Drug Interactions of antidiabetics (Part 2):

Drug Interactions of Exenatide and Pramlintide:

¢ More frequent monitoring of INR is recommended when initiating or changing the dose of exenatide during Warfarin therapy due to increased risk of bleeding.

¢ To avoid Digoxin toxicity, the plasma levels and clinical efficacy of digoxin should be monitored when Exenatide is used concurrently.

¢ Antibacterials should be taken at least one hour before Exenatide, to prevent delayed absorption and reduced efficacy of antibacterials.

¢ Increased dose of Exenatide or Pramlintide may be required due to its interaction with Thyroid hormones which decrease its effectiveness.

¢  Danazol is associated with insulin resistance and it interacts with Exenatide or Pramlintide to increase blood sugar level.

¢ The risk of hypoglycemia is increased by the concomitant use of Exenatide or Pramlintide and Trandolapril.

¢ The diabetics should bring a list of all of the drugs they are taking, including prescription drugs, over-the-counter drugs, and any supplements, herbal products, etc. during their visit to the doctor or pharmacist, to minimize the possibility of potentially dangerous combinations.

Drug Interactions of Antidiabetics (Part 1):

Interactions of Insulin:

¢ The therapeutic efficacy of Insulin either increased or decreased by interacting with other drugs.

¢ Further reductions of blood glucose or exacerbation of hypoglycemia may be resulted due to the concomitant use of Insulin and drugs such as Fluoroquinolones, Anabolic steroids (nandrolone, methandienone, testosterone propionate or stanozolol), Antimalarials (Hydroxychloroquine, chloroquine), Orlistat, Bitter melon, Ginkgo, Ginseng, Gymnema extracts, Fenugreek and Alcohol.

¢ The blood sugar level may be elevated by the coadministration of Insulin and Antipsychotics.

¢ The therapeutic efficacy of Insulin is reduced in smokers due to decreased absorption.

¢ Betablockers may delay the recovery from hypoglycemia induced by Insulin.

¢ Thiazolidinediones (Pioglitazone or rosiglitazone) may potentiate the renal effects of insulin on sodium and water retention which may increase the incidence of heart failure.

¢ The diabetics are encouraged to ask their doctor or pharmacist to look over their medication list for any potentially dangerous combinations.

Drug Interactions between Antidiabetics, Antihypertensives and Lipid regulating drugs:

More presentations from Naina Mohamed Pakkir Maideen

Ø Diabetes patients may need other drugs to control the coexisting problems-

·       ACEIs or ARBs for high blood pressure, heart, or kidney failure

·       Diuretics, CCBs or beta-blockers for high blood pressure

·       Statins for high cholesterol

·       Fibrates for high triglycerides

·       Aspirin or Clopidogrel to prevent a heart attack

Ø Combined use of Antidiabetics, Antihypertensives and Lipid regulating drugs may result into either decreased effectiveness or increased adverse effects of drugs.

Ø Thiazide diuretics tend to have diabetogenic effect and hence they reduce the effectiveness of Antidiabetics such as Sulfonylureas, Meglitinides, Thiazolidinediones and DPP4 inhibitors.

Ø The risk of hypoglycemia is increased by the concomitant use of Antidiabetics (sulfonylureas, meglitinides and Metformin) and ACE Inhbitors.

Ø Concurrent therapy with a Beta blocker and an antidiabetic may increase the risk of hypoglycemia or hyperglycemia due to altered glucose metabolism.

Ø Thiazide diuretics, Potassium sparing diuretics (Amiloride or Triamterene) or Nifedipine may increase the risk of lactic acidosis when they are coadministered with Metformin.

Ø The antihypertensive efficacy of Nifedipine and Nimodipine may be decreased by the addition of Pioglitazone.

Ø Concomitant use of repaglinide and gemfibrozil is Contraindicated due to the inhibition of CYP2C8 enzyme mediated metabolism of repaglinide by Gemfibrozil which leads to hypoglycemic risk.

Ø The risk of hypoglycemia is elevated by the coadministration of Antidiabetics (Pioglitazone, Rosiglitazone and Sulfonylureas) and Gemfibrozil.

Ø Calcium channel blockers (Verapamil or Nifedipine) inhibit CYP3A4 mediated metabolism of Statins and increase risk of musculoskeletal toxicity (Myopathy, Rhabdomyolysis).

Ø To avoid serious drug interactions, the diabetics should consult their physician or pharmacist particularly when they begin to take a new medicine.

Drug Interactions of Antidiabetics

More presentations from Naina Mohamed Pakkir Maideen

Ø Diabetes patients may take a large number of medications to treat various problems along with antidiabetics.

Ø With this amount of medicine use, the probability of drug interaction is very high.

Ø  The antidiabetic drugs are classified as…

·       Injectable Antidiabetics

o  Insulins

o  Incretin Mimetics (Exenatide, Liraglutide)

o  Amylin Analogues (Pramlintide)

·       Oral Antidiabetics

o  Sulfonylureas (Glibenclamide, Gliclazide)

o  Meglitinides (Repaglinide, Nateglinide)

o  Biguanides (Metformin)

o  Thiazolidinediones  (Rosiglitazone, Pioglitazone)

o  Alpha glucosidase Inhibitors (Acarbose, Miglitol)

o  DPP 4 Inhibitors (Sitagliptin, Vildagliptin)

o  Aldose reductase Inhbitors (Epalrestat)

o  Sodium-glucose co-transporter 2 inhibitors (Dapagliflozin, Canagliflozin)

Ø Concurrent therapy with a Beta blocker or Fluoroquinolone and an antidiabetic may increase the risk of hypoglycemia or hyperglycemia due to altered glucose metabolism.

Ø Excessive hypoglycemia, CNS depression, and seizures might be caused by the combination of Antidiabetics and MAO Inhibitors.

Ø The effectiveness of Antidiabetics is reduced by the coadministration of Thyroid hormones, Danazol, Glucosamine or Licorice which results into hyperglycemia.

Ø Concomitant use of Antidiabetics and Alpha lipoic acid, Bitter Melon, Fenugreek, Psyllium, Eucalyptus, Glucomannan, Gymnema, Ginseng or Guar gum may increase the risk of hypoglycemia due to additive blood glucose lowering effects.

Ø The diabetics should review their list with their doctor or pharmacist regularly, particularly when they begin to take a new medicine.

Alcohol - Drug interactions

More presentations from Naina Mohamed Pakkir Maideen

·Alcohol interacts with many drugs by both pharmacokinetic and pharmacodynamics mechanisms.

·Concomitant administration of Cycloserine and Alcohol is contraindicated due to increased risk of seizures.

·Disulfiram and alcohol (found in foods, medications, aftershaves, perfumes, and other products) use is contraindicated because of alcohol intolerance.

·Alcohol ingestion is contraindicated, while the patients are on the medications like Furazolidone and Metronidazole, due to Disulfiram-like reactions (abdominal cramps, nausea, vomiting, headaches and flushing).

·Alcohol use within 6 hours before or after the administration of Topiramate extended-release capsules is contraindicated due to erratic topiramate plasma concentrations.

·Concomitant use of Alcohol and Comfrey is contraindicated due to increased risk of liver damage.

· The risk of hepatotoxicity is increased by the administration of Acetaminophen (Paracetamol) in ingested patients.

·Enhanced CNS depression and impairment of motor skills have been observed in patients taking antidepressants (Amitriptyline, Clomipramine, Imipramine, Desipramine, Trimipramine, Citalopram, Escitalopram, Paroxetine, Venlafaxine, Desvenlafaxine) and alcohol together.

·Co-administration of CNS Depressants (Benzodiazepines(Clonazepam, Midazolam, Alprazolam, Diazepam, Lorazepam),Barbiturates (Amobarbital, Aprobarbital, Mephobarbital, Pentopbarbital, Phenobarbital) and alcohol may result into increased sedation.

·Increased CNS depression is expected with concomitant administration of alcohol and Phenothiazines (Fluphenazine, Prochlorperazine, Thioridazine, Trifluoperazine, Triflupromazine) and Opioids (Morphine, Oxycodone, Oxymorphone, Hydromorphone).

·Due to the inhibition of aldehyde dehydrogenase enzyme by drugs like Cephalosporins (Cefamandole, Cefmenoxime, Cefoperazone, Cefotetan and Moxalactam), Sulfonylureas Gliclazide, Glipizide, Glyburide, Tolazamide and Tolbutamide), Griseofulvin, ketoconazole, Isoniazid, Isotretinoin, Procarbazine, Tinidazole, Tolazoline and Trimethoprim, disulfiram-like reactions  (Facial flushing, Tachycardia, Increased blood pressure, and a feeling of severe intoxication) are expected with alcohol ingestion.

·The duration of Teratogenic risk of Acitretin is increased by alcohol consumption.

·The hypoglycemic effect of sulfonylureas (Gliclazide, Glipizide, Glyburide, Tolazamide and Tolbutamide), is prolonged by alcohol ingestion.

·Alcohol potentiates the bleeding time prolongation and gastrointestinal irritation caused by Aspirin.

·In summary, Adverse drug interactions of Alcohol causes mainly

v Disulfiram like reactions (Occur with Furazolidone, Metronidazole, Cephalosporins, Sulfonylureas, Griseofulvin, ketoconazole, Isoniazid, Isotretinoin, Procarbazine, Tinidazole, Tolazoline and Trimethoprim)

v Enhanced CNS depression (Barbiturates, Benzodiazepines, Phenothiazines and Opioids)

v Increased risk of Hepatotoxicity(Acetaminophen, Methotrexate, Milnacipran, Trabectedin, Comfrey, Chaparral, Germander and Pennyroyal)

v Increased risk of seizures (Cycloserine and Bupropion)

·As the alcohol consumption is involved in many adverse drug interactions, patients should be advised to avoid alcohol.

Top 10 Dangerous Drug Interactions

·       According to American Medical Directors Association (AMDA) and American Society of Consultant Pharmacists (ASCP) the following are summerised as top 10 dangerous drug combinations…

      1. Warfarin and NSAIDs

      2. Warfarin and Sulpha drugs

      3. Warfarin and Macrolides

      4. Warfarin and Quinolones

      5. Warfarin and Phenytoin

      6. ACE inhibitors and Potassium supplements

      7. ACE inhibitors and Spiranolactone

      8. Digoxin and Amiodarone

      9. Dogoxin and Verapamil

    10. Theophylline and Quinolones

·       Warfarin increases the GI bleeding risk when it is coadministered with NSAIDs.

·       Concomitant administration of Warfarin and sulpha drugs may elevate the risk of bleeding.

·       The risk of bleeding is increased by the interaction of warfarin with macrolide antibiotics such as Erythromycin, clarithromycin and telithromycin.

·       Bleeding risk is raised by the coadministration of warfarin and Quinolones too.

·       The risk of bleeding is varied with individuals due to the action of phenytoin on the metabolism of warfarin and its diaplacement from protein binding.

·       Coadministration of ACE inhibitors and Potassium supplements may increase the risk of hyperkalemia.

·       Hyperkalemia risk is also increased by the concomitant administration of ACE inhibitors and Spiranolactone.

·       Digoxin toxicity is induced when digoxin and amiodarone are administered together.

·       Digoxin toxicity is also induced by the concomitant administration of digoxin and verapamil.

·       Concomitant administration of Theophylline and Quinolones, increases the risk of Theophylline toxicity.

P –Glycoprotein (P-gp) – Drug Interactions:

v P-glycoprotein is one of the transporter protein and it helps the drugs and endogenous substances to cross biological membranes, by carrier-mediated processes.

v P-gp Substrates:

Digoxin, Loperamide, Quinidine, Vinblastine, Talinolol.

v P-gp Inducers:

Carbamazepine, Phenytoin, Rifampin, St John’s wort.

v P-gp Inhibitors:

Amiodarone, Azithromycin, Captopril, Cyclosporine, Quinidine, Quinine, Reserpine, Ritonavir, Tacrolimus, Valspodar, Verapamil.

v P-glycoprotein is an efflux pump found in the membranes of certain cells, which can push metabolites and drugs out of the cells and affect drugs’

ü Absorption (in the intestine)

ü Distribution (to the brain, testis, or placenta)

ü Elimination (in the urine and bile) of drugs

v Many drugs which are substrates for CYP3A4 are also substrates for P-glycoprotein.

v There is an overlap between CYP3A4 and P-glycoprotein inhibitors, inducers and substrates.

Cytochrome P450 enzymes - Drug Interactions

}  Cytochrome P450 (CYP) is a family of isoenzymes responsible for the oxidation of organic substances.

}  Most of the oxidative reactions of drugs are performed by six main enzymes:

v CYP 1A2

v CYP 2C9

v CYP 2C19

v CYP 2D6

v CYP 2E1

v CYP 3A4

}  Enzyme induction:

v The main drugs responsible for induction of the most clinically important cytochrome P450 isoenzymes are Griseofulvin, Phenytoin, Rifampicin, St. John’s wort, Carbamazepine, Phenobarbitone and Cigerette Smoke.

                     GPRS Cell Phone

v CYP 1A2 is induced by tobacco smoke (Smoking)

v CYP2E1 is induced by alcohol consumption.

}  Enzyme inhibition:

v The main drugs responsible for inhibition of the most clinically important cytochrome P450 isoenzymes are Sulphonamides, Antifungals ( Itraconazole, Ketoconazole, Fluconazole), Macrolide Antibiotics (Clarithromycin, Azithromycin, Erythromycin), Ciprofloxacin, Sertraline, Cimetidine, Omeprazole, Metronidazole, Antivirals (Ritonavir, Indinavir, Nelfinavir, Amprenavir), Antiarrhythmics (Amiodarone, Quinidine), Antidepressants (Fluoxetine, Paroxetine), Isoniazid and Alcohol.

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}  Understanding the mechanism underlying drug interactions helps to prevent drug toxicity or adverse effects.

}  Prediction of drug interactions in advance may reduce the number of expensive clinical studies.