Presentation on theme: "Cyclosporine KSU, Collage of Medicine, Department of pharmacology ."— Presentation transcript:
1Cyclosporine KSU, Collage of Medicine, Department of pharmacology . Prepared by : Narmeen Al-Bashrawi.Supervised by : Dr Hanan Hajar.
2Objective: Introduction to cyclosporine. Chemical structure. Physical properties.Formulation.Pharmacodynamic of cyclosporine.Pharmacokinetic of cyclosporine.Indication.Contraindicating.Adverse effects.Drug food interacting.Drug – drug interaction.
3Introduction:Cyclosporine was first isolated from the fungus Tolypocladium inflatum and originally thought to be an antifungal antibiotic with minimal clinical value.
8Physical properties:Cyclosporine have a molecular weight of 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.
13Mechanism of actionCyclosporine 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 .
14Mechanism 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 .
172-Pharmalogical effects: kidney:In the kidney, cyclosporine produced structural and functional changes predominantly affecting the:proximal tubuleThe 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
18Pharmalogical 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.
19Pharmalogical effects cont 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 .
20Pharmalogical effects cont 3-Others:Dose-dependent elevation of liver function test without histological abnormality.Activation of sympathetic system.does not cause bone marrow suppression .
22Pharmacokintic 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.
23Pharmacokintic 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).
25Different between sandimmune and Neoral FORMULAOil-based formulamicroemulsionABSORPTIONNeed more bileLess bile requireFOODIncrease absorptionLess affectedBIOAVALIBILITY30% (5-70)BetterPEAK3.5 h1.2-2hVARABILITYMoreLessOUT COMEImprove outcome(less acute rejection)
26Pharmacokintic properties cont C2 monitoring allow a more accurate and reliable evaluation of cyclosporine exposureMaintaining organ transplant patients.Identify a significant percentage of overexposed subject.Possibly limiting the rate of progression of chronic graft dysfunction .
28Pharmacokintic properties cont 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 substrates, including cyclosporine, back into the intestinal lumen against an absorption gradient.
29Pharmacokinetic properties cont Variation in liver CYP3A4 is the major contributor 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.
30Pharmacokintic properties cont Half life:Children—Approximately 7 hours (range, 7 to 19 hours).Adults—Approximately 19 hours (range, 10 to 27 hours).
31Pharmacokintic properties cont 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
33Uses of Cyclosporine cont 1- Systemic indication
34Uses of Cyclosporine cont 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.
35Uses of Cyclosporine cont 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 ) .
36Uses of Cyclosporine cont Cyclosporine remains as the mainstay of anti rejection treatments in patients especially undergoing solid organ transplants .
37Uses of Cyclosporine cont 2- Opthalmic indication
38Uses of Cyclosporine cont 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.
40Contraindication of Cyclosporine Sensitivity to cyclosporineMalignancy, current or Premalignant skin lesions.Chickenpox, existing or recent, or Herpes zoster (risk of severe generalized disease).Hepatic function impairmentHyperkalemia hypertensionInfection MalabsorptionRenal function impairment (dose reduction).
42Cyclosporine 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), andA chronic, dose- independent form with structural changes leading to a progressive and persistent decrease in GFR .
43Cyclosporine 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.
44Cyclosporine adverse effect cont 2-Cardiovascular toxicityCardiovascular 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.
45Cyclosporine adverse effect cont 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 .
46Cyclosporine adverse effect cont 6-Gingival hypertrophy :Gingival hyperplasia is usually reversible within 6 months after withdrawal of cyclosporine.
49Cyclosporine adverse effect cont Central Nervous System: convulsions, headacheAutonomic Nervous System: ParesthesiaSKIN: Hirsutism , Acne.vulnerability to opportunistic fungal and viral infections.
50Cyclosporine adverse effect cont 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.
53Cyclosporine 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 cyclosporineblood ).
54Cyclosporine Interactions 2-Drug – drug interactin
55Cyclosporine Interactions cont Cyclosporine is extensively metabolized by cytochrome P-450 3A. Substances that inhibit this enzyme could decrease metabolism and increase cyclosporine concentrations .
56Cyclosporine Interactions cont Drugs That May Potentiate Renal DysfunctionAntibioticsAntineoplasticAnti-Inflammatory DrugsGastrointestinal AgentsGentamicinMelphalanAzapropazonCimetidineTobramycinDiclofenacRanitidineVancomyci-nAntifungalsNaproxenTrimethopri-mAmphotericin B.SulindacImmunosuppressivesSulfametho-xazoleketoconazoleColchicineTacrolimus
59Cyclosporine Interactions cont Note 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 .