Transcript PowerPoint Template

Why is it IMPORTANT…..
Presented by…
Nattawan Sirichuntakul MD.
Mallika Ahuja MD.
Supervisor : Aj. Patipan LOGO
Toomthong
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.
When multiple drug therapies are
prescribed, drug interactions
become an important
consideration for the patient
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 Pharmacological
Basis of Therapeutics, 9th edn. New York: McGraw-Hill, 1996.
GOAL …..
is to decrease toxicity
while maintaining or
increase efficacy
Drugs most likely to pose interaction
problems are those having :
1
A narrow therapeutic index
2
Steep dose–response curve
3
High first-pass metabolism
4
A single, inhibitable route of elimination
•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
Phenytoin
Carbamazepine
Digoxin
Cyclosporin
Warfarin
Lithium
Theophylline
Genetic causes:
Variabiltiy in pharmacokinetics :
Variability in hepatic cytochromes
Circulating enzymes (pseudocholinesterase)
Transporters
Variability in pharmacodynamics :
Alterations in receptors
Malignant hyperthermia : variability in ryanodine receptor
Nongenetic causes :
– Aging
– Disease
– Environment toxins
– Pharmacokinetic,pharmacodynamic of
other drugs
LOGO
1
Pharmaceutical interactions
2
Pharmacodynamic interactions
3
Pharmacokinetic interactions
Chemical or physical reactions that
occur in vitro
Interaction : loss of activity of drugs or for
their aggregation , precipitation in solution
 serious sequences
Chemical deterioration or decomposition
thiopental ( 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
1
Pharmaceutical interactions
Pharmacodynamic interactions
2
3
Pharmacokinetic interactions
Drug
A
Drug
B
opposite
or similar
effects
Change in the patient’s response to the
drug without altering the drug’s
pharmacokinetics
Change in drug action without altering the
plasma concentration
alcohol
opioids
sedatives
synergistic
Hi
A+B
Response
A
B
Lo
Time
The effect of two chemicals is equal to the sum of the effect of
the two chemicals taken separately, eg., aspirin and ibuprofen.
A+B
Hi
Response
A
B
Lo
Time
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
Hi
A+B
Response
A
B
Lo
Time
The effect of two chemicals taken together is less than the sum of
their separate effect at the same doses
May result from one drug changing the
environment necessary for the safe and
effective use of a second drug
loop diuretic
• produces
potassium
wasting
digoxin
• increase
cardiotoxic
effects
1
Pharmaceutical interactions
Pharmacodynamic interactions
2
3
Pharmacokinetic interactions
1
Absorption
2
distribution
3
metabolism
4
elimination
altered by drug-induced alterations in gastrointestinal motility
Delay gastric emptying
increase gastric empting
pH of the gastrointestinal tract
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,resin)
and may be
Cholestyramine
(anion
binding
therapeutically ineffective
Warfarin (Oral anticoagulant)
Plasma warfarin concentration &
Hypoprothrombinemic effect
Robinson D, Benjamin DM, McCormack JJ. Interaction of warfarin and nonsystemic gastrointestinal
drugs. Clin Pharmacol Ther 1971: 12: 491–495.
 -acid
glycoprotein
Basic
drug
Acidic drug
plasma
albumin
inert
DRUG
(less affinity)
plasma protein
DRUG
(high affinity)
Warfarin vs NSAIDs
free concentration
drug(less affinity)
“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.
First-pass metabolism
After oral administration: some drugs are
extensively metabolized by liver before
access to systemic circulation
Propranolol & inhalation
anesthetics & opioids
Hepatic blood flow
Lipid soluble drugs
Biotransformation
More water soluble
metabolites
Excretion
(renal or hepatobiliary)
Extrahepatic microsomal enzymes
(oxidation, conjugation)
Hepatic microsomal enzymes
(oxidation,conjugation)
Hepatic non-microsomal enzymes
(acetylation, sulfation,GSH,
alcohol/aldehyde dehydrogenase,
hydrolysis, oxidation/reduction)
Markey, NIH, 2002
CYP
Enzyme that catalyzes
oxidation -reduction
reaction
CYP450
•Superfamily of
constitutive and
inducible enzymes that
catalyze most phase I
biotransformations
•Peak absorbance
@450nm
CYP3A4
Family of CYP450
one of the most
important enzymes
involved in the
metabolism
CYP 3A4
Specific enzyme
Subfamily
Family
GENE for
mammalian
cytochrome
• CYP Substrates
• CYP Inducers
• CYP Inhibitors
CYP2D6
19%
CYP3A4
40%
CYP2C19
CYP2C9
CYP1A2
CYP2A6
CYP2E1
CYP2B6
Most drugs metabolised by more than one isozyme
Bupivacaine
Lidocaine
Ropivacaine
Alprazolam
Midazolam
Diazepam
Fentanyl
Alfentanil
Sufentanil
Codeine
Methadone
Acetaminophen
CYP3A4
Digitoxin
Verapamil
Diltiazem
Felodipine
Nicardipine
Nifedipine
Warfarin
Anti-HIV drug
(NNRTIs, PIs)
Omeprazole
Pantoprazole
Statins
Cortisol
Anzenbacher P, Anzenbackerová E: Cytochromes P450 and metabolism of xenobiotics. Cell
Mol Life Sci 58:737, 2001
CYP2D6
Captopril
Codeine
Hydrocodone
Metoprolol
Ondansetron
Propranolol
Timolol
CYP2C9
Diclofenac
Ibuprofen
Indomethacin
CYP2C19
Diazepam
Omeprazole
Propranolol
Venkatakrishnan K, von Moltke LL, Greeblatt DJ: Human drug metabolism and the cytochrome
P450: Application and relevance of in vitro models. J Clin Pharmacol 41:1149,2001.
Substrates Inhibitors
Inducers
CYP3A4
Midazolam
Atorvastatin
Felodipine
Ritonavir
Ketoconazole
Grapefruit juice
Rifampin
Carbamazepine
Phenytoin
CYP2D6
Risperidone
Amitryptiline
Codeine
Quinidine
Fluoxetine
Cimetidine
Nil clinically
relevant
CYP1A2
Clozapine
Theophylline
Caffeine
Fluvoxamine
Cimetidine
Ciprofloxacin
Smoking
Omeprazole
Cruciferous veg
Clopidogrel is an inactive
thienopyridine prodrug
CYP3A4
Atorvastatin,
another CYP3A4
substrate
active metabolite.
“ Use of a statin not metabolized by CYP3A4 and point-of-care
platelet function testing may be warranted in patients treated with
clopidogrel.”
Wei C. Lau, MD; Lucy A.et al . Atorvastatin Reduces the Ability of Clopidogrel to Inhibit Platelet Aggregation.
Circulation. 2002;106:r62-r67.
kidney  primary organ for excretion
Other sites  liver, lungs,gastrointestinal
tract, saliva, sweat, tears, and breast milk
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/min
Levophed 2.67 mcg/min
Pain on her finger
Physical examinations
• V/S: T 36.6º C, BP 130/92 mmHg, PR 122/min, RR 30/min
SpO2 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 murmur
Decrease radial, brachial, posterior tibial and dorsalis pedis
pulses bilaterally
• RS: normal breath sounds, no adventitious sounds
Physical examination
Peripheral pulses
Femoral arteries
Popliteal arteries
Dorsalis pedis arteries
Posterior tibial arteries
Brachial arteries
Radial arteries
Right
Left
2+
-
2+
-
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 = 8.6
• Magnesium = 1.6
• EKG: normal
Phosphorus = 3.8
Glucose = 93
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.)
Previous History
• Admit 10 – 16 April 2012
Diagnosis:
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……….
What was happening to the patient….??
Ergotism
LOGO
History of Ergotism
Claviceps purpurea
Ergotism
ergotamine
Protease inhibitor &
macrolides
CYP 3A4
metabolism
ergotism
Ergotism
Clinical manifestations
peripheral vasospasm and thrombosis
neurologic side effects (headache, psychosis)
alimentary symptoms (nausea, cramping, diarrhea)
Ergotism
calcium channel blockers
heparin
catheter-based
intra-arterial dilation
systemic vasodilator
therapy
Treat
ment
prazosin
adrenergic blocker
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
•drowsiness.
•Volume overload
•K =6.6
Cr 1.4
•CPK = 14,310
•Mx : Hemodialysis & ETT
day3
day4
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
Take Home Message
LOGO
Ergot
Anti-migraine drug
Fatal drug interaction
1.Anti-HIV drug
•Avamigram
•Neuramizone
Saquinavir, indinavir, nelfinavir, lopinavir,
ritonavir, atazanavir, darunavir, efavirenz
Oxytocic drug
2.Macrolide antibiotics
•Expogin
•Methergin
Azithromycin, erythromycin,
roxithromycin, midecamycin
Neurodegenerative drug
3.Azole antifungal
•Hydergine
•Hydergine FAS
Fluconazole, ketoconazole, itraconazole,
miconazole
LOGO