Defination• It is the modification of the effect of one drug (the objectdrug ) by the prior concomitant administration ofanother (precipitant drug).• Concomitant use of several drug in presence of anotherdrug is often necessory for achiving a set of goal or in thecase when the patient is suffering from more than onedisease.• In these cases chance of drug interction coud increase.
content• Defination• Epidemiology• Risk factor• Out come of interaction• Mechanism of interactiona. pharmacokineticb. pharmacodynemic• Case study• Reference
Epidemiology• In harvard medical practice study of adverse event 8% were consider to be due to drug interaction.• US community pharmacy study revealed 4.1 % incidence of drug interaction in hospitalised patient.• Australian study found that 4.4% of all ADR , which resulted in hospital due to interaction.
Risk factors• Poly pharmacy• Multiple prescribers• Multiple pharmacies• Genetic make up• Specific population like e.g, females , elderly, obese, malnouresed , criticaly ill patient , trasplant recipient• Specific illness E.g. Hepatic disease, Renal dysfunction,• Narrow therapeutic index drugs Cyclosporine, Digoxin, Insulin, Lithium , Antidepressant, Warfarin
Outcomes of drug interactions1) Loss of therapeutic effect2) Toxicity3) Unexpected increase in pharmacological activity4) 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
Mechanisms of drug interactions Pharmacokinetics PharmacodynamicsPharmacokinetics involve the effect of a drug on another drugkinetic that includes absorption ,distribution , metabolismand excretion. Pharmacodynamics are related to the pharmacological activity of the interacting drugs E.g., synergism , antagonism, altered cellular transport effect on the receptor site.
Pharmacokinetic interactions1) Altered GIT absorption. •Altered pH •Altered bacterial flora • formation of drug chelates or complexes • drug induced mucosal damage • 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.
Ex1., antiacids Decrease the tablet dissolution of Ketoconazole (acidic) Ex2., H2 antagonists Therefore, these drugs must be separated by at least 2h in the time of administration of both .
b) Altered intestinal bacterial flora ;EX., 40% or more of the administered digoxin dose is metabolised by the intestinal flora. Antibiotics kill a large number of the normal flora of the intestine Increase digoxin conc. and increase its toxicity
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
d) Drug-induced mucosal damage. Antineoplastic agents e.g., cyclophosphamide vincristine procarbazine Inhibit absorption of several drugs eg., digoxin e) Altered motility Metoclopramide (antiemitic)Increase the toxicity Increase absorption of cyclosporine dueof cyclosporine to the increase of stomach empting time
f) Displaced protein binding It depends on the affinity of the drug to plasma protein. The most likely bound drugs is capable to displace others. The free drug is increased by displacement by another drug with higher affinity. Phenytoin is a highly bound to plasma protein (90%), Tolbutamide (96%), and warfarin (99%) Drugs that displace these agents are Aspirin Sulfonamides phenylbutazone
g) Altered metabolism The effect of one drug on the metabolism of theother is well documented. The liver is the major site of drugmetabolism 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.
E.g., Enzyme induction A drug may induce the enzyme that is responsiblefor 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 and Vice versa N.B enzyme induction involves protein synthesis .Therefore, it needs time up to 3 weeks to reach a maximal effect
Eg., 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. When an enzyme inducer ( e.g. carbamazepine) isadministered with an inhibitor (verapamil) The effect of the inhibitor will be predominant
Ex.,Erythromycin inhibit metabolism of astemazole and terfenadine Increase the serum conc. of the antihistaminic leading to increasing the life threatening cardiotoxicity Inhibits oxidative EX., Omeprazole of diazepam metabolism
•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 halflives of the drugse.g., cimitidine inhibits metabolism of theophylline.Cimitidine has a long half life, while, theophylline has a shortone.When cimitidine is administered to a patient regimen forTheophylline, interaction takes place in one day.
First-pass metabolism: Oral administration increases the chance for liver and GIT metabolism of drugs leading to the loss of a part of the drug dose decreasing its action. This is more clear when such drug is an enzyme inducer or inhibitor. EX., Rifampin lowers serum con. of verapamil level by increase its first pass . Also, Rifampin induces the hepatic metabolism of verapamil
Renal excretion:•Active tubular secretion It occurs in the proximal tubules. The drug combines with a specific protein to pass through the proximal tubules.When a drug has a competitive reactivity to the protein that isresponsible for active transport of another drug .This will reduce such a drug excretion increasing its con. and hence its toxicity. EX., Probenecid ….. Decreases tubular secretion of methotrexate.
* Passive tubular reabsorption; Excretion and reabsorption of drugs occur in the tubules By passive diffusion which is regulated by concentration and lipid solubility. Ionized drugs are reabsorbed lower than non-ionized ones Ex1., Sod.bicarb. Increases lithium clearance and decreases its action Ex2., Antacids Increases salicylates clearance and decreases its action
Pharmacodynemic interaction It means alteration of the dug action without change in its serum concentration by pharmacokinetic factors.EX., Propranolol + verapamil Synergistic or additive effect Additive effect : 1 + 1 =2 Synergistic effect : 1 +1 > 2 Potentiation effect : 1 + 0 =2 Antagonism : 1-1 = 0
Pharmacodynamic interactions• Receptor interaction – Competitive – Non-competitive• Sensitivity of receptor – Number of receptor – Affinity of receptor • Alter neurotransmitter release /drug transportation • Alter water/electrolyte balance
Drug-Food interactions• Grapefruit juice and Terfenadine• Grapefruit juice and cyclosporin• Grapefruit juice and felodipine• Grapefruit contains : furanocoumarin compounds that can selectively inhibit CYP3A4
Pharmacogenetics PharmacogenomicsPharmacology + Genetics/Genomics • The study of how individual’s genetic inheritance affects the body’s response to drugs (efficacy & toxicit y) • The use of genetic content of humans for drug discovery
Variations in drug response and drug toxicity may result fromVariation in drug Variation in drug metabolizing transporters • P-glycoprotienenzymes • Cytochromes Variation in disease P450 • Thiopurine S- modifying genes • Apolipoprotein (APOE methyltransferaseVariation in drugtargets •Beta2-adrenergic
DNA polymorphism Changes in the DNA sequence such as – Nucleotide mutation •The most frequent DNA variation found in the human genome is single nucleotide
Common genetic polymorphism of human drug metabolizing enzymes E zm ny e P in id n e M c ec Du s b t ae r g u sr t s D xr mt r p a e t o eho h n CPD Y26 C u a ia s5 0 a c s n -1 % b t -b c e s ea lo k r A ia s1 s n % A t r yh ic nia r t m s At e rsa t nid pe s ns N uo pic e r le t s Mp e yo e h n t in Mp o a b a e h b r it l C P C9 Y21 C u a ia s2 % a c s n -5 H x b r it l e o ab a A ia s7 3 s n -2 % D zpm ia e a O e r z le mpa o L n o r s le a s pa o T lb t m e o ua id CPC Y29 C u a ia s<1 acs n % (S)-W ra in af r P e yo h n t in N ID SA sThiopurine S- Azathioprinemethyltransferase Caucasians & Asians 0.3% 6-Mercaptopurine 6-Thioguanine
Management of an adverse interaction Dose related events may be managed by changing the dose of the affected medicine.• Eg.,when miconazole oral gel causes an increase in bleeding time of warfarin then redusing the warfarin dose will bring the bleeding time back into range and reduse the risk of haemorrhage• It is important to retitrate the dose of warfarin when the course of miconazole is coumplete.
The potential severity of some interaction require immediate Cessation of the combination.• Eg,.the combination of erythromycin and terfenadine can produse high terfenadine level with the risk of developing Torsel de Points. Dose spacing is appropriate for interction involving the inhibition of absorption in the GI tract .• Eg.,avoidig the binding of ceprofloxacin by ferous salts
Case study• Aim : Evaluation of p’kinetic drug interaction The proposal of the study was approved by the ethical committee of the shaheed beheshti medical university. At first questionnaries was designed for collecting data. First part of the questionnaries contain demographic data of patients including sex and age. In the second part there was a table for writing all drugs prescribed including drug name, dosage form, dosage amount, rout of administration and timing of the administration.
Continue….• A total number of 116 patients of ICU ward were visited during the study and one questionnaire was filled for each visit.• Data for total number of 567 prescriptions were recorded. The extent of occurrence and frequency of potential pharmacokinetic drug interactions were investigated based on the reference text Drug Interaction Facts published in the year 2004.
Continue…..• All of the potential pharmacokinetic drug interactions were extracted and classified in terms of mechanism, significance, onset, severity .• Onset shows how rapidly the clinical effects of interaction can occur. This determines the urgency with which preventive measures should be instituted to avoid the consequences of the interaction.
Severity of interactions is classified in 3 categories:
Result• A total number of 116 patients were enrolled the study with the mean age of 46(± 7) years. 65 (%56.03) patients were male and 51 (%43.97) were female.• From 567 prescriptions, 413 pharmacokinetic interactions were identified. . Four of the most common types have shown respectively in table 1.
Table 1. The most common pharmacokinetic interactions inthe studied ICU prescriptionsNo. Interaction between Number in 413 Percentage in 413 cases of cases of interactions interactions1 Ciprofloxacin- Sucralfate 137 33.172 Ciprofloxacin- 22 5.32 Magnesium sulfate3 Digoxin- Metoclopramide 17 4.114 Theophylline- Rifampin 16 3.87
• Among the mechanisms of pharmacokinetic interactions, the most dominant type was metabolic interaction with a total percentage of %60.05.• Table 2. Distribution of different mechanisms of the pharma- cokinetic interactions Mechanism Total number percentage Metabolism 248 60.05 Absorption 158 38.26 Elimination 4 0.97 distribution 3 0.72
Interaction type Number of interaction PercentageOnsetDelayed Table 3. Categories 251 drug interactions of 61%Rapid 162 39%SeverityMajor 72 17.43%Moderate 335 73.61%Minor 0 0%Unknown 37 8.96%DocumentationEstablised 102 24.7%Probable 166 39.95%Suspected 109 26.39%Unknown 37 8.96%Significance1 72 17.43%2 335 73.61%Unknown 37 8.96%
discussion• Whenever a patient receives multiple drug therapy, the possibility of a pharmacokinetic interaction exists.• This study shows the most prevalent pharmacokinetic interactions in ICU may be metabolic and those related to absorption alterations (about %98.31).• Interaction between ciprofloxacin and sucralfate, an absorption type, was the most prevalent one .• In the ICU, nurses usually determine timing of drug administration.
Continue…• Study showed the higher the number of drugs in prescriptions, the higher the number of interactions. Therefore, polypharmacy should be avoided as much as possible .
Reference :• Text book of Clinical pharmacy by Parth sarthi.• K.D.Tripathi• Iranian journal of p’ceutical research .page 215-218,2006 by school of pharmacy shahid baneshti university of medical science and health services.