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Drug Interaction…Why is it IMPORTANT…..

Supervisor : Aj. Patipan Toomthong

Presented by…

Nattawan Sirichuntakul MD.

Mallika Ahuja MD.

When multiple drug therapies are prescribed, drug interactions become an important consideration for the patient

The patient may be taking more than one drug to treat multiple disorders or they may be taking multiple drugs to treat a single disorder.

It is estimated that the incidence of clinical drug interactions ranges from 3 to 5% in patients taking a few medications, but increases to 20% in patients receiving 10–20 drugs.

Hardman JG, Limbird LE, Molinoff PB, Ruddon RW,Gilman AG, eds. Goodman & Gilman’s The PharmacologicalBasis of Therapeutics, 9th edn. New York: McGraw-Hill, 1996.

GOAL …..

is to decrease toxicity while maintaining or increase efficacy

Why combine drugs?

A narrow therapeutic index1

Steep dose–response curve2

High first-pass metabolism3

A single, inhibitable route of elimination4

Drugs most likely to pose interaction problems are those having :

• Herman R. Drug interactions and the statins. Can Med Assoc J 1999: 161: 181–186. 7. • Thummel K, Wilkinson G. In vitro and in vivo drug interactions involving Human CYP3A. Annu

Rev Pharmacol Toxicol 1998: 38: 389–430.

Phenobarbitone Digoxin Warfarin

Phenytoin Cyclosporin Lithium

Carbamazepine Theophylline

Some drugs with a low therapeutic index

Alterations in receptors

Malignant hyperthermia : variability in ryanodine receptor

Genetic causes:

Variabiltiy in pharmacokinetics :

Variability in pharmacodynamics :

Variability in hepatic cytochromes

Circulating enzymes (pseudocholinesterase)

Transporters

Variability in drug response

– Aging– Disease– Environment toxins– Pharmacokinetic,pharmacodynamic of

other drugs

Nongenetic causes :

Variability in drug response

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MECHANISMS OF DRUG INTERACTIONS

1 Pharmaceutical interactions

2 Pharmacodynamic interactions

3 Pharmacokinetic interactions

Mechanism of drug interactions

Chemical or physical reactions that occur in vitro

1.Pharmaceutical interactions

Interaction : loss of activity of drugs or for their aggregation , precipitation in solution serious sequences

Chemical deterioration or decompositionthiopental ( powder VS addition of water)cathecholamines ( decomposed by light)

Predictable , not important cause of complications in anesthesia

Only one drug should be added to crystalloid solution

No additives in infusions of blood , blood products, lipid emulsions, amino acid preparaitons or hypertonic saline

Prevention of pharmaceutical interaction

1 Pharmaceutical interactions

2 Pharmacodynamic interactions

3 Pharmacokinetic interactions

Mechanism of drug interactions

2.Pharmacodynamic interactions

opposite or similar

effects

Drug B

Drug

A

Change in the patient’s response to the drug without altering the drug’s pharmacokinetics

Change in drug action without altering the plasma concentration

2.Pharmacodynamic interactions

2.Pharmacodynamic interactions

synergistic

sedatives

alcohol opioids

Response

Hi

Lo

Time

A B

A + B

The effect of two chemicals is equal to the sum of the effect of the two chemicals taken separately, eg., aspirin and ibuprofen.

Additive Effects

Response

Hi

Lo

Time

A B

A + B

The effect of two chemicals taken together is greater than the sum of their separate effect at the same doses, e.g., alcohol and other drugs

Synergistic Effects

Response

Hi

Lo

Time

A B

A + B

The effect of two chemicals taken together is less than the sum of their separate effect at the same doses

Antagonistic Effects

May result from one drug changing the environment necessary for the safe and effective use of a second drug

2.Pharmacodynamic interactions

loop diuretic

• produces potassium wasting

digoxin

• increase cardiotoxic effects

1 Pharmaceutical interactions

2 Pharmacodynamic interactions

3 Pharmacokinetic interactions

Mechanism of drug interactions

Absorption1

distribution2

metabolism3

elimination4

3.Pharmacokinetic interactions

3.1 Absorption

altered by drug-induced alterations in gastrointestinal motility

Narcotics & anticholinergics agents

rate of drug absorption

Delay gastric emptying

Prokinetic agents (metoclopramide)

increase gastric empting

rate of drug absorption

pH of the gastrointestinal tract

3.1 Absorption

Weak acids

acidic environment

weak bases

basic environment

more absorbable more absorbable

Drug adsorption: a drug is adsorbed onto a binding agent and the drug is no longer easily absorbed into the blood, and may be therapeutically ineffective

3.1 Absorption

Robinson D, Benjamin DM, McCormack JJ. Interaction of warfarin and nonsystemic gastrointestinal drugs. Clin Pharmacol Ther 1971: 12: 491–495.

Cholestyramine (anion binding resin)

Warfarin (Oral anticoagulant)

Plasma warfarin concentration &

Hypoprothrombinemic effect

3.2 Distribution

inertAcidic drug

plasma albumin

Basic drug

-acid glycoprotein

DRUG (less affinity)

DRUG(high affinity)

free concentration drug(less affinity)

plasma protein

3.2 Distribution

Warfarin vs NSAIDs

“In patient with depressed cardiac function, normal dose of IV agents can produce greater cardiovascular & CNS effects, due to increase in tissue drug concentration or sensitivity.”

• Recent studies suggest that the most clinically important drug interactions involve pathways of metabolism.

3.3 Metabolism

After oral administration: some drugs are extensively metabolized by liver before access to systemic circulation

3.3 Metabolism

First-pass metabolism

Hepatic blood flow

Propranolol & inhalation anesthetics & opioids

Lipid soluble drugs

More water soluble metabolites

Excretion (renal or hepatobiliary)

Biotransformation

Biotransformation

Hepatic microsomal enzymes (oxidation,conjugation)

Extrahepatic microsomal enzymes (oxidation, conjugation)

Hepatic non-microsomal enzymes (acetylation, sulfation,GSH, alcohol/aldehyde dehydrogenase,hydrolysis, oxidation/reduction)

Markey, NIH, 2002

Biotransformation

What is cytochrome(CYP) ?

• Superfamily of constitutive and inducible enzymes that catalyze most phase I biotransformations

• Peak absorbance @450nm

Enzyme that catalyzes oxidation -reduction reaction

Family of CYP450 one of the most important enzymes involved in the metabolism

CYP CYP450 CYP3A4

Cytochrome (CYP)

CYP 3A4

GENE for mammalian cytochrome

Family

Subfamily

Specific enzyme

• CYP Substrates

• CYP Inducers

• CYP Inhibitors

Cytochrome P450 Nomenclature

Proportion of drugs metabolised by CYP450 isozymes

CYP3A440%

CYP2E1

CYP2B6

CYP2A6

CYP1A2

CYP2D619%

CYP2C9

CYP2C19

Most drugs metabolised by more than one isozyme

Drug Interactions (Liver)

CYP Substrate

CYP Inhibitor

Substrate concentration Toxicity

CYP Substrate

CYP Inducer

Substrate concentration

Efficacy

Anzenbacher P, Anzenbackerová E: Cytochromes P450 and metabolism of xenobiotics. Cell Mol Life Sci 58:737, 2001

Substrates of CYP450 Encountered in Anesthesiology

CYP3A4

Fentanyl

Alfentanil

Sufentanil

Codeine

Methadone

Acetaminophen

Alprazolam

Midazolam

Diazepam

Bupivacaine

Lidocaine

Ropivacaine

Digitoxin

Verapamil

Diltiazem

Felodipine

Nicardipine

Nifedipine

Warfarin

Anti-HIV drug (NNRTIs, PIs)

Omeprazole

Pantoprazole

Statins

Cortisol

CYP2D6 CYP2C19

CaptoprilCodeineHydrocodoneMetoprololOndansetronPropranololTimolol

DiclofenacIbuprofenIndomethacin

DiazepamOmeprazolePropranolol

Substrates of CYP450 Encountered in Anesthesiology

CYP2C9

Venkatakrishnan K, von Moltke LL, Greeblatt DJ: Human drug metabolism and the cytochromes P450: Application and relevance of in vitro models. J Clin Pharmacol 41:1149,2001.

Substrates Inhibitors Inducers

CYP3A4 MidazolamAtorvastatinFelodipine

RitonavirKetoconazoleGrapefruit juice

RifampinCarbamazepinePhenytoin

CYP2D6 RisperidoneAmitryptilineCodeine

QuinidineFluoxetineCimetidine

Nil clinically relevant

CYP1A2 ClozapineTheophyllineCaffeine

FluvoxamineCimetidineCiprofloxacin

SmokingOmeprazoleCruciferous veg

Examples of CYP 450 Substrates, Inhibitors & Inducers

Wei C. Lau, MD; Lucy A.et al . Atorvastatin Reduces the Ability of Clopidogrel to Inhibit Platelet Aggregation. Circulation. 2002;106:r62-r67.

“ Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel.”

Clopidogrel is an inactive thienopyridine prodrug

active metabolite.

CYP3A4Atorvastatin,

another CYP3A4 substrate

Other sites liver, lungs,gastrointestinal tract, saliva, sweat, tears, and breast milk

kidney primary organ for excretion

4.Elimination

Mechanism Altered renal excretion • changes in urinary pH• competition for the same transport system• changes in active tubular secretion• changes in renal blood flow

Why do we have to know????

Present illness

A 51 year-old HIV infected woman

Diagnosis : Acute diarrhea with septic shock

Dopamine 8 mcg/kg/minLevophed 2.67 mcg/min

Pain on her finger

• V/S: T 36.6º C, BP 130/92 mmHg, PR 122/min, RR 30/minSpO2 96% (on O2 canula 3 LPM)

• GA: Alert, not pale, no jaundice, no edema, peripheral cyanosis all extremities, delayed capillary refill

• CVS: normal S1S2, no murmurDecrease radial, brachial, posterior tibial and dorsalis pedis pulses bilaterally

• RS: normal breath sounds, no adventitious sounds

Physical examinations

Peripheral pulses Right Left

Femoral arteries 2+ 2+Popliteal arteries - -Dorsalis pedis arteries - -Posterior tibial arteries - -Brachial arteries - -Radial arteries - -

Physical examination

Laboratory and Investigations

• CBC : –Hb 10.9 g/dl, Hct 33.9%, WBC

14,080/μl (N : 89.3%, L : 4.5%, no band form )

• Blood chemistry: –BUN 10.6 Cr 0.9 Na 137, K 4.1,

Cl- 103, HCO-3 18 ( mmol/L )

Laboratory and Investigations

• LFT: –TB/DB = 0.6/0.3, AST 13 , ALT

10, ALP 60 –Albumin/Globulin = 3.8/4.2

• Total calcium = 8.6Phosphorus = 3.8

• Magnesium = 1.6Glucose = 93

• EKG: normal

CXR

Previous History

• Current medication:-Lopinavir/Ritonavir (100/25) 4 tab po bid pc (8am, 8pm.) -Tenofovir (300) 1 tab po OD (8 am.)-Lamivudine (150) 1 tab po bid pc (8am, 8pm.)

• Admit 10 – 16 April 2012Diagnosis:

Adenomyosis with Intramural myoma with left endometriotic cyst Operation:

TAH with bilateral salpingo-oophorectomy Anesthetic technique:

combined spinal block MO with GA

Previous History

• 2 days after the operation headache-Ergotamine (1) 1 tab po 13/4/55, 14/4/55-Paracetamol (500) 1 tab po prn for headache q 4-6 hr

• After discharge she had 1 tab of ergotamine on 16/4/2012

• TOTAL ergotamine : 3 tab……….

Previous History

What was happening to the patient….??

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Ergotism

History of Ergotism

Claviceps purpurea

Ergotism

Protease inhibitor & macrolidesergotamine

metabolism

CYP 3A4

ergotism

Ergotism

peripheral vasospasm and thrombosis

neurologic side effects (headache, psychosis)

alimentary symptoms (nausea, cramping, diarrhea)

Clinical manifestations

Ergotism

Treatment

heparin

calcium channel blockers

prazosin

adrenergic blocker

systemic vasodilator therapy

catheter-based intra-arterial dilation

Garcia G, Goff J, Hadro N, O’Donnell S, Greatorex P. Chronic ergot toxicity: A rare cause of lower extremity ischemia. J Vasc Surg 2000;31: 1245-7.

Progression

day1 day2 day3 day4

• Stop vasoactive drug.• Heparin 3000 u push then 600 u/hr drip.• Sodium nitroprusside1.5mg/hr titrate to 6 mg/hr• Phenobarbital gr 1 was given as enzyme inducer.• Femoral A-line monitored.

Progression

day1 day2 day3 day4

• drowsiness.• Volume overload• K =6.6 Cr 1.4• CPK = 14,310

• Mx : Hemodialysis & ETT

Progression

day1 day2 day3 day4

• Still drowsy.• Off phenobarbetal• Start methylprednisolone

1 mg/kg

Clin Toxicol (Phila). 2008 Dec;46(10):1074-6.Reversal of ergotamine-induced vasospasm following methylprednisolone. Rahman A, Yildiz M, Dadas E, Donder E, Cihangiroglu M, Eken C, Bozdemir MN. Source

Progression

day1 day2 day3 day4

• Not gain conscious.• Volumn overload• K =6.4 Cr 2.3• CPK = 16,490

DEAD

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Take Home Message

Ergot Fatal drug interaction

Anti-migraine drug•Avamigram•Neuramizone

1.Anti-HIV drugSaquinavir, indinavir, nelfinavir, lopinavir, ritonavir, atazanavir, darunavir, efavirenz

Oxytocic drug•Expogin•Methergin

2.Macrolide antibioticsAzithromycin, erythromycin, roxithromycin, midecamycin

Neurodegenerative drug•Hydergine•Hydergine FAS

3.Azole antifungalFluconazole, ketoconazole, itraconazole, miconazole

Fatal drug-drug interaction

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THANK YOU !