drug interaction-f

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Drug Interactions : 

Drug Interactions Dr.Hesham El refaey Pharmacology and toxicology Dept. Al Azhar University heshamelrefaey@hotmail.com

Defining a Drug Interaction : 

Defining a Drug Interaction “A measurable modification of the action of one drug by prior or concomitant administration of another substance.” Drug-drug (Rx, OTC, herbal) Drug-food, drug-alcohol Drug-lab, drug-disease, drug-chemical

Why Are There So Many drug interactions? : 

Why Are There So Many drug interactions? Two-thirds of patient visits result in Rx 3 BILLION outpatient Rx per year Specialists give 2.3 Rx per visit -- 89.2% take a prescription medicine daily 46.1% take ≥5 prescriptions chronically 53.6% take meds Rxed by 2 or more doctors 5% obtain an Rx from non-trusted origins

Slide 4: 

Most new drugs have only ~3000 patient exposures. Some drugs have rare drug interaction. To detect such rare effects , more than 60,000 patients must be exposed after the drug is marketed. It is difficult to determine if a drug or another clinical cause is responsible It is reported only if absolutely certain One reported case can’t make a difference . Drug interactions are an important contributor to the number of ER visits and hospital admissions. That is Why; Knowledge of clinical pharmacology of drug interactions is valuable.

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* Risk factors: High risk drugs; these are the drugs that show narrow therapeutic index e.g. corticosteroids, rifampin, oral contraceptives and quindine. 2) High risk patients; these are the groups of patients that should be treated with caution due to a specific heath condition e.g., pregnant women, malignant cases, diabetic patients, patients with liver or kidney disorders asthmatic patients and cardiac disorders.

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Onset of drug interaction It may be seconds up to weeks for example in case of enzyme induction, it needs weeks for protein synthesis , while enzyme inhibition occurs rapidly. The onset of action of a drug may be affected by the half lives of the other drugs e.g., cimitidine inhibits metabolism of theophylline. Cimitidine has a long half life, while theophylline has a short one. When cimitidine is administered to a patient regimen for theophylline, interaction takes place in one day.

Slide 7: 

1. Loss of therapeutic effect 2. Toxicity 3. Unexpected increase in pharmacological activity 4. Beneficial effects e.g additive & potentiation (intended) or antagonism (unintended). 5. Chemical or physical interaction e.g I.V incompatibility in fluid or syringes mixture Outcomes of drug interactions

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Drug Interactions Outside Body Pharmacodynamic Pharmacokinetic

Mechanism of drug interaction : 

Mechanism of drug interaction Pharmacokinetic interactions Absorption Distribution Biotransformation*** Excretion Pharmacodynamic interactions Receptor interaction Receptor sensitivity Neurotransmitter release/Drug transportation Electrolyte balance Physical interactions Pharmaceutical interactions

Interactions before Administration : 

Interactions before Administration Phenytoin precipitates in IV dextrose solutions (e.g., D5W) Amphotericin precipitates in IV saline Gentamicin is physically/chemically incompatible when mixed with most beta-lactam antibiotics, resulting in loss of both antibiotics’ effects

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Pharmacokinetic Interaction Drug A alters the effect of Drug B by changing the plasma concentration of Drug B

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Pharmacokinetic interactions 1. Altered GIT absorption. Altered pH, Altered bacterial flora, formation of drug chelates or complexes, drug induced mucosal damage and altered GIT motility. a. Altered pH The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form does.

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Ex1. antiacids Decrease the pH Decrease the tablet dissolution of Ketoconazole (acidic) Ex2. H2 antagonists pH Therefore, these drugs must be separated by at least 2h in the time of administration of both .

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b. Altered intestinal bacterial flora ; EX., In 10% 0f patients receiving digoxin…..40% or more of the administered dose is metabolized by the intestinal flora Antibiotics kill a large number of the normal flora of the intestine Increase digoxin conc. and increase its toxicity

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c. Complexation or chelation; EX1. Tetracycline interacts with iron preparations or Milk (Ca2+ ) Unabsorpable complex Ex2. Antacid (aluminum or magnesium) hydroxide Decrease absorption of ciprofloxacin by 85% due to chelation

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d. Drug-induced mucosal damage. EX 1. Antineoplastic agents e.g., cyclophosphamide vincristine procarbazine Inhibit absorption of several drugs eg., digoxin e. Altered motility Metoclopramide (antiemitic) Increase absorption of cyclosporine due to increase of stomach empting time Increase the toxicity of cyclosporine

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f. Displaced protein binding It depends on the affinity of the drug to plasma protein. The most likely bound drugs with higher affinity are capable to displace others Increases the free drug EX1. Phenytoin is a highly bound to plasma protein 90% Tolbutamide (96%), and warfarin (99%) Examples of drugs that may displace these agents are Aspirin, Sulfonamides and phenylbutazone

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g. Altered metabolism The effect of one drug on the metabolism of the other is well documented. The liver is the major site of drug metabolism but other organs can also do e.g., WBC,skin,lung, and GIT. CYP450 family is the major metabolizing enzyme in phase I (oxidation process). Therefore, the effect of drugs on the rate of metabolism of others can involve the following examples.

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EX1. Enzyme induction A drug may induce the enzyme that is responsible for the metabolism of another drug or even itself e.g. Carbamazepine (antiepileptic drug ) increases its own metabolism Phenytoin increases hepatic metabolism of theophylline Leading to decrease its level Reduces its action N.B enzyme induction involves protein synthesis, therefore, it needs time up to 3 weeks to reach a maximal effect

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EX2. Enzyme inhibition; It is the decrease of the rate of metabolism of a drug by another one. This will lead to the increase of the concentration of the target drug and leading to the increase of its toxicity . Inhibition of the enzyme may be due to the competition on its binding sites , so the onset of action is short may be within 24h. N.B; When an enzyme inducer (e.g.carbamazepine) is administered with an inhibitor (verapamil) The effect of the inhibitor will be predominant

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Renal excretion: Active tubular secretion; The drug combines with a specific protein to pass through the proximal tubules. When a drug has a competitive reactivity to the protein that is responsible for active transport of another drug .This will reduce the drug excretion increasing its con. and hence its toxicity. EX. Probenecid . Decreases tubular secretion of methotrexate.

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* Passive tubular reabsorption; Excretion and reabsorption of drugs occur in the tubules by passive diffusion which is regulated by concentration and lipid solubility. Ex1. Sod.bicarb. Increases lithium clearance and decreases its action Ex2. Antacids Increases salicylates clearance and decreases its action

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Pharmacokinetic Interactions: Drug Metabolism Drugs that cause induction / inhibition of enzymes in Phase I Barbiturates, Antibiotics (rifampicin, choramphenicol, erythromycin) Ethanol, Phenytoin Carbemazepine, Corticosteroids MAO inhibitors, Paracetamol Cimetidine, Oral contraceptives

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Pharmacodynamics The study of the action and effects of medications on physiologic function Pharmacodynamic drug interactions can be: Additive (two or more analgesics) Synergistic Antagonistic (dexamethasone and glyburide)

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Pharmacodynamic interactions It means alteration of the dug action without change in its serum concentration by pharmacokinetic factors. EX. Propranolol + verapamil Synergistic or additive effect Synergism means =1+1=3 Additive means= 1+1=2 Potentiation means= 1+0=2 Antagonism means 1+1=0 or 0.5 Effect at the receptor site Antiadrenegic anticholinergic

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Pharmacodynamic interactions Often take a 2 - agonist (salbutimol) to induce broncodilation Often take  blockers (propanolol) to reduce heart, rate force of contraction Asthmatics Hypertension Diminished effect of 2 - agonist

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Pharmacodynamic interactions Antidepressants Sympathomimetics Monoamine Oxidase Inhibitors (MAOI’s) Inhibit breakdown of Noradrenaline Dopamine Decongestants (pseudoephidrine) Asthma (salbutimol) Foods rich in tyramine Beer, Hot Dogs, Wine, Beans MAOI’s enhance effects of these drugs and enhance the action of tyramine

Slide 29: 

Pharmacodynamic Interactions NSAID’s Antihypertensives For inflammation/ headache. Most block Prostaglandin synthesis. PGE2 and PGI2 cause renal arteriolar dilation 1 Antagonist 1 Antagonist Angiotensin Converting Enzyme (ACE) Inhibitors Diuretics Loss of ability to dilate renal arterioles (via PGE2 and PG2) can lead to hypertensive crisis in people taking antihypertensives

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Pharmacodynamic Interactions Benzodiazepines (and antihistamines, anticonvulsants, barbiturates) Alcohol CNS depressant CNS depressant ‘Additive’ CNS depression Respiratory depression, hypotension, coma

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Interactions aren’t all bad………………… Synergistic interaction of general Anaesth. + sedatives eg Ketamine + Ketamine + Ketamine Stage III Ketamine + Diazepam Stage III and calm and sleepy

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Pharmacodynamic and Pharmacokinetic Interactions Warfarin, Vitamin K  Antibiotics Vitamin K important in coagulation (blood clotting) Warfarin (an anticoagulant) inhibits coagulation too much Vitamin K (Vitamin supplements, leafy greens) Reduced effectiveness of warfarin

PharmacogeneticsPharmacogenomics : 

PharmacogeneticsPharmacogenomics Pharmacology + Genetics/Genomics The study of how individual’s genetic inheritance affects the body’s response to drugs (efficacy & toxicity) The use of genetic content of humans for drug discovery

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Genetic variations in drug response and drug toxicity may result from Variation in drug transporters P-glycoprotien Variation in disease modifying genes Apolipoprotein (APOE) Variation in drug metabolizing enzymes Cytochromes P450 Thiopurine S-methyltransferase Variation in drug targets Beta2-adrenergic receptor ACE Dopamine receptor

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Changes in the DNA sequence such as Nucleotide mutation The most frequent DNA variation found in the human genome is single nucleotide polymorphism (SNP) Nucleotide deletion Nucleotide insertion Gene deletion Gene duplication DNA polymorphism

Slide 36: 

Caucasians & Asians 0.3% Azathioprine 6-Mercaptopurine 6-Thioguanine Thiopurine S-methyltransferase

Slide 37: 

Life-threatening complication after cough suppression therapy with codeine 62 yr man with pneumonia treated with codeine (25 mg tid) for cough 4 days after drug administration , the pt’s consciousness rapidly deteriorated, and he became unresponsive. At the time of the pt’s coma, plasma morphine was 80 μg/L (normal 1-4 μg/L) morphine-3-glucuronide was 580 μg/L (normal 8-70 μg/L) morphine-6-glucuronide was 136 μg/L (normal 1-13 μg/L ) CYP2D6 genotyping : ultra rapid metabolism N Engl J Med 2004;351:2827-31

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Targeted prescription of medicine: applied pharmacogenomics

Slide 40: 

* Prevention of drug interaction Monitoring therapy and making adjustments Monitoring blood level of some drugs with narrow therapeutic index e.g., digoxin, anticancer agents…etc Monitoring some parameters that may help to characterize the the early events of interaction or toxicity e.g., with warffarin administration, it is recommended to monitor the prothrombin time to detect any change in the drug activity. Increase the interest of case report studies to report different possibilities of drug interaction

Drug-Drug Interaction Prevention: A Stepwise Approach : 

*These programs are not endorsed by the FDA Drug-Drug Interaction Prevention: A Stepwise Approach 1. Take a medication history (AVOID Mistakes mnemonic) 2. Remember high-risk patients Any patient taking ≥ 2 medications Patients Rxed anticonvulsants, antibiotics, digoxin, warfarin, amiodarone, etc. 3. Check pocket reference or PDA 4. Consult pharmacists or drug info specialists 5. Check up-to-date computer program Medical Letter Drug Interaction Program* www.epocrates.com* and others

Slide 42: 

Mrs. F. is a 92 year old nursing home resident with a history of HTN, “heart disease”, osteoarthritis, and a stroke. She has been declining recently, with a decreased appetite. Her meds are HCTZ 12.5, ASA 81, digoxin .125, and enalapril 10. She has been on the same meds and dosages for years. On exam, she looks frail BP 130/80 P60 R 16. Other than being thin, her exam is fairly unremarkable. She has no signs of CHF. She has mild left sided weakness and hyper-reflexia, and her MMSE is 27/30, she is not depressed. Her gait is slow with a walker. Labs: Hgb12, Cr 1.3, BUN 20, digoxin level 1.7, others normal. Her EKG is normal except for borderline bradycardia and nonspecific ST changes, which are old. What do you think is wrong?

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Mr. W. is a 86 year old man with pulmonary HTN, COPD, CRI (creatinine of 2.2), CHF with an ejection fraction of 20%, mild dementia, depression, and severe anemia. He is frequently admitted to the hospital because of severe disease and poor adherence with his medical regimen. His discharge medications on last admission one month ago were aspirin 325mg, 02, enalapril 20mg QD, furosemide 80mg BID, combivent, and sertraline 50mg. The inpatient team decided that he was undertreated, and added metoprolol 12.5mg BID, aldactone, FeSo4 325mg TID, and 3 inhalers. He was readmitted within a week. How might you approach his regimen?

Questions…..No! thxs : 

Questions…..No! thxs

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