1 KSU, Collage of Medicine, Department of pharmacology. Prepared by : Narmeen Al-Bashrawi. Supervised by : Dr Hanan Hajar

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KSU, Collage of Medicine, Department of pharmacology .KSU, Collage of Medicine, Department of pharmacology .Prepared by : Narmeen Al-Bashrawi.Prepared by : Narmeen Al-Bashrawi.Supervised by : Dr Hanan Hajar.Supervised by : Dr Hanan Hajar.

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Objective: Introduction to cyclosporine. Chemical structure. Physical properties. Formulation. Pharmacodynamic of cyclosporine. Pharmacokinetic of cyclosporine. Indication. Contraindicating. Adverse effects. Drug food interacting. Drug – drug interaction.

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Introduction:

Cyclosporine was first isolated from the fungus Tolypocladium inflatum and originally thought to be an antifungal antibiotic with minimal clinical value.

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introduction cont

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Introduction cont

Its immunosuppressive activity was first detected by Borel in 1976 who discovered that cyclosporine was relatively nontoxic to bone marrow and remarkably immunosuppressive

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Chemical structure:

Cyclosporine is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acid.

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chemical structure cont

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Physical properties:

Cyclosporine have a molecular weight of 1202.6 and occurs as a white solid with a melting point of 148°C to 151°C (natural) and 149°C to 150°C (synthetic).

slightly soluble in water and soluble in organic solvents.

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Cyclosporine formulation: 1-Sandimmune (Cyclosporine) Soft Gelatin . 2-Sandimmune Oral Solution . 3-Sandimmune Injection .

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Pharmacodynamic Properties

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Pharmacodynamic Properties:

1-Mechanism of action

12Mechanism of Mechanism of actionaction

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Mechanism of action

Cyclosporine is lipophilic peptide that easily crosses the membranes cells, such as T lymphocytes.

Its effects depending on binding to cytosol proteins (cyclophilin). The drug-immunophilin complex in turn bind to calcineurine .

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Mechanism of action cont

As a result, the transcription factor is enabled to enter the nucleus, which is the essential step for the activation and transcription of certain genes interleukin-2 by T lymphocyte.

leading to Reduce the migration of monocytes to the targt and helping to protect the transplanted organ from normally aggressive host defense mechanisms .

15Mechanism of Mechanism of actionaction

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Pharmacodynamic Properties cont:

2-Pharmalogical Effects

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2-Pharmalogical effects:

kidney: In the kidney, cyclosporine produced structural and

functional changes predominantly affecting the: proximal tubule The afferent arteriole. Increased thronboxane A2 levels cause renal

vasoconstriction and proliferation of vascular smooth muscle cells into the intimae.

Reduced the release of vasodilatory kinins. So , Cyclosporine has an indirect vasoconstrictor effect,

which has been associated with hypertension and renal dysfunction

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Pharmalogical effects cont

cardiovascular system : Blood pressure and cardiac hypertrophy: The principle cause of hypertension after

organ transplantation is the treatment with a cyclosporine which is (CIN).

The price mechanism(s) are not known.

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Lipid metabolisms and athergenic profile:The pathogenesis of impaired lipid metabolism

with cyclosporine has not fully elucidated . Glucose metabolism:Cyclosporine maintain insulin resistance but

decrease insulin secretion (may predispose to post tranplantation diabetes mellitus PTDM) dose-depended and reversible .

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3-Others: Dose-dependent elevation of liver

function test without histological abnormality.

Activation of sympathetic system. does not cause bone marrow suppression

.

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Pharmacokintic Properties

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Pharmacokintic Properties

Absorption: Absorption is dependent on the presence of bile and

there for prone to variability.

the drug is poorly absorbed, Variable and incomplete from gastrointestinal tract after oral administration with a bioavailability of about 30% (range 5% to 70%).

The original cyclosporine formula showed high intra- and inter-patient variability and low bioavailability.

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Pharmacokintic Properties cont

A microemulsion Neural was introduced To address the wide intra and interindividual differences in absorption, distribution, metabolism, and elimination of the oil-based formulation of cyclosporine (Sandimmune).

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Pharmacokintic Properties cont

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Different between sandimmune and Neoral

Sandimmune Neoral

FORMULA Oil-based formula microemulsion

ABSORPTION Need more bile Less bile require

FOOD Increase absorption Less affected

BIOAVALIBILITY 30% (5-70) Better

PEAK 3.5 h 1.2-2h

VARABILITY More Less

OUT COME Improve outcome(less acute rejection)

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Pharmacokintic properties cont

C2 monitoring allow a more accurate and reliable evaluation of cyclosporine exposure

Maintaining organ transplant patients. Identify a significant percentage of

overexposed subject. Possibly limiting the rate of progression of

chronic graft dysfunction .

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2-Distribution:

plasma, 33%-47%

erythrocyte, 41%-58%

lymphocytes, 4%-9%

granulocytes, 5%-12%

plasma

erythrocyte

granulocytes

lymphocytes

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3-Metabolism: cytochrome P450 enzyme (CYP3A4) in the liver

(mainly), and for leaser extent in small intestine. Glycoprotein P is a transport protein present in the

brush border of the human small intestine that functions to pump sub strates, including cyclosporine, back into the intestinal lumen against an absorption gradient.

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Pharmacokinetic properties cont

Variation in liver CYP3A4 is the major con tributor to overall variability in oral Cyclosporine metabolism. Changes in Cyclosporine formulations may reduce but will not entirely eliminate significant intra- and interaction differences in cyclosporine metabolism.

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Half life:

Children—Approximately 7 hours (range, 7 to 19 hours).

Adults—Approximately 19 hours (range, 10 to 27 hours).

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Excretion: Elimination is primarily biliary. only 6% of the dose (parent drug and

metabolites) excreted in the urine. 0.1% of a cyclosporine dose is excreted

unchanged in the urine

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Uses of Cyclosporine

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Uses of Cyclosporine cont

1- Systemic indication

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Organ transplantation to prevent graft rejection in kidney, liver, heart, lung, and combined heart-lung transplants.

It is used to prevent rejection following bone marrow transplantation and Prophylaxis of graft-versus-host disease.

Treatment of chronic rejection in patients previously treated with other immunosuppressant.

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A treatment of autoimmune diseases. Cyclosporine therapy in severe ulcerative colitis,

refractory to steroids . Tacrolimus – related adverse effects . Psoriasis. Atopic dermatitis. Rheumatoid arthritis. Nephrotic syndrome(steroid-dependent and

steroid-resistant nephrotic syndrome ) .

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Cyclosporine remains as the mainstay of anti rejection treatments in patients especially undergoing solid organ transplants .

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2- Opthalmic indication

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Cyclosporine is useful for patients with various inflammatory ocular surface disorders.

reversing inflammation of the ocular surface and lacrimal glands .

improving the signs and symptoms of dry eye syndrome.

Keratoconjunctivitis sicca (treatment) . Neurotrophic keratopathy . Atopic keratoconjunctivitis.

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Contraindication of Cyclosporine

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Contraindication of Cyclosporine

Sensitivity to cyclosporine Malignancy, current or Premalignant skin lesions. Chickenpox, existing or recent, or Herpes zoster

(risk of severe generalized disease). Hepatic function impairment Hyperkalemia hypertension Infection Malabsorption Renal function impairment (dose reduction).

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Cyclosporine adverse effect

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Cyclosporine adverse effect

1-Cyclosporine Nephrotoxicity:

Cyclosporine toxicity is classified in two phases: An acute, functional, dose-dependent decrease in

renal blood flow and glomerular filtration rate (GFR), and

A chronic, dose- independent form with structural changes leading to a progressive and persistent decrease in GFR .

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Cyclosporine adverse effect cont

Nephrotoxicity correlates with drug exposure, C2 measurements of blood concentrations early after transplantation (unlike trough levels C0) are likely to serve as an accurate tool for the avoidance of both under immunosuppression and toxicity.

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2-Cardiovascular toxicity

Cardiovascular disease is one of the major causes of mortality and morbidity.

arterial hypertension in 50% to 80%. high total cholesterol level. high low density lipoprotein(LDL) . de novo post trasplant diabetes mellitus.

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3-hypertention: Chronic arterial hypertension, increasing with

time after transplantation, is associated with decrease allograft survival.

4-hyperlipidaemia.5- De novo post transplant diabetes mellitus

(PTDM): Diabetes mellitus has become one of the most

common causes of renal failure .

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6-Gingival hypertrophy :

Gingival hyperplasia is usually reversible within 6 months after withdrawal of cyclosporine.

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7-Other adverse effects: human carcinogen (mainly lymphoma or

skin cancer ). facial dimorphism . Dose dependent hyperkalemia( tubular

aldosteroine insensitivity ). Post-transplant lymphoproliferative

disorders. Gastrointestinal disturbances.

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Respiratory: breathing difficulties .

Hematopoietic:Leukopenia .

hyperuricemia and gout.

hypomagnesaemia ( clearance).

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Central Nervous System: convulsions, headache

Autonomic Nervous System: Paresthesia

SKIN: Hirsutism , Acne.

vulnerability to opportunistic fungal and viral infections.

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In general about adverse effect: Cyclosporine had a narrow therapeutic range (fine line

between adequate immunosuppressant and the risk of drug-induced side effect) .

Variable Cyclosporine exposure is now believed to be a key determinant of acute rejection, chronic rejection,which is the principle cause of late graft loss.

Thus optimal therapy with cyclosporine requires predictor of drug exposure and a clear rang of therapeutic level.

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Cyclosporine Interactions

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1-with Dietary Supplements

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Cyclosporine Interactions with Dietary Supplements

Vitamin ECombining vitamin E and cyclosporine requires medical

supervision to avoid cyclosporine toxicity.

Omega 3 fatty acid.(reduce high blood pressure).

Food (increases the absorption of cyclosporine ) Grape fruit juice (increase in cyclosporine

blood ).

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2-Drug – drug interactin

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Cyclosporine Interactions cont

Cyclosporine is extensively metabolized by cytochrome P-450 3A. Substances that inhibit this enzyme could decrease metabolism and increase cyclosporine concentrations .

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Drugs That May Potentiate Renal Dysfunction

AntibioticsAntibiotics AntineoplasticAntineoplastic Anti-Anti-Inflammatory Inflammatory DrugsDrugs

GastrointestiGastrointestinal Agentsnal Agents

Gentamicin Gentamicin Melphalan Melphalan AzapropazonAzapropazon Cimetidine Cimetidine

Tobramycin Tobramycin Diclofenac Diclofenac Ranitidine Ranitidine

Vancomyci-Vancomyci-n n

Antifungals Antifungals Naproxen Naproxen

TrimethopriTrimethopri-m -m

Amphotericin B.Amphotericin B. SulindacSulindac ImmunosuppresImmunosuppressives sives

Sulfametho-Sulfametho-xazole xazole

ketoconazole ketoconazole Colchicine Colchicine Tacrolimus Tacrolimus

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Cyclosporine Interactions cot

Calcium Calcium Channel Channel BlockersBlockers

AntifungalsAntifungals AntibioticsAntibiotics GlucocortiGlucocorticoidscoids

Diltiazem Diltiazem Fluconazole Fluconazole Clarithromycin Clarithromycin MethylpredMethylprednisolone nisolone

NicardipinNicardipine e

ItraconazoleItraconazole ErythromycinErythromycin

VerapamilVerapamil KetoconazoleKetoconazole QuinupristinQuinupristinDalfopristin Dalfopristin

Drugs That Increase Cyclosporine Concentrations

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AntibioticsAntibiotics AnticonvulsantAnticonvulsantss

Other Other Drugs/Dietary Drugs/Dietary SupplementsSupplements

Nafcillin Nafcillin CarbamazepinCarbamazepine e

Octreotide Octreotide

Rifampin Rifampin Phenobarbital Phenobarbital Ticlopidine Ticlopidine

Phenytoin Phenytoin Orlistat Orlistat

Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations

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Note thatNote that:: Reduction in the blood concentrations of

cyclosporine, resulting in subtherapeutic levels, rejection of transplanted organs, and graft loss.

Cyclosporine may reduce the clearance of digoxin.

Severe digitalis toxicity has been seen within days of starting cyclosporine in several patients taking digoxin .

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Thank you for your Thank you for your attentionattention

Documents

1 KSU, Collage of Medicine, Department of pharmacology. Prepared by : Narmeen Al-Bashrawi. Supervised by : Dr Hanan Hajar