Sunitha -Drug Interactions (1) (1)

8/2/2019 Sunitha -Drug Interactions (1) (1)

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Definition:

It is the modification of the effect of one

drug (the object drug ) by the priorconcomitant administration of another(precipitant drug).


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1. Use of non prescription drugs

2. Multiple pharmacological effects

3. Multiple physicians

4. Patient noncompliance5. Drug abuse


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1) Loss of therapeutic effect

2) Toxicity

3) Unexpected increase in pharmacologicalactivity


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Pharmacokinetic interactions are those which can

affect the processes by which drugs are:

Absorbed

Distributed

Metabolized and Excreted

(the so-called ADME interactions).

A change in blood concentration causes a changein the drugs effect


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Altered GIT absorption

1. Formation of drug chelates or complexes

Antacids + Tetracycline

Impact: tetracycline complexes with divalent cationsforming an insoluble complex

Cholestyramine + digoxin

Impact: Cholestyramine is an anionic resin used

therapeutically to bind bile salts , but may bind todrugs like digoxin resulting in poor absorption


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2. Altered GI motility

Metoclopramide + paracetmol

Impact: Metoclopramide increases GI motility sothe time required for paracetmol to reach

small intestine decreases, thus decrease the

onset time for analgesia

Anticholinergics+ Digoxin

Impact: under normal GI conditions 20- 30% of the

drug is absorbed , anticholinergic drugs slow

down the intestinal transit and thus increase

its absorption and may precipitate toxicity


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3. Altered intestinal bacterial flora

Broad spectrum antibiotic + oralcontraceptives

Impact: bowel bacteria cleave the conjugated metabolite

of estrogen to release free estrogen, if the bacterial

population decreases , the amount of free estrogenreleased is reduced which may not be sufficient to

inhibit ovulation and prevent conception .

Broad spectrum antibiotic + Warfarin

Impact: bowel bacteria synthesise vitamin K (antagonistof coumarin anticoagulants ), broad spectrum

antibiotics decrease bacterial population thus reducing

amount of vitamin K absorbed and enhance the action

of warfarin


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4. Alterations in gastric pH

ketoconazole + antacids

(proton pump inhibitors)

Impact: reduced ketoconazole absorption due to

reduced dissolution


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Altered drug distribution

1.protein binding Displacement

It depends on the affinity of the drug toplasma protein.

The most likely bound drugs is capable todisplace others.

The free drug is increased by displacementby another drug with higher affinity.


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Tolbutamide (A) +dicumerol (B)

Warfarin (A) +phenyl butazone (B)

Impact: In both the cases drug A is displaced

by drug B so the plasma concentration of

drug A is increased .Phenytoin + Sodium valproate

Impact:sodium valproate displaces phenytoin

and also inhibits its metabolism.


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Most of the drugs are metabolised by the

microsomal enzymes in the liver. The main drug metabolising isoenzyme

systems are CYP2D6 and CYP3A4

Some drugs are metabolised by other systems

like CYP1A2, 2C9, 2C19,2E1.

Enzyme inducers : increase the activity of

hepatic enzymes

eg: phenobarbitone, tolbutamide, alcoholEnzyme inhibitors: decrease the activity of

hepatic enzymes

eg: cimetidine


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increases the metabolism of thedrug

decrease of the levels of thesubstrate in the body

increase of the metaboliteconcentration

If pharmacological

activity is due to the

parent drug then the

levels of the drug are

low and activity isdecreased

Eg:

Rifampicin(CYP3A4

inducer) +

cyclosporin,

phenobarbital +

If pharmacological

activity is due to

the metabolite

then activity

/toxicity is

increased

Eg: paracetmol+

alcohol/isoniazid

(CYP2E1 inducer)


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Decreases the metabolism of thedrug

increase of the levels of thesubstrate in the body

Decrease of the metaboliteconcentration

If pharmacological

activity is due to the

parent drug then the

levels of the drug are

high and activity/toxicity is increased

Eg: Diltiazem(CYP3A4

inhibitor) +

cyclosporin

If pharmacological

activity is due to

the metabolite

then activity is

decreased


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Some individuals may have deficiency ofisoenzyme like CYP2D6, CYP2C9, CYP2C19responsible for metabolism and may

experience therapeutic failure if the drugrequires conversion to a metabolite.

Eg: codiene


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Active tubular secretion; It occurs in the proximal tubules (a portion

of renal tubules).

The drug combines with a specific proteinto pass through the proximal tubules.

When a drug has a competitive reactivityto the protein that is responsible for activetransport of another drug .This will reducesuch a drug excretion increasing its con.and hence its toxicity.

Eg: probencid decreases tubular secretionof methotrexate


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Passive tubular reabsorption

Excretion and reabsorption of drugs occurin the tubules By passive diffusion whichis regulated by concentration and lipid

solubility.Ionized drugs are reabsorbed lower than

non-ionized ones

Eg: antacids+aspirin

Impact: antacids reduce the tubular reabsorptionof salicylate via an increase in urine pH


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Increase/ decrease in Renal Blood Flow

Example: hydralazine + digoxinImpact: hydralazine increases the renal

clearance of digoxin

Example: NSAIDS+ lithium salts

Impact: NSAIDS inhibit prostaglandins

that maintain the blood flow in the

renal glomeruli. This decreases the

amount of lithium filtered out throughthe glomeruli and so increasing its

plasma levels


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It means alteration of the dug actionwithout change in its serum concentrationby pharmacokinetic factors

Synergism means =1+1=3

Additive means= 1+1=2

Potentiation means= 1+0=2

Antagonism means 1+1=0 or 0.5


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Trimethoprim +sulphamethoxazoleMAOI + Sympathomimetics

PHARMACOLOGICAL ANTAGONISM

Acetyl choline +Atropine

THIAZIDE DIURETIC + NSAID


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High risk drugs;these are the drugs thatshow a narrow therapeutic index

e.g., corticosteroids, rifampin, oralcontraceptives, quindine, lidoquine

High risk patients;these are the groups ofpatients that should be treated withcaution due to a specific heath conditione.g., pregnant women, malignant cases,

diabetic patients, patients with liver orkidney disorders asthmatic patients andcardiac disorders


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Garlic is used for lowering

blood cholesterol,

triglyceride levels and blood

pressure.Garlic may increase bleeding,

especially in patients already

taking certain anti-clotting

medications


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St. John's Wort is used

for mild to moderate

depression or anxiety

and sleep disorders.

St. John's Wort may

prolong the effect of

certain anesthetic

agents.


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Food may effect the drug bioavilability.

Pencillin and tetracyclines should be given on empty

stomach to achieve maximum absorption.

Milk and other dairy products contain calcium which

retards absorption of tetracyclines Cheese and alchoholic beverages contain tyramine.

Tyramine is metabolised by monoamine oxidase in the GIT

wall . If MAO inhibitors are given with cheese large

amounts of tyramine gets absorbed and may result in

hypertensive crisis. VITAMIN K concentration altered with food may effect

anticoagulant therapy.


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Prevention of drug interaction1) Monitoring therapy and making adjustments

2) Monitoring blood level of some drugs with narrow

therapeutic index e.g., digoxin, anticanceragentsetc

3) Monitoring some parameters that may help tocharacterize the the early events of interaction

or toxicity e.g., with warfarin administration, it

is recommended to monitor the prothrombin time

to detect any change in the drug activity.

4) Increase the interest ofcase report studies to

report different possibilities of drug interaction


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A 67-year-old man receiving a stable maintenance dosage of

warfarin experienced an increased international normalized ratio

(INR) without bleeding when his atorvastatin therapy was

switched to fluvastatin. His warfarin dosage was reduced and his

INR stabilized. The fluvastatin was switched back to atorvastatin,

and the warfarin dosage was increased to maintain the patient's

goal INR. The literature supports a drug interaction between

warfarin and fluvastatin due to the strong affinity of fluvastatin

for the cytochrome P450 enzyme 2D6. This interaction has not

been seen with atorvastatin. Lovastatin also reportedly has

caused increases in INR when coadministered with warfarin. It isunclear whether simvastatin interacts with warfarin, but it may

increase INRs slightly or increase serum simvastatin levels. One

case report describes an interaction between simvastatin and the

anticoagulant acenocoumarol, which resulted in an elevated INR.

Pravastatin does not appear to interact with warfarin but has

caused an increased INR when combined with the anticoagulantfluindione. Thus, until more definitive data are available,

clinicians should monitor the INR closely after starting statin

therapy in any patient receiving anticoagulation therapy


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In one study, coadministration of a kaolin pectin suspension and

digoxin, delayed absorption of the latter and decreased by 62%

the amount absorbed. When the antidiarrhoeal preparation wasgiven two hours before the digoxin, the absorption rate was not

affected although the extent of absorption was reduced by

about 20%. When the antidiarrhoeal was given two hours after

the digoxin, neither the rate nor the extent of absorption was

altered.


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CASE SUMMARY: A 72-year-old white man (178 cm, 77.2 kg) withdiabetes mellitus, hyperlipidemia, hypertension, and mild

azotemia was hospitalized on September 21, 2004, with thigh

weakness, achiness, and dark urine for 7 days. Coronary artery

bypass had been performed on July 7, 2004. Amiodarone 200mg/day was started on July 10, and simvastatin 80 mg/day was

initiated on August 13. Laboratory testing on the present

admission included creatine kinase (CK) 19 620 U/L (reference

range 60-224), blood urea nitrogen 50 mg/dL, creatinine 2.6

mg/dL, aspartate aminotransferase (AST) 912 U/L (30-60),

alanine aminotransferase (ALT) 748 U/L (30-60), urine myoglobin71100 g/L (


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An 80-year-old man with a 4-year history of type 2 diabetes who had been

treated with lifestyle changes as well as repaglinide 0.5 mg 3 times/day

for the previous 2 years was admitted to the hospital with severe

hypoglycemia. Before admission, his diabetes had been well controlled,

with his blood glucose levels ranging from 100-200 mg/dl and his

hemoglobin A1c 6.5%.

Several days before admission, the patient had been diagnosed with

gastric Helicobacter pylori infection, and clarithromycin 500 mg twice/day and

amoxicillin 250 mg twice/day were started; omeprazole was also continued at

20 mg twice/day. Forty-eight hours after starting this therapy, his blood

glucose level had decreased to 25 mg/dl (measured by his home glucometer).

The patient became unresponsive, and an emergency team was called to hishome by his wife. Intravenous glucose was administered and resolved the

problem. Clarithromycin therapy (as well as amoxicillin and omeprazole) was

continued. However, 48 hours later, the patient again was unresponsive. A

second blood glucose level was less than 30 mg/dl. The patient was

hospitalized, and intravenous glucose administration again resolved the

problem. Repaglinide therapy was stopped, and no further hypoglycemic

episodes occurred.

Discussion: clarithromycin likely altered the bioavailability ofrepaglinide through inhibition of CYP3A4 and/or Pglycoprotein.

Conclusion:this case report suggests that clarithromycin maycause hypoglycemia in patients with type 2 diabetes who are

taking repaglinide.


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an unwanted or harmful reaction experienced following

the administration of a drug or combination of drugs under

normal conditions of use and suspected to be related to

the drug

An adverse drug reaction (ADR) is a response to amedicine which is noxious, undesirable and unintended,

and which occurs at doses normally used in human for

diagnosis, prophylaxis and treatment .

(or)


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EPIDEMIOLOGY

5% adults in US are allergic to >1 drugs

30% of medical inpatients develop an ADR

3% of all hospital admissions are due to ADRs

Risk of an allergic reaction is approximately

1-3%for most drugs


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Intrinsic factors of the drugPharmacological

Idiosyncratic

Carcinogenicity, Mutagenicity

Teratogenicity

Extrinsic factorsAdulterantsContamination

Underlying medical conditions

Interactions

Wrong usage

Possible Causes of Adverse Reactions


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Type A (Augmented) reactions

Reactions which can be predicted from the

known pharmacology of the drug

Dose dependent

can be alleviated by a dose reduction

E.g. Bleeding with anticoagulants, bradycardia

with beta blockers, headache with nitrates,

postural hypotension with prazosin


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Type B (Bizarre) reactions

Non-dose related;

bizarre and unpredictable.

Intolerance (e.g. tinnitus with use of Aspirin).

Immune related such as hypersensitivity reactions

(e.g. Anaphylaxis with penicillin administration ).

Non-immune reactions such as porphyria,neuroleptic malignant syndrome, or malignant

hyperthermia.

Idiosyncratic reaction(e.g. development of anemia

with the use of anti-oxidant drugs in Thepresence of glucose-6 phosphate dehydrogenase

deficiency).As the mechanisms of these specific

reactions are better understood, these reactions

may be re-classified as Type A.


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Type C (Chemical) reactions Biological characteristics can be

predicted from the chemical structureof the drug/metaboliteE.g. paracetamol hepatotoxicity

Type D (Delayed) reactions

Occur after many years of treatment.Can be due to accumulationE.g. Secondary tumours after treatment

with chemotherapy, teratogeniceffects of phenytoin taken during

pregnancy, analgesic nephropathy,tardive dyskinesia with antipsychoticagents


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Type E ( End of treatment) reactions

Occur on withdrawal especiallywhen drug is stopped abruptly

E.g. withdrawal seizures on

stopping phenytoin,adrenocortical insufficiency on

withdrawal of steroids


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Describing ADR

ADRs may be described by their frequency and severity

FrequencyThe World Health Organization recommends standardization

of descriptions of frequency.

very common (>1/10 patients)

common (>1/100)

uncommon (>1/1000)

rare (>1/10,000)very rare (


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Mechanisms

As research better explains the biochemistry of drug use, less ADRs

are Type B ('idiosyncratic') and more are Type A (pharmacologically

predictable). Common mechanisms are:Abnormal pharmacokinetics due to

genetic factors

comorbid disease statesSynergistic effects between either

a drug and a diseasetwo drugs


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Abnormal pharmacokinetics

Comorbid disease statesVarious diseases, especially those that cause renal

or hepatic insufficiency, may alter drug metabolism.

Resources are available that report changes in a drug'smetabolism due to disease states.

Genetic factorsAbnormal drug metabolism may be due to inherited

factors of either Phase I oxidation or Phase II

conjugation. Pharmacogenomics is the study on the

inherited basis of drug reactions. Among drugs

frequently cited in adverse drug reactions, 60% are

metabolized by enzymes with genetic variations in

metabolism. 7% to 22% of randomly selected have such

variation.


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Phase I reactionsInheriting abnormal alleles of cytochrome P-450 can alter

drug metabolism. Tables are available to check for drug

interactions due to cytochrome P-450 interactions.

Inheriting abnormal butyrylcholinesterase(pseudocholinesterase) may affect metabolism of drugs

such as succinylcholine

Phase II reactionsInheriting abnormal N-acetyltransferase which

conjugated some drugs to facilitate excretion may affect

the metabolism of drugs such as isoniazid, hydralazine,and procainamide.

Inheriting abnormal thiopurine S-methyltransferase may

affect the metabolism of the thiopurine drugs

mercaptopurine and azathioprine


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Impaired hepatic functionFood and Drug Administration provides guidance

on the labeling of prescription medications to guide

dosing for patients with impaired hepatic function.Impaired renal function

The National Kidney Disease Education Program

provides guidance on dosing drugs in patients with

reduced glomerular filtration rate. Food and Drug

Administration provides guidance on the labeling of

prescription medications to guide dosing for patients with

impaired renal function. Although this categorization uses

estimated creatinine clearance, using estimated

glomerular filtration yields similar recommendations for

dosing adjustments.


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Synergistic effectsAn example of synergism is two drugs that

both prolong the cardiac QT interval.

Other factors that my increase ADRs

PolypharmacyThe risk of drug interactions may

be increased with polypharmacy.

Age (elder & young)

Gender (Female 1.5-1.7 fold greater risk

of ADR than male


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Different forms have been developed for

reporting ADRs:

MEDWATCH by FDA

YELLOW CARD


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To improve the detection of previously unknownserious ADRs and knowledge about regulatoryactions taken in response to reporting of theseevents, FDA introduced MEDWATCH in 1993.FDA

encourages health professionals to monitor forand report serious adverse events and productproblems to FDA. MedWatch is designed toeducate health professionals about the critical

importance of being aware of, monitoring for, andreporting adverse events and problems to FDA .


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It is designed to enhance the effectiveness of postmarketing surveillance of medical products asthey are used in clinical practice and to rapidlyidentify significant health hazards associated withthese products. To increase awareness of drugand device-induced disease

To clarify what should (and should not) bereported to the agency

To facilitate reporting by operating a single systemfor health professionals to report ADRs andproduct problems

To provide regular feedback to the health carecommunity about safety issues involving medicalproducts.


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The CSM yellow card scheme is regarded as oneof the worlds best spontaneous reportingschemes for suspected ADRs, acting as an earlywarning system for the identification ofpreviously unrecognized reactions. It has helped

to identify many safety issues including: renal failure due to aristolochia in Chinese herbs

severe esophageal reactions with alendronate

serious cardiovascular reactions with cisapride.

About 20,000 yellow card reports are submittedeach year by doctors, dentists,pharmacists,nurses and the pharmaceuticalindustry. About half that number representserious


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ADRs, but it is generally accepted that there

is under-reporting to CSM by a factor of 10.Itfollows from this that about 100,000 peoplein the UK suffer a serious ADR every year.The CSM has an expert working group on

pediatric medicines. Its remit is to improvethe availability of medicines for childrenwithin the regulatory framework and toadvise on safety issues relating to specificmedicines used in children. More information

about registering an ADR can be located from http://www.MHRA.gov.uk/aboutagency/regfr

amework/csm/csmhome.htm

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Sunitha -Drug Interactions (1) (1)