Transcript Drug Interactions

Thomas M Penders MD
Associate Professor
Brody School of Medicine
To Err is Human

September, 1999 Institute of Medicine issued report on
preventable medical errors.
Estimated that 50 – 100,000 patients die in hospitals as a
result of errors made by medical care providers.
Economic loss of $17 to 29 billion in costs of care and
lost productivity
Drug-Drug Interactions

Errors in administration of drugs are a significant
portion of this problem.
Excessive dosages
Failure to monitor results of drug administration
Drug-drug interactions – 5% of hospitalizations per
year.

Multiple Drug Overdose

Definition

Clinically significant interaction takes place when the
therapeutic or toxic effects of a medication are altered
by co-administration of another drug.
Increasing pharmacopeia and lengthening life span
make co-administration of drugs commonplace
Particularly notable when drugs have a narrow
therapeutic index e.g. Lithium, Digoxin, tricyclics
Common Examples

CNS depression – additive with multiple sedating
agents – antidepressants and antipsychotics
Interference with or potentiation of drug metabolism
Fluoxetine – Antipsychotics
Tobacco tars & several antipsychotics
Ciprofloxin & clozaril through P450
Drug metabolism 
Pharmacokinetics – What the body does to the drug –
Absorption, bioavailability, metabolism, excretion
Pharmacodynamics – What drug does to the body.
Drugs effect on end organ or receptor site
Pharmacokinetic
Interactions
Interactions due to one drugs
effect on movement

through the body.
Absorption – Gut – pH, food administration
Distribution – Protein binding – free drug is active
e.g. Warfarin
Metabolic – result in change in drug concentration
Excretion – Change in ability to eliminate – e.g.
diuretics and lithium
Steady state

Pharmacodynamic
Interactions

Drugs influence on another drugs effects
Occurs at end organ or receptor site
Most commonly additive effects
e.g. SSRIs and MAOIs
Purpose of Metabolism

Over course of history plants that developed toxins
survived.
Animal developed enzyme systems to detoxify plant
and other toxins
Metabolic enzymes are oxidative – render toxins less
active and prepare for further degradation and
elimination
Red Queen

P450 system

Primary purpose is to metabolize endogenous
compound such as steroids and neuropeptides
Secondary role for enzymes in GI tract and liver is to
detoxify ingested chemicals
Including foods, medicines, smokes or other
environmental exposures
Characteristics of P450

40 enzymes identified in humans
Capable of metabolism of multiple substances
Six enzymes responsible for 90% of drug oxidation
1A2, 3A4, 2C9, 2C19, 2D6 and 2E1.
Metabolism

Most drugs are lipophilic
Lipophilic compounds are difficult to eliminate
Biotransformation to more polar and water soluble
compounds facilitates elimination
Metabolites exit via urine, bile or stool
Sites of Drug
Metabolism
in liver and gut wall.
Most drug metabolism occurs
First-pass effect – Enzymes in endoplasmic reticulum of
gut and liver cells alter most drugs and toxins upon
absorption into hepatic circulation
CYP 3A4 accounts for 70% of intestinal activity
Metabolism proceeds in two phases; phase I oxidation
Phase II - glucuronidation
Phase I metabolism
Addition of small polar groups through oxidative
 O-dealkylination,
mechanisms; N-dealkylination,
hydroxylation, N-oxidation, s-oxidation and
deamination
P450 enzymes contain red-pigmented heme, absorb at
wavelength 450 nm.
Each enzyme is encoded by one gene
Other enzyme systems: Alcohol dehydrogenase,
esterase, amidase and flavin monoxygenase
Variability of drug
response

Inhibition
Induction
Genetic polymorphisms
Enzyme Variability

Inhibition

Drugs metabolized by a common enzyme type will be
competing for sites in the liver endoplasmic reticulum
A drug’s affinity for an enzyme is “inhibitory potential”
Values (Ki) are published from in vitro studies
Drugs with little affinity have high Ki and do not bind
Drugs with low Ki bind and compete for enzyme
Inhibition

Drugs with Ki <2 μM are potent inhibitors
When two drugs are co-administered, the one with
greater affinity (lower Ki) will competetively inhibit
Some drugs inhibit without utilizing the enzyme
Drugs that inhibit lead to elevated serum levels of the
other drug.
Inhibition

Inhibition

Leads to more potent and prolonged pharmacological
effect that might result in drug toxicity.
Inhibition is rapid in onset and in offset upon
discontinuation of blocking agent
Effects of inhibition are rapid in developing and
disappear quickly.
Inhibition
P450 greatly affected by competetive
 inhibition
Ketoconazole has low Ki for 3A4 - PROBES
When co-administered with terfenadine (metabolic
product fexofenadine), leads to elevated levels of
terfenidine
Toxic cardiac arrhythmias result
Terfenidine removed from the market after several
deaths
Induction
Some xenobiotics stimulate
synthesis of P450 enzymes.

With more sites available metabolic activity increases
This may lead to decreases in amount of parent drug
and increased amounts of metabolic product
Co-administration of a potent inducer may result in
decline in serum levels below that required for
therapeutic effect. Carbamazepine induces metabolism
of many antidepressants
Induction

Induction

Drugs utilizing P450 may have increased side effects or
become toxic if active metabolic product increases
Hepatotoxicity of Valproic Acid likely due to such a
mechanism
3A4, 2D6, 1A2, 2C9 2C19 and 2E1 may all be induced
Genetic Polymorphisms

Drug metabolism varies between groups and
individuals
Each individual has two copies of each allele
Most common sequence is “wild type”
Genetic alterations result in minor changes an sequence
affecting enzymatic activity
Metabolizer types

Poor metabolizers – slower biotransformation
Extensive metabolizers – homozygous wild type
transform substrate at rate expected for population
Ultra-extensive metabolizers – transform at a higher
rate than population resulting in reduced levels of drug
at site of action
Population variation in enzyme
activity

Phase II metabolism

Conjugation reactions provide water soluble products
easily excreted
In most cases more than one enzyme is involved in
metabolism of a particular drug
Less likely involved in clinically significant DDI
Result in glucuronidation, sulfation, methylation
Glucuronidation

Most abundant phase II enzymes inlcude uridine 5’diphosphate glucuronyltransferases (UGTs).
Major detoxification system. Most activity in liver
Most drugs go through phase I
Some are directly glucuronidated; lorazepam,
oxazapam and temazepam
UGTs

These benzodiazepines are favored with liver disease
Lamotrigine, valporate, NSAIDs, zidovudine, most
opiates
Methylation

S-adenosylmethionine – SAMe
Used as treatment for depression
Catecol O-Methyltransferase (COMT)
One of two ways that catecholamines are metabolized
(other is monoamine oxidases)
Some CNS drugs are inhibitors of COMT
Phase III - transporters

Located in intestines and liver as well as blood-brain
barrier
SLC transporters – importing transporters
ABC - effluxing transporters
2D6

N-demethylates fluoxetine to norfluoxetine (half life of
up to 16 days with long term use).
For many psychotropics 2D6 is considered a low
capacity, high affinity enzyme
Clears drugs at lower concentrations. When inhibited
processing with flow to 3A4 and 1A2, high capacity,
low affinity enzymes
Drug clearance will be slower and blood levels higher
2D6

Present in brain, bone marrow, gut and liver
Only 2% of all enzyme by concentration
Most action in liver. Plays a major role in degradation
of fluoxatine, tricyclics, most antipsychotics,
methadone, codeine, benztropine, amphetamines,
donepazil
25% of all psychotropics
2D6

Strong Inhibitors: Fluoxetine, Paroxetine, Quinidine
Moderate Inhibitors: Duloxetine, Fluphenazine,
Risperidone, Buproprion
Weak Inhibitors: Venlafaxine, Sertaline, Citalopram
Substrates: Most antidepressants, Most Antipsychotics,
Benztropine, Diphenhydramine, Metprolol
Pro drugs - Codeine
Analgesic effect depends on
conversion to morphine.
Depends on 2D6. Inhibition can result in poorer pain control.
Fluoxetine and Paroxetine are strong inhibitors
Fluoxetine is oxidized to norfluoxetine
Fluoxetine (Ki .22) and norfluoxetine (Ki 1.48) – may require
a 4-8 week washout period before introduction of other 2D6
Metabolized agents
Paroxetine

Potent 2D6 inhibitor (Ki 2.0)
Half life 21 hours, no active metabolites
Fluoxetine and Paroxetine are relative contraindicated
together with drugs that increase QT interval
i.e. tricyclics, phenothiazines, some second generation
antipsychotics
Other Drugs

Ritanovir – potent 2D6 inhibitor (Ki .16)
Also inhibits most other enzymes
2D6 is induced in pregnancy
Not a lot of evidence of drug induction of 2D6
Tamoxifen
Used to treat estrogen receptor
 positive beast cancer.
Active metabolite, endoxefen, has 10 to 100X the
affinity to estrogen receptor.
Breast cancer survivors suffer depression and hot
flashes frequently treated with SSRIs
Woman on Tamoxifen plus fluoxetine, paroxetine and
sertriline have relapse rate of 16% compared to usual
rate of 7.5%.
Tamoxifen

2D6 genetics
Wild type exists in 90%, PMs in about 8% of caucasians

Asians have 1% PMs. Northern African populations have
high prevalence of UEMs (29% Ethiopians)
Over 100 SNPs for 2D6 gene identified.
Those with greater potency as enzymes has side effects
To codeine (nausea), Tamoxifen (hot flashes) and other
agents.
Star D suggested ultra rapid metabolizers may fail to
respond to some SSRIs.
3A4

Accounts for 30% of P450 activity in liver and 70% in gut
Performs the bulk of oxidative metabolism of drugs
Phase I metabolism of endogenous and exogenous
compounds including hydroxylation, demethylation and
dealkylation
Metabolism of endogenous steroids, cholesterol and lipids
Including oral contraceptives
Genetic variability

50 variations identified
High activity variants seen require increased doses of
drugs metabolized by 3A4
Poor metabolism alleles are likely incompatible with
life
Inhibitors

Strong inhibitors increase plasma levels of substrate 3
to 5 times.
Nefazodone, ketoconazole, grapefruit juice
Some drugs affected by 3A4 inhibition; fentanyl,
quinidine, pimozide
Deaths prompted contraindication of pimozide with
any azole antifungals, macrolide antibiotic or protease
inhibitor
Benzodiazepines

Alprazolam, midazolam, triazolam depend on 3A4
50% dose reduction recommended for alprazolam
75% reduction of triazolam when administered with
nefazodone.
Buspirone levels enhanced with 3A4 blockers i.e.
Erythromycin, efaverenze
Grapefruit juice

Furanocoumarins inhibit 3A4
6-8 ounces of Grapefruit juice taken with a 3A4
substrate will significantly increase blood levels
Drug sparing and augmentation – cimetidine and
Clozaril
Inducers

Carbamazepine – induces its own metabolism
Also Topiramate, Methylprednisone, modafanil,
prednisone and St. John’s Wort
May lead to lower levels of oral contraceptives
2C9

A main metabolic pathway for oral hypoglycemics and
NSAIDS. Substrates include Phentoin, Warfarin,
modafanil
10 % of caucasians are 2C9 poor metabolizers (these
polymorphs rare in African Americans or Asians
Valproate is an inhibitor of 2C9 and may lead to
increased levels of substrates
2C19
Polymorphs common; Asians have high prevalence of

poor metabolizers
Most proton pump inhibitors metabolized by this
pathway
Citalopram, Escitaloprem, Sertaline, diazepam levels
are increased in populations who have poor
metabolism
Fluoxetine is a potent inhibitor
2C19

Overall 14% of population are PMs
Clopidogrel (Plavix) is a pro-drug metabolized by 2C19
Inhibitors (proton pump inhibitors, antidepressants)
Reduce effectiveness i.e. reinfarction rate with
concomiant use
Ampli-Chip

Several services now available to provide a profile of
P450 activity
Roche’s Amplichip Gene Test approved by FDA to
confirm genotypes for 2D6 and 2C19. Cost $600.00
This test only provides genotyping, an approximation
of the phenotype
1A2
Enzyme important in the 
metabolism of many
xenobiotics including polycyclic hydrocarbons found in
cigarette smoke
Linked to carcinogenesis
Major enzyme in oxidation of melatonin and
methylxanthines: caffeine and theophylline
Expressed in liver, codon on chromosome 15
1A2
About 20 variations known,
mostly rare.
SNPs involved with inducibility of enzyme
One SNP associated with susceptibility to Tardive
Dyskinesia. Same SNIP (1a2*F) associated with
increased QT with antipsychotics
Relationship between caffeine metabolism and plasma
concentrations of olanzapine and clozapine
1A2

Fluvoxamine is a potent inhibitor and may increase
clozapine levels tenfold
Ciprofloxin increases clozapine levels threefold
Estrogen containing oral contraceptives or replacement
hormones moderately inhibit 1A2 leading to toxicities
with use of caffeine, clozapine and haldol.
1A2
1A2 induced by hydrocarbons in cigarette smoke.

1A2 induction increases clearance of many
antipsychotic drugs: clozapine and olanzapine
Smoking cessation in schizophrenic patients leads to
elevated blood levels of substrate
Alternately stabilization of schizophrenic symptoms on
a smoke free inpatient unit leads to increased clearance,
declining blood levels and relapse upon resumption of
smoking
1A2

Other inducers of 1A2 include brussel sprouts, broccoli
and cabbage, charcoal grilling
Heavy exercise will induce as potently as heavy
cigarette smoking.
2E1
Unique enzyme with limited
but important substrates.
Inactivation of industrial solvents, acetaminophen
hepatotoxicity, activator of chemical carcinogenesis and
producer of free radicals causing cytotoxicity and tissue
damage
Role in metabolism of alcohol
Anesthetics
2E1
Inhibitors include acute alcohol, isoniazid, disulfram,

watercress
Chronic alcohol use increases enzyme activity 10 fold
Uncontrolled diabetes, obesity, smoking (including
marijuana) may result in induction
Organic compounds are metabolized to compounds
which are carcinogenic. Increase 2E1 associated with
increased cancer risk
2E1
Acetaminophen is metabolized by glucuronadation.

When glucuronide is overwhelmed (i.e. overdose) it is
metabolized by 2E1.
The metabolic product of this interaction (NAPQI) is
hepatotoxic.
Situations where glutathione levels are reduced or 2E1
(smoking, opiate consumption, HIV, Hepatitis C) carry
Higher risk for acetaminophen hapatotoxicity
Renal Clearance

Drugs or active metabolites cleared primarily by renal
excretion:
Lithium Carbonate – thiazides increase levels
Excretion enhanced by xanthines (Caffeine, theobromine)
Gabapentin – Excreted unchanged in urine with no known
interactions involving elimination
Board Questions 1
 is true in regard to
Which of the following statements
venlafaxine?
A.
B.
C.
D.
It is highly protein bound
It is unlikely to inhibit cytochrome P450 enzymes
It has a flat dose-response curve
It is not FDA approved for generalized anxiety
disorder (GAD)
E. It has a high risk of inducing hypertension at low
doses
B.
Board Questions 2

A 68 year old man with bipolar I disorder has done well
on lithium. His most recent blood level was 0.8 mEq/L.
He has a variety of medical problems. He now presents
with pressured speech, racing thoughts and insomnia.
Serum lithium level is now 0.3 mEq/L. Wife noted
changes about two weeks after addition of a new
medication. You are confident of adherence to lithium
regimen.
What class of drug was added to his regimen?
Board Questions 2

A.
B.
C.
D.
E.
E
ACE inhibitor
Beta blocker
NSAID
Thiazide diuretic
Xanthine bronchodilator
Board Question 3

A 27 year old patient announces she is pregnant despite
having taken an oral contraceptive for 4 years. Which of
the following four medications might account for
failure of oral contraceptives?
A. Lithium
B. Divalproex
C. Carbamazepine
D. Lamotrigine
E. Gabapentin
C
Board Question 4

Which of the following will double blood levels of
lamotrigine?
A.
B.
C.
D.
B
Carbamazepine
Divalproex
Phentoin
Phenobarbital
Board Question 5

A 38 year-old woman with a history of estrogen
receptor positive breast cancer is currently taking
tamoxifen. She has recently become tearful, withdrawn
and anergic. She notes difficulty with sleep and hot
flashes since initiation of tamoxifen. Which of the
following is the most appropriate agent to use to treat
her depressive symptoms?
Board Question 5

A.
B.
C.
D.
E.
B
Venlafaxine
Paroxetine
Gabapentin
Fluoxetine
Duloxetine