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

2. 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.

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

4. introduction cont

5. 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

6. Chemical structure:
Cyclosporine is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acid.

7. chemical structure cont

8. Physical 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.

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

10. Pharmacodynamic Properties

11. Pharmacodynamic Properties:
1-Mechanism of action

12. Mechanism of action

13. 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 .

14. 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 .

15. Mechanism of action

16. Pharmacodynamic Properties cont:
2-Pharmalogical Effects

17. 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

18. 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.

19. Pharmalogical 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 .

20. Pharmalogical effects cont
3-Others:
Dose-dependent elevation of liver function test without histological abnormality.
Activation of sympathetic system.
does not cause bone marrow suppression .

21. Pharmacokintic Properties

22. 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.

23. 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).

24. Pharmacokintic Properties cont

25. Different between sandimmune and 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)

26. 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 .

27. Pharmacokintic properties cont
2-Distribution:

28. Pharmacokintic 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.

29. Pharmacokinetic 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.

30. Pharmacokintic properties cont
Half life:
Children—Approximately 7 hours (range, 7 to 19 hours).
Adults—Approximately 19 hours (range, 10 to 27 hours).

31. Pharmacokintic 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

32. Uses of Cyclosporine

33. Uses of Cyclosporine cont
1- Systemic indication

34. Uses 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.

35. Uses 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 ) .

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

37. Uses of Cyclosporine cont
2- Opthalmic indication

38. Uses 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.

39. Contraindication of Cyclosporine

40. 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).

41. Cyclosporine adverse effect

42. 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 .

43. 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.

44. Cyclosporine adverse effect cont
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.

45. Cyclosporine 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 .

46. Cyclosporine adverse effect cont
6-Gingival hypertrophy :
Gingival hyperplasia is usually reversible within 6 months after withdrawal of cyclosporine.

47. Cyclosporine adverse effect cont
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.

48. Cyclosporine adverse effect cont
Respiratory: breathing difficulties .
Hematopoietic:Leukopenia .
hyperuricemia and gout.
hypomagnesaemia ( clearance).

49. Cyclosporine adverse effect cont
Central Nervous System: convulsions, headache
Autonomic Nervous System: Paresthesia
SKIN: Hirsutism , Acne.
vulnerability to opportunistic fungal and viral infections.

50. Cyclosporine 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.

51. Cyclosporine Interactions

52. Cyclosporine Interactions
1-with Dietary Supplements

53. Cyclosporine Interactions with Dietary Supplements
Vitamin E
Combining 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 ).

54. Cyclosporine Interactions
2-Drug – drug interactin

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

56. Cyclosporine Interactions cont
Drugs That May Potentiate Renal Dysfunction
Antibiotics
Antineoplastic
Anti-Inflammatory Drugs
Gastrointestinal Agents
Gentamicin
Melphalan
Azapropazon
Cimetidine
Tobramycin
Diclofenac
Ranitidine
Vancomyci-n
Antifungals
Naproxen
Trimethopri-m
Amphotericin B.
Sulindac
Immunosuppressives
Sulfametho-xazole
ketoconazole
Colchicine
Tacrolimus

57. Cyclosporine Interactions cot
Drugs That Increase Cyclosporine Concentrations
Calcium Channel Blockers
Antifungals
Antibiotics
Glucocorticoids
Diltiazem
Fluconazole
Clarithromycin
Methylprednisolone
Nicardipine
Itraconazole
Erythromycin
Verapamil
Ketoconazole
Quinupristin Dalfopristin

58. Cyclosporine Interactions cont
Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations
Antibiotics
Anticonvulsants
Other Drugs/Dietary Supplements
Nafcillin
Carbamazepine
Octreotide
Rifampin
Phenobarbital
Ticlopidine
Phenytoin
Orlistat

59. Cyclosporine 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 .

61. Thank you for your attention