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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 !