of low molecular weight heparins". Sem. Thromb. Hem. 25 (3): 5-16.
5. ^ Green, D. Hirsh, J. Heit, J. et al (1991). "Low molecular weight heparin: A critical analysis of clinical trials". Pharmacol. Rev. 2: 45-50.
6. ^ Barrowcliffe, T. W. (1995). "Low molecular weight heparin(s)". Br. J. Haematol. 90: 1-7.
7. ^ Donayre C. E. (1996). "Current use of low molecular weight heparins". Semin. Vascul. Surg. 9: 362-371.
8. ^ Hunt, D. (1998). "Low molecular weight heparins in clinical practice". Southern Medical J. 91: 2-10.
9. ^ Fareed, J. Jeske, W. Hoppensteadt, D. Clarizio, R. Walenga, J. M. (1998). "Low molecular weight heparins: Pharmacologic profile and product differentiation". Am. J. Cardiol. 82: 3L-10L.
10. ^ Ramos-Sánchez MC, Barrio-Arredondo MT, De Andrés Santos AI, Martín-Gil J, Martín-Gil F.J. (1995). "Thermal analysis of aqueous solutions of heparins". Thermochim Acta 262: 109-115.
11. ^ Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M (2003). "Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer". N Engl J Med 349 (2): 146-53. PMID 12853587.