7.1.Immuno suppressant Drugs

AZATHIOPRINE

General  Information:

Drug Code                                           Preparation                                  Strength

      292                                 Tab. Azathioprine                              50 mg

Description of the Drug

Azathioprine is an immunosuppressive agent. It is an antimetabolite which exerts its effects after conversion to 6-mercaptopurine.

Mode of Action

It interferes with nucleic acid synthesis which occurs after antigenic stimulation in activated lymphocytes. Hence it destroys sensitized lymphocytes and both humoral and cellular immunity are depressed.

Pharmacokinetics

It is well absorbed from the GIT . Maximum activity is achieved 1 hour after ingestion. It is extensively metabolized in the liver by xanthine oxidase and is excreted in the urine.

Clinical Information

Indications

·    In the prevention of transplant rejections eg. allograft.

·    Severe rheumatoid arthritis , not responding to other therapeutic agents like NSAIDS, gold steroids etc.,

·    Can also be used in auto immune hemolytic anaemia, idiopathic thromobocytopenic purpura, SLE, Crohns disease and other immune disorders.

Dosage

·    For prevention of renal transplant rejection:

Initial dose is 3 – 5 mg/ kg single dose to be started 1 –3 days before transplantation.

·    For treatment of rheumatoid arthritis :

Initial dose is 1 mg/kg/day. Gradually increased by increments of 0.5 mg/kg every 4 to 8 weeks depending on clinical response.

Dose to be individualized to every patient.

Route of Administration     Oral:

Contraindications

·    Pregnancy and lactation.

·    Hypersensitivity.

·    Rheumatoid arthritis patients already treated with alkylating agents like cyclophosphamide (due to risk of development of lymphomas).

·    Porphyria.

Precautions / Practice Points

·    Should not be used in established graft rejection.

·    Patients on allopurinol should have doses of azathioprine reduced to half or quarter the normal dosage.

·    Frequent monitoring of blood counts (weekly) and the dose to be decreased if depression of bone marrow occurs. Ask patient to report immediately if signs of bone marrow depression like sorethroat, easy bruising etc., and Stop therapy when WBC count falls below 3000 cells/3 mm.

·    Frequent monitoring of SGOT and SGPT to detect hepatotoxicity.

·    Administration Instruction:

-  Administer tablet with meals to decrease gastro intestinal side effects.

Drug Interactions

Potentially fatal:

·    With allopurinol, metabolism of azathiporine by xantine oxidase is inhibited, increasing its serum levels and toxicity. Hence, dose reduction is required.

Non – fatal:

·    Risk of leucopenia may be increased by other drugs like cotrimoxazole, ACE inhibitors.

Adverse Effects

       Are dependent on dose and duration of therapy.

Common effects:

·    Bone marrow depression – agranulocytosis, anemia, thrombocytopenia.

·    GI toxicity – nausea, vomiting, diarrhoea.

·    Severe infections due to immunosuppression – systemic fungal, viral, bacterial or protozoal infections should be looked for and treated vigorously.

Rare effects:

·    Hepatotoxicity – elevation of liver enzymes, hepatitis, especially with doses more than 25 mg/kg/day.

·    Hypersensitivity  - rashes, drug fever, malaise, arthralgia, chloestatic jaundice, arrhythmias etc., may occur.

·    Carcinogenic – increased risk of  Lymphomas and skin cancers.

·    Infertility, alopecia, pancreatitis and pneumonitis may occur.

Drug Toxicity

·    Initially nausea, vomiting and diarrhoea may occur. Abnormalities in liver function (increase in SGOT and SGPT levels).

·    Later marrow hypoplasia, bleeding, overwhelming infections and death may occur.

Treatment of Toxicity

·    Gastric lavage if the drug has been recently ingested.

·    Haemodialysis.

·    Platelet or blood transfusion to combat bleeding.

·    Symptomatic treatment.

Storage

      Protect from light.

Shelf Life                    2 years.

7. 2.      Cytotoxic Drugs

DOXORUBICIN

General  Information

Drug Code                                   Preparation                                       Strength

        293                                      Inj. Doxorubicin                                  10 mg/vial

Description of the Drug

Doxorubicin (adriamycin) is an anthracycline antibiotic isolated from streptomyces peucetius.

Mode of Action

It acts by the following mechanisms.

·    Binds to and breaks DNA strands.

·    Binding to cell membranes and altering ion transport.

·    Generation of oxygen radicals.

·    Its effects are mainly seen in the cells and in the G2 phase.

Pharmacokinetics

Following I.V. injection, the drug is rapidly distributed to tissues and cleared from the plasma in 5 minutes. It is eliminated slowly from tissues by undergoing metabolism in the liver and excretion mainly in the bile and some amounts in the urine.

Clinical information

Indications

·    Acute lymphatic leukemia.

·    Acute myeloid leukemia.

·    Hodgkins lymphoma and non Hodgkins lymphoma.

·    Neuroblasmtoma.

·    Wilm’s tumour.

·    Soft tissue tumours.

·    Osteosarcomas and other bone tumours.

·    Transitional cell bladder cancers.

·    Ovarian carcinoma.

·    Breast carcinoma.

·    Thyroid  carcinoma.

·    Gastric carcinoma.

·    Small cell type of lung cancer.

·    Carcinoma of the endometrium.

Dosage

            Usual dose (dosages may differ in individual protocols):

·    Given as a single agent in doses of 60 – 75 mg m2 for every 21 days.

·    In combination therapy 40 – 60 mg/m2 per every 3 or 4 weeks.

Routes of Administration

            I.V.bolus, continuous IV infusion.

Contraindication

·    Preexisting heart disease.

·    Severe bone marrow depression.

·    Hypersensitivity.

Precautions / Practice Points:

·    Dose should be reduced to 75 % if serum bilirubin is more than 3 mg/dl. And 50 % if serum bilirubin is 1.2 to 3 mg/.dl.

·    Cardiac function tests (ECG, LVEF, Echo) should be done prior or therapy in patients at risk for cardiac toxicity (elderly age and mediastinal radiation) at frequent intervals.

·    Periodic blood count monitoring and liver function tests to check for bone marrow depression and hepatotoxicity.

·    Administration Instructions;

-  Should not be given intramuscularly or subcutaneously, as severe tissue necrosis will occur.

-  Reconstitute in N.S. or sterile water to a concentration of 2 mg/ml (5 ml for a 10 mg vial) can be given as a bolus dose to further diluted in N.S. or 5 % dextrose and administered as an IV infusion.

-  Do not mix with steroids, sodium bicarbonate, aminopuylline, heparin, 5 – flurouracil, antibiotics, diazepam or frusemide in the same syringe or IV  set.

     -  Do not use materials made of aluminium.

  -  Take care not be make contact with bare skin as doxorubicin  has a severe

  vesicant action.

     -  Flush IV cannula with N.S before and after drug administration.

Drug Interaction

Potentially fatal:

·    When doxorubicin is combined with cyclophosphamide or calcium channel blockers like verapamil, increased risk of myocardial toxicity occurs.

·    Doxorubicin enhances the nephrotoxicity of cyclosporin.

Non fatal:

·    Phenytoin levels are decreased by doxorubicin; phenobarbitone increases the excretion of
doxorubicin.

Adverse Effects

Common effects:

·    Reddish discoloration of urine 1 –2 days after administration.

·    Local – severe cellulits, vesication and necrosis if extravasation occurs.

·    Other effects common to anti cancer agents like hyperuricemia, alopecia, bone marrow
depression and its consequences, infertility and teratogencity, GI toxicity like nausea,
vomiting, stomatitis, mucositis with ulceration can occur.

Rare effects:

·    Myocardial toxicity is dose dependent and is more common with higher doses of drug.
Manifested as congestive heart failure and can occur even months to years after stopping therapy due to cumulative toxicity in cardiac tissue. Children treated with doxorubicin
develop cardiomyopathy at a later stage. Supra ventricular taehycardia may occur during
administration of the drug.

·    Hypersensitivity reactions – fever, chills, urticaria have occurred.

Drug Toxicity

Severe nausea and vomiting, arrhythmias and other manifestations of myocardial toxicity and myelosuppression can occur.

Treatment of Toxicity

·    Antimicrobials, platelet transfusion for bone marrowdepression, supportive and symptomatic treatment.

·    Treament of extravasation of the drug – ice packs, every 15 minutes, for one day; elevation and rest of the limb.  If severe, skin grafts after wide local excision.

Adverse effects :

Common effects :

GI – abdominal pain, anorexia, stomatitis, vomiting, nausea.

·    CNS – headache, neuritis, convulsions, ataxia etc.

Rare effects:

·    In individuals allergic to sulpha drugs, potentially serious adverse effects can occur :

·    Steven Johnson’s syndrome, toxic epidermal necrolysis, erythema multiform, urticaria, serum
sickness, exfoliative dermatitis and photosensitization.  If any indication of skin rash appears , discontinue drug immediately.

·    Blood – agranulocytosis, haemolytic anemia, methemoglobinemia, thromobocytopenia, a plastic anemia etc.

·    Pulmonary infiltrates can occur on long-term therapy.

Drug Toxicity

Symptoms are abdominal pain, vomiting, anorexia, crystalluria, convulsions, thrombocytopenia and leucopenia.

Treatment of Toxicity:

Emesis and gastric lavage. Adequate hydration to ensure diuresis. Administer diazepam if convulsions occur and folinic acid if thrombocytopenia or leucopenia occurs, Monitor Kidney and haematopoietic functions.

Storage

            Protect from light.

Shelf Life                     2 years

6.5.    Anti virals

ACYCLOVIR

General  Information

Drug Code                                   Preparation                                    Strength

      359                                        Tab. Acyclovir                                   200 mg

      404                                        Inj.   Acyclovir                                   250 mg/vial

      360                                       Ointment Acyclovir                          5 % w/w

Description of the Drug

Acyclovir is synthetic analogue of guanine used in the treatment and prophylaxis of viral infection.

Mode of Action

It inhibits the viral DNA synthesis and replication by inhibiting the Herpesvirus DNA polymerase enzyme. It hase non-activity against latent viruses.

Pharmacokinetics

15 – 30 5% is absorbed from GIT, Following I.V. injection plasma acyclovir is eliminated in a biphasic pattern. Following topical application only small amount get absorbed through intact skin. It iswidely distributed . Excreted through the kidneys . It crosses the placental barrier and small amount is secreted in the milk. Plasma half-life is 2.5 – 3 hours.

Clinical Information

Indications

Tablet acyclovir :

·    Systemic treatment of herpes simples infection of skin and mucous membranes (genital herpes) both initial attacks and for suppression of recurrent disease.

·    Herpes zoster infections – acute treatment of H.zoster.

·    Chickenpox – Varicella zoster infections.

·    Prophylaxis and prevention of recurrence of Herpes infections in the immunocompromised.

Ointment acyclovir :

·    Topical application in genital herpes simplex, both initial and recurrent epidsodes.

·    Muck cutaneous herpes lesions like herpes labialis.

IV Infusions:

·    Disseminated herpes infection in immunocopromised, AIDS patients.

·    Herpes encephalitis and in initial treatment of severe genital herpes.

·    Varicella zoster in immunocopromised or AIDS patients.

·    Prophylaxis of CMV, herpes infection in post transplant immunosuupression.

Dosage

Ointment – 5 %

            Apply every 4 hours or 5 times daily for 5 – 10 days.

Tablets:

·    Genital herpes simplex – for adults and children over 2 years – 200 mg, 5 times daily for 5 days.

-  For child less than 2 years – half the adult dose.

   -  In immunocopromised – double the dose.

            -  For prevention of recurrence – 200 mg quid or 400 mg bed reduced

               gradually, for upto 6 months.

·    Varicella and Herpes zoster – adult – 800 mg 5 times daily for 1 week.

    Child : 20 mg/kg (maximum 800 mg) quid for 5 days.

I.V.Preparation :

·    For disseminated herpes simplex infection = 5 mg/kg every 8 hours for 5 days.

·    For encephalitis and Varicella zoster in immunocompromised patient – double the dose to 10 mg/kg.

Routes of Administration    Oral, I.V. infusion, Topical

Contraindications

·    Children below 6 months.

·    Renal failure

Precautions / Practice Points

·    Administer acyclovir as early as possible. Best results are obtained if given at onset of infection (within 48 hours).

·    Use with caution in patients with renal impairment and doses should be adjusted according to creatinine clearance.

·    Avoid combining with other nephrotoxic drugs.

·    Use with caution during pregnancy and in lactating mothers.

·    In dehydrated patients, rehydrate before administration of acyclovir or crystals may precipitate in renal tubules causing acute renal  failure.

·    Monitor renal parameters (blood, urea, nitrogen, serum creatinine and urine analysis) and liver parameters while on therapy.

·    Administration Instruction:

- Rapid or bolus injection should be avoided. Injection should be made-up in distilled water and then infused in normal saline or glucose solution over an hour.

- 5 % ointment should not be applied in the eye (only 3 % ointment to be applied in keratitis).

Drug Interactions

Non fatal :

Probebecid increases the plasma concentration of acyclovir by decreasing excretion.

Adverse Effects

Common effects:

·    General – fever , headache, malaise and fatigue.

·    Local – thromobophlebitis on IV administration, hypotension may occur rarely.

Rare effects:

·    Confusion , dizziness, hallucinations, paraesthesias, tremors.

·    Rashes.

·    Rise in bilirubin and liver enzymes.

·    Renal impairment – rise in blood urea nitrogen and creatinine.

Drug Toxicity

Drug toxicity can occur when rapid and massive infusions are given. Anuria and renal failure may occur.

Treatment of Toxicity

·    Maintain adequate hydration and urine ourpur.

·    Hemodialysis is highly effective.

·    Supportive and symptomatic treatments.

Storage

            Store in airtight chambers.

Shelf Life                   

            Acyclovir oint.  -           2 years.

            Acyclovir tab.               -           3 years.

            Acyclovir inj.                -           3 years.