effects 9035673 9035673 9035673 9035673.ppt

effects

1. LOGO
Drug Interaction…
Why is it IMPORTANT…..
Supervisor : Aj. Patipan Toomthong
Presented by…
Nattawan Sirichuntakul MD.
Mallika Ahuja MD.

2. 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.

3. 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.

4. GOAL …..
is to decrease toxicity
while maintaining or
increase efficacy
Why combine drugs?

5. A narrow therapeutic index
1
Steep dose–response curve
2
High first-pass metabolism
3
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.

6.  
Phenobarbitone Digoxin
Warfarin
Phenytoin Cyclosporin
Lithium
Carbamazepine Theophylline
Some drugs with
a low therapeutic index

7. 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

8. –Aging
–Disease
–Environment toxins
–Pharmacokinetic,pharmacodynamic of
other drugs
Nongenetic causes :
Variability in drug response

9. LOGO
MECHANISMS OF
DRUG INTERACTIONS

10. 1
Pharmaceutical interactions
2
Pharmacodynamic interactions
3
Pharmacokinetic interactions
Mechanism of drug interactions

11. 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 decomposition
thiopental ( powder VS addition of water)
cathecholamines ( decomposed by light)

12. 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

13. 1 Pharmaceutical interactions
2 Pharmacodynamic interactions
3 Pharmacokinetic interactions
Mechanism of drug interactions

14. 2.Pharmacodynamic interactions
opposite
or similar
effects
Drug
B
Drug
A

15. 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

16. 2.Pharmacodynamic interactions
synergistic
sedatives
alcohol
opioids

17. 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

18. 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

19. 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

20. 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

21. 1 Pharmaceutical interactions
2 Pharmacodynamic interactions
3 Pharmacokinetic interactions
Mechanism of drug interactions

22. Absorption
1
distribution
2
metabolism
3
elimination
4
3.Pharmacokinetic interactions

23. 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

24. pH of the gastrointestinal tract
3.1 Absorption
Weak acids
acidic environment
weak bases
basic environment
more absorbable
more absorbable

25. 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

26. 3.2 Distribution
inert
Acidic drug
plasma
albumin
Basic
drug

-acid
glycoprotein

27. DRUG
(less affinity)
DRUG
(high affinity)
free concentration
drug(less affinity)
plasma protein
3.2 Distribution
Warfarin vs NSAIDs

28. “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.”

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

30. 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

31. Lipid soluble drugs
More water soluble
metabolites
Excretion
(renal or hepatobiliary)
Biotransformation
Biotransformation

32. 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

33. What is cytochrome(CYP) ?

34. •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)

35. CYP
3A4
GENE for
mammalian
cytochrome
Family
Subfamily
Specific enzyme
• CYP Substrates
• CYP Inducers
• CYP Inhibitors
Cytochrome P450
Nomenclature

36. Proportion of drugs metabolised
by CYP450 isozymes
CYP3A4
40%
CYP2E1
CYP2B6
CYP2A6
CYP1A2
CYP2D6
19%
CYP2C9
CYP2C19
Most drugs metabolised by more than one isozyme

37. Drug Interactions (Liver)
CYP Substrate
CYP Inhibitor
 Substrate
concentration
 Toxicity
CYP Substrate
CYP Inducer
 Substrate
concentration
 Efficacy

38. 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

39. CYP2D6 CYP2C19
Captopril
Codeine
Hydrocodone
Metoprolol
Ondansetron
Propranolol
Timolol
Diclofenac
Ibuprofen
Indomethacin
Diazepam
Omeprazole
Propranolol
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.

40. SubstratesInhibitorsInducers
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
Examples of CYP 450
Substrates, Inhibitors & Inducers

41. 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.
CYP3A4
Atorvastatin,
another CYP3A4
substrate

42. 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

43. Why do we have to know????

44. 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

45. •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 examinations

46. Peripheral pulses Right
Left
Femoral arteries 2+ 2+
Popliteal arteries - -
Dorsalis pedis arteries - -
Posterior tibial arteries - -
Brachial arteries - -
Radial arteries - -
Physical examination

47. 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 )

48. 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
Phosphorus = 3.8
•Magnesium = 1.6
Glucose = 93
•EKG: normal

49. CXR

50. 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.)

51. •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

52. •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….??

53. LOGO
Ergotism

54. History of Ergotism
Claviceps purpurea

55. Ergotism
Protease inhibitor &
macrolides
ergotamine
metabolism
CYP 3A4
ergotism

56. Ergotism
peripheral vasospasm and thrombosis
neurologic side effects (headache, psychosis)
alimentary symptoms (nausea, cramping, diarrhea)
Clinical manifestations

57. Ergotism
Treat
ment
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.

58. 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.

59. Progression
day1 day2 day3 day4
•drowsiness.
•Volume overload
•K =6.6 Cr 1.4
•CPK = 14,310
•Mx : Hemodialysis & ETT

60. 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

61. Progression
day1 day2 day3 day4
•Not gain conscious.
•Volumn overload
•K =6.4 Cr 2.3
•CPK = 16,490
DEAD

62. LOGO
Take Home Message

63. Ergot Fatal drug interaction
Anti-migraine drug
•Avamigram
•Neuramizone
1.Anti-HIV drug
Saquinavir, indinavir, nelfinavir, lopinavir,
ritonavir, atazanavir, darunavir, efavirenz
Oxytocic drug
•Expogin
•Methergin
2.Macrolide antibiotics
Azithromycin, erythromycin,
roxithromycin, midecamycin
Neurodegenerative drug
•Hydergine
•Hydergine FAS
3.Azole antifungal
Fluconazole, ketoconazole, itraconazole,
miconazole
Fatal drug-drug interaction

64. LOGO
THANK YOU !