DRUG INTERACTIONS

dr. Kinanti Narulita D, M.Si

DEPARTMENT OF PHARMACOLOGY
FACULTY OF MEDICINE UNISSULA
 INTRODUCTION
Drug interactions were once thought to represent an
insidious threat to public health.
Although initial estimates predicted huge numbers of
dangerous drug interactions, in practice they do not
appear to be as menacing as they once appeared.
RISK FACTORS FOR DRUG
INTERACTIONS
High Risk Patients
Elderly, young, very sick, multiple disease
Multiple drug therapy
Renal, liver impairment
High Risk Drugs
Narrow therapeutic index drugs
Recognised enzyme inhibitors or inducers
 SOME DRUGS WITH
A LOW THERAPEUTIC INDEX

Lithium Digoxin

Carbamazepine Cyclosporin

Phenytoin Phenobarbitone

Theophylline / Warfarin
Aminophylline
PHARMACEUTICAL
INTERACTIONS
PHARMACEUTICAL INTERACTIONS =
DRUGS INCOMPATIBILITY
Interactions that occur prior to systemic administration.
For example incompatibility between two drugs mixed in
an IV fluid. These interactions can be physical (e.g. with a
visible precipitate) or chemical with no visible sign of a
problem.
PHARMACODYNAMIC DRUG
INTERACTIONS
 PHARMACODYNAMIC DRUG
INTERACTIONS
A measurable modification (in magnitude or duration) of the action
of one drug by prior or concomitant administration of another
substance.
Drug-drug (Rx, OTC, herbal)
Drug-food, drug-alcohol
Drug-lab, drug-disease, drug-chemical
One drug causes a change in patient response to another drug
without altering that drugs pharmacokinetics.
Pharmacodynamic drug interactions can be : additive, supra-
additive (synergistic), potentiation, and antagonistic.
A. INTERACTIONS BASED ON ADDITIVE EFFECTS

ADDITIVE
Additive interaction describes the algebraic summing of the effects of 2
drugs. The 2 drugs may or may not act on the same receptor to
produce such effects. Examples :
Patient with moderate to severe hypertension maintained on one
drug is at risk of excessive lowering of blood pressure if another drug
with a different site of action is added at high dosage.
The additive depression of CNS function caused by concomitant
administration of hypnotics sedatives (benzodiazepine) and
opioids with each other or associated with the consumption of
ethanol.
A. INTERACTIONS BASED ON ADDITIVE EFFECTS

Beta blocker (propranolol) with calcium channel blocker

(nifedipine) A-V conduction disturbances and sinus bradycardia
heart block. Mnemonic : propranolol > atenolol > metoprolol
Additive effects of anticoagulant drugs (warfarin) is enhanced by
aspirin (via an antiplatelet action), thrombolytics (via plasminogen
activation), and the thyroid hormones (via enhanced clotting factor
catabolism) can lead to bleeding complications.
Addictive effects of MAOI & decongestan stimulate NE risk of
hypertension.
 A. INTERACTIONS BASED ON ADDITIVE EFFECTS

SUPRA-ADDITIVE (SYNERGISTIC)
Occur when the result of interaction is greater than the sum of the drugs used alone.
The best example is the therapeutic synergism of certain antibiotic combinations
such as sulfonamides and dihydrofolic acid reductase inhibitors (trimethoprim).
Codein with paracetamol to increase analgesic effect.

POTENTIATION
Occur when a drugs effect is increased by another agent that has no such effect.
The best example of this type of interaction is the therapeutic interaction of -
lactamase inhibitors such as clavulanic acid with -lactamase susceptible
penicillins. Clavulanic acid with amoxicillin in order to overcome bacterial
resistance to the antibiotic.
B. INTERACTIONS BASED ON OPPOSING ACTIONS
Antagonism, the simplest type of drug interaction, is often predictable.
For example :
Bronchodilating effects of 2-adrenoceptor activators used in asthma
is to be anticipated if a blocker is given for another condition.
Some drug antagonisms do not appear to be based on receptor
interactions. NSAIDs may decrease the antihypertensive action of
angiotensin-converting enzyme (ACE) inhibitors by reducing renal
elimination of sodium. Dexamethasone increase blood glucose and
glibenclamide decrease it.
The action of a catecholamine
on heart rate (via -
adrenoceptor activation) is
antagonized by an inhibitor of
acetylcholinesterase that acts
through acetylcholine (via
muscarinic receptors).
 SISTEM SARAF OTONOM
TEMPAT TONUS PALING DOMINAN
Arterioles1 Sympathetic (adrenergic)
Veins1 Sympathetic (adrenergic)
Heart Parasympathetic
Radial muscle of the iris Sympathetic ( adrenergic)
Sphincter muscle of the iris Parasympathetic
Ciliary muscle of the eye Parasympathetic
Mllers muscle Sympathetic ( adrenergic)
Bronchial smooth muscle Parasympathetic
Gastrointestinal tract Parasympathetic
Urinary tract Parasympathetic
Salivary glands Parasympathetic
Eccrine sweat glands Sympathetic (cholinergic)
Apocrine sweat glands Sympathetic ( adrenergic)
Pilomotor muscles Sympathetic ( adrenergic)
Adapted from Goodman and Gilmans The Pharmacological Basis of Therapeutics
1The
vast majority of blood vessels do not receive parasympathetic innervation
 PHARMACOKINETIC
DRUG INTERACTIONS
 Pharmacokinetic drug interactions

1. Drug absorption 2. Drug distribution

Gastric motility Ratio of Blood flow to tissue mass
Gastric pH Competition of Protein binding
First Pass metabolism Body mass index
Hepatic blood flow Adiposity

3. Drug metabolism
Induction of drug metabolism enzymes 4. Drug excretion
Inhibition of drug metabolism enzymes
Enhanced or diminished diuresis
Altered urinary pH

Handbook of Drug Interaction,

A.Wayne Jones,2012)
PHARMACOKINETIC DRUG NTERACTIONS

One drug alters the rate or extent of ADME (absorption,

distribution, metabolism or excretion) of another drug.
A change in blood concentration causes a change in the drugs
effect.
 IMPROVING AWARENESS OF
DRUG INTERACTIONS
The frightening thing about drug interactions is the daunting
number of potential interactions. This is most readily confronted
by looking at a pivot table. Constructing a pivot table can present
a daunting variety of potential drug interactions.
Medications in pivot table are listed A to Z on the y axis, and Z to A
on the x axis.
Because of the vast number of potential drug interactions new
ones are being discovered every day but only if one listens
carefully to patientss descriptions of adverse reactions that they
have experienced after adding a new drug to their regimen.
 MEDICATIONS FOR THIS LECTURE
FAMOUS INTERACTIONS

Aspirin Nifedipine
Cimetidine Phenytoin
Digoxin Propranolol
Erythromycin Terfenadine
Fluconazole Tetracycline
Iron Warfarin
 PIVOT TABLE
war tet ter pro phe nif iro flu ery dig cim asp
Aspirin
Cimetidine
Digoxin
Erythromycin
Fluconazole
Iron
Nifedipine
Phenytoin
Propranolol
Terfenadine
Tetracycline
Warfarin
Fortunately since an interaction between drug A and drug B is the same as the
interaction between drug B and drug A, the table can be cut diagonally in half.

war tet ter pro phe nif iro flu ery dig cim asp

Aspirin
Cimetidine
Digoxin
Erythromycin
Fluconazole
Iron
Nifedipine
Phenytoin
Propranolol
Terfenadine
Tetracycline
Warfarin
Next, one eliminates the overdose line the diagonal that represents a drug interacting with itself,
and one is left with a neat chart of boxes which can contain potential drug interactions. Although
there is frequently more than one kind of drug interaction between any two given drugs, there is
usually one interaction that predominates.
war tet ter pro phe nif iro flu ery dig cim
Aspirin
Cimetidine
Digoxin
Erythromycin
Fluconazole
Iron
Nifedipine
Phenytoin
Propranolol
Terfenadine
Tetracycline
 ABSORPTION

a. Chelation : Divalent cations such as calcium or iron can bind to

certain medications and prevent their absorption.
Ex : iron with tetracycline : tetracycline inhibits iron absorption.
b. Absorption pH : Weak acids need to be absorbed at a low pH.
Raising the pH with antacid medication considerably hinders
absorption.
- Iron with cimetidine
- Aspirin with cimetidine
 ABSORPTION
Drug Acids Absorption
@ pH=1 @ pH=8
Salicylic Acid 61% 13%
Thiopental 46% 34%

Drug Bases
Aniline 6% 56%
Quinine 0% 18%
ALTERED ABSORPTION (AVAILABILITY)

Change in gastrointestinal pH : ketoconazole needs acidic

conditions in gut
Drug binding in GI tract : e.g. tetracycline and calcium
Change in gastrointestinal flora : antibiotics with oral
contraceptive
Change in gastrointestinal motility : metoclopramide and digoxin
Malabsorption caused by other drugs : orlistat and fat soluble
vitamins
 PIVOT TABLE
war tet ter pro phe nif iro flu ery dig cim
Aspirin
A
Cimetidine A
Digoxin
Erythromycin
Fluconazole
Iron A
Nifedipine
Phenytoin
Propranolol
Terfenadine
Tetracycline
 Divalent cations (such as calcium, iron, and magnesium) all bind
numerous medications (notably tetracycline, digoxin and
ciprofloxacin). The way to avoid the interaction with calcium is to
dose the medications at different times.
Although interactions with calcium and magnesium have not been
documented, it would be wise to anticipate this interaction and
avoid dosing these medications together.
 DIVALENT CATIONS
war tet ter pro phe nif iro ca ma flu ery dig cim
Aspirin T ? A
Cimetidine M M M A M M ?
Digoxin A M ? E
Erythromycin M M M
Fluconazole M M M M
Iron
A
Calcium ? T ?
Magnesium
Nifedipine M
Phenytoin M
Propranolol ? M
Terfenadine
Tetracycline
Anti Transporters P-Glycoprotein (Pgp)
ATP-dependent drug efflux pump pada apikal
Substrate for Pgp :
Digoxin, quinadine, anti cancer, bilirubin,
immunosupressive, glucocorticoid, HIV-1 protease
inhibitor, dll
Coded by MDR-1 gene (ABCB1) :
Diinduksi oleh rifampin
Diinhibisi oleh verapamil, quinidine, cyclosporine,
ketonocazole, itraconazole, erythromycin,
azithromycin
Ekspresi pada beberapa sel spt :
Intestine : mempengaruhi absorpsi
Liver : mempengaruhi biotransformasi
Kidney : mempengaruhi ekskresi obat
Brain : mempengaruhi distribusi obat
Examples of Transporter Inhibitors and
Inducers
 Digoxin + P-gp inhibitor (quinidine, itraconazole, atorvastatin)
kadar digoxin dalam darah meningkat

Digoxin + P-gp inducer (rifampin) kadar digoxin dalam darah

menurun

Rosuvastatin + cyclosporine A kadar rosuvastatin dalam

darah meningkat

Ketoconazole + fexofenadine kadar fexofenadine dalam darah

meningkat

Erythromycin + fexofenadine kadar fexofenadine dalam darah

meningkat
 DISTRIBUTION

One large group of potential drug interactions that are seldom

clinically important consists of drugs that displace one another
from binding sites on plasma albumin (acid frugs) or -1 acid
glycoprotein (AAG) (base drugs) or within tissues.
The displacing drug will increase the effects of the displaced
drug by increasing its free (unbound) concentration is seldom
evident in clinical practice.
Disease state can change the number and affinity of binding proteins

Albumin :
Cirrhosis
Burns
Renal failure
Pregnancy

Alpha-1-Acid glycoprotein :
Surgery
Myocardial infarction
Crohns disease
Arthritis
PROTEIN BINDING DRUG DISPLACEMENT

Drug B PLASMA TISSUE

Drug A
protein bound

Drug A Drug A
free free

Drugs A and B both bind to the same plasma protein

When a second displacing drug is commenced, the free concentration of the first
drug rises.
 42

Class IA antiarrhythmic : quinidine

Displacement may occur if :
the drug (e. g. warfarin) is highly protein-bound; and
the displacer (e. g. salicylic acid) occupies most of the binding site.
KRITERIA OBAT PENDESAK (DISPLACER)

Asam organik
Afinitas terhadap albumin sangat kuat
Harga Vd kecil (mendekati volume plasma)
Kadar terapi dalam darah = 150mg/ml, BM:250
Kadar dalam plasma mendekati atau lebih besar dari 0.06 mM
 Sebelum Setelah Prosen
Obat Pendesakan Pendesakan kenaikan

Obat A
% drug bound 95 90
% drug free 5 10 + 100
Obat A
% drug bound 50 45
% drug free 50 55 + 10
 DISTRIBUTION

NSAID : phenylbutazone displaces warfarin from binding

sites on albumin excessive anti coagulation.
NSAID : indometacin displaces warfarin from binding sites
on albumin bleeding and interfering with platelet function.
Quinidine displaces digoxin from tissue binding sites, and
can cause digoxin toxicity.
 war tet ter pro phe nif iro flu ery dig cim
Aspirin
D A
Cimetidine
M A M
Digoxin
Erythromycin
M M
Fluconazole
Iron A
Nifedipine T
Phenytoin
Propranolol
Terfenadine
Tetracycline
 METABOLISM

Metabolism refers to the processing of medications after they

are absorbed. Most of these interactions inactivate
medications and prepare them for elimination. Most of these
occur in the liver. Most of the metabolic interactions are
mediated by the CYP enzymes.
 METABOLISM
Phase 1 (usually inactivated)
CYP Enzymes
Oxidation
Reduction
Dealkylation
Hydrolysis
Phase 2 (ear-marked for destruction)
Conjugation
Glucuronidation
Sulfation
Methylation
Acetylation
 DRUG METABOLISM
Active Drug to Inactive Metabolite
hydroxylation
Phenobarbital Hydroxyphenobarbital

Active Drug to Active Metabolite

acetylation
Procainamide N-acetylprocainamide

Inactive Drug to Active Metabolite

demethylation
Codeine Morphine

Active Drug to Reactive Metabolite

Acetaminophen Reactive metabolite
CYP450 NOMENCLATURE

Family

CYP2D6
Sub-Family Individual Gene
 WHERE ARE THESE ENZYMES ?

Most cells
Predominantly in endoplasmic reticulum of hepatocytes
Also present in gut wall
Kidney lungs and brain
Liver is main site of drug metabolism
 ENZYME CHARACTERISTICS GENETIC
POLYMORPHISM
CY2D6
PM : 5-10% Caucasians, <1% Asians (also super-fast metabolizers)
CYP2C9
PM : 1-3% Caucasians
CY2C19
PM : 3-5% Caucasians, 15-20% Asians
 CYP ENZYMES IN DRUG METABOLISM

Substrates Inhibitors Inducers

Cyp1A2 Warfarin Cimetidine Phenytoin
Cyp2B6 Bupropion Thiotepa Rifampin
Cyp2C9 Phenytoin Isoniazid Rifampin
Cyp2C19 Diazepam Ketoconazole N/A
Cyp2D6 Metoprolol Cimetidine N/A
Cyp2E1 Ethanol Disulfiram INH
Cyp3A4,5,7 Terfenadine Erythromycin Phenytoin

(and everything!)
 CYP 450 SYSTEM DEFINITIONS

Substrate :
Drug is metabolised by the enzyme system.

Inducer :
Drug that will increase the synthesis of CYP450 enzymes.

Inhibitor :
Drug that will decrease the metabolism of a substrate.
SOME ENZYME INDUCERS
Barbiturates : phenobarbitone (3A) St Johns Wort (3A)
Carbamazepine (2C19, 3A) Ethanol (2E1)
Phenytoin (3A) Troglitazone (3A)
Rifampicin (2C19, 2C9, 3A) Tobacco (1A2)
Cigarette smoke Omeprazole (1A2)
Nevirapine (3A)

Mnemonic: carb, barb, pheny, and rif

 ENZYME INHIBITION
Often rapid, reversible and relatively short acting. E.g. erythromycin
and cyclosporin. Erythromycin is a substrate and an inhibitor of
CYP 3A4.
May be prolonged due to long half - life of drug. E.g. amiodarone
and S-Warfarin. Amiodarone is an inhibitor of CYP2C9 but not a
substrate for this CYP.
Amitriptylline is metabolized by CYP1A2. Cimetidine inhibits
CYP1A2. Coadministration results in elevated Amitriptylline levels.
Ranitidine inhibits CYP1A2 BUT to a much lesser degree (lower
Ki).
 POTENT INHIBITORS

Fluoroquinolones (ie: ciprofloxacin)

H2Blockers (ie: most notably cimetidine)
Imidazoles (ie fluconazole)
INH
Ritonavir

Mnemonic: cip, cim, con, INH, and rit

 H1 BLOCKERS
H1 Blockers (terfenadine) is extensively (99%) metabolized by
CYP3A4 to an active acid metabolite (terfenadine
carboxylate), surprisingly toxic when their metabolism is
inhibited. And they are usually inhibited by medications that
seem relatively benign : ketoconazole, itraconazole,
erythromycin, and troleandomycin; and liver dysfunction.
Terfenadine and astemizole were so bad that they were
removed from the market. Loratadine fortunately turns out to
be relatively benign.
Mnemonic : ter>ast>lor
secondary to the blockade of cardiac potassium channels
 H2 BLOCKERS

H2 Blockers follow the same rules as H1 Blockers; Cimetidine

is the most potent inhibitor, ranitidine to a lesser degree, and
famotidine slightly lesser. Mnemonic : cim>ran>fam.
 MACROLIDES

Macrolide antibiotics are aggressively metabolized by CYP3A4

with the exception of azithromycin which is metabolized by a
different mechanism. Clarithromycin is one of the most potent
utilizers of CYP3A4 and entertains vast potential for
competitive inhibition with many other medications.
Mnemonic: clar>ery>azith
 ANTIFUNGALS

Antifungals of the imidazole class are metabolized with

varying affinities for the CYP enzymes. Fluconazole turns out
to be one of the more benign medications whereas
ketoconazole is a very potent inhibitor of CYP3A4.
Mnemonic: keto>itra>flu
 METABOLISM
war tet ter pro phe nif iro flu ery dig cim
Aspirin A
Cimetidine M AM
Digoxin
Erythromycin
M M
Fluconazole
Iron A
Nifedipine
Phenytoin
Propranolol
Terfenadine
Tetracycline
 METABOLISM
war tet ter ast lor pro phe nif iro flu ery dig cim
Aspirin
T ? A
Cimetidine
M M MAM M ?
Digoxin
A M ? E
Erythromycin
M M M M
Fluconazole
M M MM
Iron A
Nifedipine
T ?
Phenytoin MM
Propranolol ? M M
Terfenadine
Astemizole
Loratadine
Tetracycline
 EXCRETION / ELIMINATION
Drug A increases or reduces the excretion (usually renal) of Drug
B.
Blood levels of B fall below becomes ineffective; or rise above
normal therapeutic range becomes toxic.
Excretion interactions :
Mechanisms of urinary excretion :
- Simple filtration
- Active secretion
Mechanisms for active secretion :
- Acids
- Bases
 ELIMINATION

Certain medications can compete for excretion :

Digoxin with erythromycin effect of clarithromycin on renal
excretion of digoxin; interaction with P-glycoprotein. Although this
report was regarding clarithromycin, the caution was extended to all
macrolides. Erythromycin inactivate P-glycoprotein inhibit digoxin
excretion in to tubule tubulus
The classic elimination interaction is penicillin with probenecid which
inhibit penicillin excretion enables prolonged effects from single
doses of penicillin.
 EXCRETION INTERACTIONS

Active secretion mechanisms have limited capacity. e.g. One acid

drug may saturate the acid drug active secretion mechanism.
Another acid drug will then be secreted less efficiently.
Excretion Interaction Lithium + Thiazides. Probable Mechanism :
Thiazides cause diuresis and initial sodium loss
hiponatremia reabsorb more lithium along with sodium;
hipernatremia excrete more lithium and need higher doses.
 EXCRETION INTERACTION
CHANGE IN RENAL BLOOD FLOW

Methotrexate and NSAIDs :

Reduced clearance of MTX and active (toxic) metabolite
NSAIDS can decrease renal blood flow by inhibition of renal
prostaglandins
 Adverse Effects Associated with NSAIDs on Renal Function

Afferent Efferent
arteriole arteriole
normal PGs not participated
NSAIDS,
Low volume
Poor renal PGs vasodilator when angiotensin
perfusion II or catercholamines elevated

ACEI/ ARB
 ELIMINATION
war tet ter pro phe nif iro flu ery dig cim
Aspirin
T A
Cimetidine M AM
Digoxin
E
Erythromycin
M M
Fluconazole
Iron A
Nifedipine T
Phenytoin
Propranolol
Terfenadine
Tetracycline
 CONCLUSION
Examining medications encourages careful review of
medications
Famous interactions should be memorized and form the basis of
a broader understanding of drug interactions in general
Grouping medications allows one to extrapolate known data to a
certain extent across a drug groups
Hearing patients complaints can help alert the physician to
identifying previously unreported reactions
 DRUG-NUTRIENT/FOOD INTERACTION

Drug-nutrient interaction : the result of the action between a drug

and a nutrient that would not happen with the nutrient or the drug
alone
Food-drug interaction : a broad term that includes drug-nutrient
interactions and the effect of a medication on nutritional status
Patients at Risk for Food-Nutrient Interactions

Patient with chronic disease

Elderly
Fetus
Infant
Pregnant woman
Malnourished patient
Allergies or intolerances
 Food and Drug-Related Risk Factors
Special diets
Nutritional supplements
Tube feeding
Herbal or phytonutrient products
Alcohol intake
Polypharmacy
Drugs of abuse
Non-nutrients in foods
Excipients in drugs or food
 Malnutrition Effect on Drugs
Low albumin levels can make drugs more potent by increasing
availability to tissues.
Lower doses often recommended for persons with low albumin
Warfarinand phenytoin are highly protein bound in blood;
albumin can result in poor seizure control (phenytoin) or
hemorrhage (warfarin)
Body composition : obese or elderly persons have a higher ratio
of adipose tissue; fat soluble drugs may accumulate in the body
risk of toxicity.
 Food / Nutrient Effects on Drugs
Absorption
Presence of food and nutrients in intestinal tract may affect
absorption of drug

Metabolism
Changes in diet may alter drug action
Theophylline : a high protein, low CHO diet can enhance clearance of
this and other drugs
Grapefruit / juice : inhibits the intestinal metabolism (CYP 450 3A4
enzyme) of numerous drugs (calcium channel blockers, HMG CoA
inhibitors, anti-anxiety agents) enhancing their effects and increasing
risk of toxicity
Grapefruit Inhibits Metabolism of Many
Drugs
Inactivates metabolizing intestinal enzyme resulting in
enhanced activity and possible toxicity
Effect persists for 72 hours so it is not helpful to separate the
drug and the grapefruit
Many hospitals and health care centers have taken grapefruit
products off the menu entirely
Drugs known to interact with grapefruit
juice
Anti-hypertensives
(filodipine, nifedipine,
nimodipine, nicardipine,
isradipine)
Immunosuppressants
(cyclosporine, tacrolimus)
Antihistamines (astemizole)
Lipid-Lowering Drugs
(atorvastatin, lovastatin,
simvastatin)
Anti-anxiety, anti-depressants
(buspirone, diazepam,
midazolam, triazolam, zaleplon,
carbamazepine, clomipramine,
trazodone
 Food / Nutrient Effects on Drugs
Excretion
Patients on low sodium diets will reabsorb more lithium along
with sodium; patients on high sodium diets will excrete more
lithium and need higher doses
Urinary pH: some diets, particularly extreme diets, may affect
urinary pH, which affects resorption of acidic and basic
medications
 Food / Nutrient Effects on Drugs

Monoamine oxidase inhibitors (MAOI) interact with pressor

agents in foods (tyramine, dopamine, histamine)
Significant intake of high-tyramine foods (aged cheeses, cured
meats) by pts on MAOIs can precipitate hypertensive crisis
 Food / Nutrient Effects on Drugs : Caffein

Increases adverse effects of stimulants such as amphetamines,

methylphenidate, theophylline, causing nervousness, tremor,
insomnia
Counters the antianxiety effect of tranquilizers
 Food / Nutrient Effects on Drugs : Anti
Clotting
Warfarin (anticoagulant) acts by preventing the conversion of
vitamin K to a usable form
Ingestion of vitamin K in usable form will allow production of more
clotting factors, making the drug less effective
Pts must achieve a balance or steady state between dose of drug
and consumption of vitamin K; recommend steady intake of K
Other foods with anticlotting qualities may also have an effect
(garlic, onions, vitamin E in large amounts, and ginseng)
Food / Nutrient Effects on Drugs : Enteral
Feeding

Most medications should not be mixed with enteral feedings;

physical incompatibilities can occur including granulation, gel
formation, separation of the feeding leading to clogged tubes
Enteral feedings interfere with phenytoin absorption; window the
feeding around drug dose (2 hours before and after)
 Avoiding Food-Drug Interactions :
Prospective

When medications are initiated, patients should be provided with

complete written and verbal drug education at an appropriate
reading level including food-drug interaction information
Patients should be encouraged to ask specific questions about
their medications and whether they might interact with each other
or with foods
In acute-care settings, patients receiving high risk medications
should be identified and evaluated
Nurses should have information regarding drug-food interactions
and drug administration guidelines available at the bedside
 Avoiding Food-Drug Interactions :
Retrospective

Clinicians including dietitians should obtain a full drug and diet

history including the use of OTC and dietary supplements and
review potential drug-food interactions
When therapeutic goals are not met, clinicians should ask
questions about how and when drugs are being taken in relation
to foods and nutritional supplements
Clinicians should evaluate whether medical problems could be
the result of drug-food interactions
Often it may be the dietitian who is most aware of these issues
 Summary

Most drugs have nutritional status side effects.

Always look for therapeutically significant interactions
between food and drugs
Identify and monitor high risk patients, those on
multiple medications and marginal diets
 ALCOHOL - MEDICATION INTERACTION
Alcohol (Ethanol = C2H5OH)
The alcohol had important
place in humankind for at least
8000 years (1600 BCE Egyptian)
Alcohol beverage (Beer 3-6%,
Wine 16%, Whisky 40%, Vodka
60%, etc) as a social lubricant,
for recreational, pleasurable,
anxiolytic (relieves anxiety and
depression), increases
socialization
Alcohol is drug reinforcer,
addictive drug, CNS
depressant, and sedative
AbleStock
 How common are Alcohol Drug Interaction ?
77% of prescription drug user were exposed to Alcohol. 60% of men and 30% of women
in USA have had one or more adverse alcohol drug interaction (NCADD,2014)
Alcohol interact with a wide variety of illicit and prescription drugs (NIAAA,1995;
Tanaka,2001)
Alcohol-medication interactions may be a factor in at least 26% of ED admissions in USA
(NIAAA, 1995,2012; SAMHSA,2010).
20 50% of drivers killed in road traffic crashes were under the influence of alcohol and
drug (USA,2014)
BAC required for fatal overdoses are lower when alcohol is combined with prescription
drugs (Jones et al ,2011)
Data from the National Epidemiologic Study on Alcohol and related condition indicate that
the combined use of alcohol and other drug peaks in the 18 to 24 y age (McCabe et al,2008)
Rates of hospitalization for alcohol overdoses,drug overdoses,and their combination all increased
from 1999 to 2008 among 18 24 yo (J.Stud.Alcohol Drugs,72,774-786,2011)
The availability of alcohol beverages and the use as recreational drugs creates a
heightened risk for an adverse drug-alcohol interaction

Adverse drug-alcohol interaction represent a major problem to days

Alcohol + other drugs dangerous interactions can occur
Some Celebrities All died from lethal Alcohol-Drug
combination:
Jimi Hendrix, who died from asphyxia caused by Alcohol and Barbiturates
Elvis Presley, who had over 10 Drugs and Alcohol
Freddy Soto from fentanyl, xanax and alcohol
Elizabeth Ann Hulette aka Miss Elizabeth from alcohol, alprazolam, temazepam,
oxycodone, hydrocodone, and anabolic steroids
Louie Spicolli from soma, alcohol, painkillers, and benzodiazepines
Jimi Hendrix, who died from asphyxia caused by alcohol and barbiturates
Deep Purple's Tommy Bolin, who died from alcohol and prescription and illegal drugs in
combination
Steve Clark of rock group Def Leppard, who died from combining antidepressants,
tranquilizers and alcohol
Bridgette Andersen, who died from combining alcohol and multiple drugs
Edie Sedgwick, who died from combining barbiturates with alcoholic drinks
Rory Gallagher, died from alcohol and polydrug abuse
Eric Douglas who died from alcohol, painkillers and tranquilizers
 Alcohol - Drug interactions

Pharmacokinetics Pharmacodynamics

The effect of acute/chronic of alcohol consumption on drug

pharmacokinetic and pharmacodynamics

The effect of acute/chronic of drug use on alcohol pharmacokinetic

and pharmacodynamic

*
Pharmacokinetics
Absorption Small molecule, Soluble in fat and water
Rapidly absorb after oral administration
(20% stomach, 80% upper intestine)
85-95% metabolized in liver and the rest
Metabolism in gastric. Alcohol is metabolized by
ADH, ALD, MEO, Catalase, FAEE

Distribution Distribute through total body water

Crosses BBB and placenta barrier
No binds to plasma protein
Elimination 5-15% excreted unmetabolized through
exhaled breath, sweat, and kidney

www.youngpharmacists.com
 (10%)

Ethyl
Glucoronide
(85%)
( < 1%)

H2O, CO2

Acetaldehyde adduct
Formation
Increase ROS formation Hector et al,Arch.
Increase NADH/NAD ratio Med.Res 1997.vol 28,No 4
W. Tassaneeyakul
 ALCOHOL DEHYDROGENASE (ADH)

ADH is found in high concentrations within the human liver, brain,

stomach and kidney
Ethanol is oxidized by ADH into acetaldehyde and NADH is formed
Acetaldehyde, a more toxic molecule than ethanol
Throughout these processes, water molecules are lost and
dehydration could set in after prolonged imbibing.
Excess NADH production lead to metabolic disorders, lactic acidosis
and hypoglycemia
Competition between Methanol and Ethanol for ADH form the basis of
the use of Ethanol in Methanol poisoning
 tor

ADH1B*2 : Vmax than ADH1B

30-45% Chinese, Japanese, Koreans
10% European
5% Russian
(Schuckit,MA.,2014)
Acetaldehyde Dehydrogenase (ALDH)
Acetaldehyde is oxidized in liver by mitochondrial NAD
dependent aldehyde dehydrogenase
The product is acetate. Acetate is formed which is further
metabolized to CO2 and water
Increased ratio of NADH/NAD+ reduced gluconeogenesis,
hypoglycemia, ketoacidosis, decreased level of glutathione
Not so easily saturated, requires a great amount of alcohol
to saturate and then acetyldehyde accumulates, contributing
to hangover
ALDH2 Gene mutation ALDH2*2 (glycin 487 lysine) : 5 10% Japanese, Chinese, Korean
For whom severe adverse reactions occurs after consumption of one drink or less
Consequently their risk for severe repetitive heavy drinking is close to zero
Metabolic disruptions in liver due to alcohol metabolism:
Horrible Aldehyde poisoning = The Acetaldehyde Syndrome =
Disulfiram-like reaction

Excess of Acetaldehyde (very reactive compound) :

Facial flushing, weakness, headache, tachycardia, nausea, vomiting, sweating,
vertigo, life-threatening arterial hypotension, shock and myocardial
infarction and sudden death
(Borja,CR;Oliveira, J.Pharmacovigilance,2:5, 2014)
Microsomal Ethanol Oxidizing System (MEOS = CYP2E1)
At concentration below 100 mg/dl the MEOS has little contribution to the
ethanol metabolism.
MEOS work when ethanol concentration rises above 100 mg/dl.
During chronic consumption there is an induction in enzyme activity
Enzyme inducing drugs like phenobarbital may increase activity of MEOS.
During chronic alcohol consumption, MEOS (CYP2E1) activity is induced.
As a result metabolism of other drugs (in-active, active or toxic
metabolite) which are metabolized by cytochrome P450 increases.
The greater the alcohol consumption, the more enzyme activity and thus
more adverse effects
 Yang-Ming Tseng et al.
Toxicol. Sci. 2009;111:267-276

1
Diagram showing physiological and toxic activities associated with hepatic CYP2E1
Acute Ethanol Intake Chronic Ethanol Intake
 In the absence of
alcohol

After moderate
alcohol consumption

In chronic heavy
drinkers

In chronic heavy drinkers

who are intoxicated
 Catalase
Catalyzes the hydrogen peroxide (H2O2 )-dependent oxidation of ethanol yielding
acetaldehyde and two molecules of water.
Its main expression and function is in peroxisomes.
It contributes very little to total ethanol elimination because of the limited availability of
hydrogen peroxide
May be involved in the metabolism of alcohol to acetaldehyde in the brain. This has led to
implications of a role for acetaldehyde in mediating some of the behavioral effects of alcohol.

Catalase
CH3CH2OH + H2O2 CH3CHO + 2 H2O

Juan Caballeria,, Annal of Hepatology (2).,60-68,2003

 Pharmacodynamic of Ethanol
- Ethanol is CNS depressant : anti anxiety, sedation
- Ethanol is drug reinforcer : a substance whose
pharmacological effects drive the user to continue to use it
(caused addicted).
- Reinforcing effects : Gain pleasure, altered consciousness,
relief of stress and negative emotions, relief of withdrawal
symptoms.
In the 19th century it was used as an anesthetic.
Problems : Duration too long, could not be controlled.
The effective dose for surgical analgesia is closed to the lethal
dose.

Alcohol affects several neurotransmitters in the brain (neuromodulator).

As psychoactive drug, Alcohol-induced changes brain chemistry to
produce a wide range of behaviors.

Nestler,J : 2014
ACUTE CNS EFFECTS OF ALCOHOL
Blood Alcohol Level Effect
(gram/100 ml)
< 0.04% Mild euphoria
0.05 - 0.09% Disinhibition, increased self confidence, alteration of judgment
0.10 - 0.14% Confusion, loss of critical judgment, memory impairment,
sleepiness
0.15 - 0.29% Ataxia, analgesia, disorientation, exaggeration of emotions
0.30 - 0.39% Stupor, marked incordination (808 fatal acohol poisonings)
>0.4% Anesthesia, deep coma, death
(NIAA Review,2014)

Blood alcohol limit in USA = 0.08% or 17.4 mM

Pharmacodynamic drug interactions
Nerve transmission at synaps
Partition into lipids
Receptor binding
Release of neurotransmitter
Altered configuration of receptor
proteins
Opening or blocking ion channel
Drug transport proteins
Trancription factor

Altered behavioral response

Antagonism
Additive
Synergistic
Handbook of Drug Interaction, A.Wayne Jones,2012)
 Neuropharmacology of Alcohol
Effects on GABA System (BAC >= 0.06 g/dL)
Results in GABA release, facilitates the response of the GABAA receptor, interaction with GABA-A receptor
and facilitation of GABA transmission : sedative and anxiolytic effects , ataxia, amnesia, withdrawal
(Krystal et al,2006; Dick et al,2006)
Effects on Dopamine System BAC ( 0.01 0.05 g/dL)
Increase synaptic DA in VTA & nucleus accumben, increase dopamine in mesocorticolimbic system :
reinforcing, rewarding effects, euphoria, pleasure (Cruz et al,2008)
Effects on Opioid Peptide System (BAC 0.01 0.05 g/dl)
- Causes the release beta endorphine, activate opioid receptor in VTA and nucleus accumbens
- Activation of opioid peptide system : reinforcing and rewarding effects (Mu), aversion (Kappa), craving,
euphoria, pleasure (Pastor and Aragon,2006)
Effects on NMDA Glutamate system (BAC 0.02 0.2 g/dL)
Blockage NMDA and Kainate receptor function : sedative / hypnotic effects, neuroadaptation, withdrawal
(Shuckit,2014)
Effects on Serotonin system (BAC 0.01 0.05 g/dL)
Can significant increase Serotonin in synaptic space, and up regulate 5-HT receptor : neuroadaptation,
nausea, aversion (Barr et al,2005)
Effects on Canabinoid system :
Can activate CB1 receptor, affects, DA, GABA, glutamate in reward Circuit in the Brain
(Hutchinsons etal,2008, Perra et al, 2008)
Enhances the activity of Ca activated K channel (Aryal et al ,2009)
Increases Ach in VTA, subsequent release Dopamine in n.accumbens (Joslyn et al,2008)
 Some Neurotransmitter in CNS and Function Affected
Distribution
Neurotransmitter Functions Affected
in the Central Nervous System

Midbrain, Ventral tegmental area (VTA), Pleasure and reward Movement, Attention,
Dopamine
Cerebral cortex, Hypothalamus Memory

Midbrain, VTA, Cerebral cortex,

Serotonin Mood, Sleep, Sexual desire, Appetite
Hypothalamus

Midbrain, VTA, Cerebral cortex, Sensory processing, Movement, Sleep, Mood,

Norepinephrine
Hypothalamus Memory, Anxiety

Endogenous opioids Widely distributed in brain but regions Analgesia, Sedation, Rate of bodily functions,
(endorphin and enkephalin) vary in type of receptors, Spinal cord Mood

Hippocampus, Cerebral cortex,

Acetylcholine Memory, Arousal, Attention, Mood
Thalamus, Basal ganglia, Cerebellum

Endogenous cannabinoids Cerebral cortex, Hippocampus,

Movement, Cognition and memory
(anandamide) Thalamus, Basal ganglia

Neuron activity (increased rate), Learning,

Glutamate Widely distributed in brain
Cognition, Memory

Gamma-aminobutyric acid Neuron activity (slowed), Anxiety,

Widely distributed in brain
(GABA) Memory, Anesthesia
 Conclusion :
Alcohol does not appear to activate specific receptors.
However, alcohol influences the activity of many
transmitter systems including
GABA, Glutamate, Opioids, Dopamine, Central
Cholinergic, Dopamine, Serotonin, Cannabinoids
(CNS Modulator)
Alcohol : Drug Reinforcer
Glutamate
Excitatory Input
Enkephalin or
Dynorphin Alcohol
Inhibitory Neuron

k Opioid Dopamine Receptors

Enkephalin Receptors
Inhibitory Dopamine Neuron GABA
Neuron Neuron

m Opioid REWARD
Receptors

GABA-A Receptors

GABA Inhibitory Feedback

GABA Presynaptic
Inhibitory Opioid
Neuron Receptors
Alcohol (m, d?)

Ventral Tegmental Nucleus Accumbens

Area (VTA) (NAc)
 Depressants (downers) ALCOHOL
Stimulants (uppers) Depressants (downers)
NEUROTRANSMITER

NEUROTRANSMISSION
Sedatives/Hypnotics
Antidepressants
Antianxiety drugs
RECEPTOR FOR NEUROTRANSMITER
Antipsychotics
Mood Stabilizers
Psychomotor Stim.
Hallucinogenic Signal transduction
Antiepilepsy CELLULAR ACTIVITY
Anti parkinsonism PERUBAHAN ANTAR POPULASI NEURON
Opioid
Muscle Relaxant
Antihistamine
CNS ACTIVITY
Bucholz et al., 1995;
NIAAA, 1998

ANTAGONISM ADITIVE / SYNERGISM

 Alcohol and ADH inhibitor

Pyrazol, Fomepizole, Cimetidine, Ranitidine, Aspirine,

Methanol and other aliphatic alcohol

Blood Alcohol Concentration

increased

Toxic effects of Alcohol

(Stockley, 2012)
 Alcohol & ALDH inhibitor
Alcohol + Disulfiram, Furazolidone, Cotrimoxazol, Cephalosporin
Antibiotic (Cefoperazone, Moxalactame, Cefamandole, Cefotetan, Cefuroxime),
Nitroimidazol (Metronidazole, Ornidazole, Tinidazole), Tacrolimus, Pimecrolimus,
Chlorpropamide, Gliburide, Nilutamide, Chloramphenicol, Lopinavir, Ritonavir,
Sulfomethoxazole, Sulfisoxazole, Nitrofurantoin, Isotretoin, Procarbazine, Tolazoline,
Fomepizole, Cyanamide, Isosorbide dinitrate, Nitroglycerine, Tolbutamide, Nitrefazole,
Phenylbutazone, Phenacetin, Tolazamide, Procarbazine

Disulfiram-like reaction = Acetaldehyde Syndrome

Contraindicated
Disulfiram should not be administered for at least 12 hours after exposure to alcohol.
The patient should be fully informed of the disulfiram-alcohol reaction.
The patient should be warned to avoid ALL alcohol, including alcohol found in foods, medications, aftershaves,
perfumes, and other products.
Exposure to even small amounts of alcohol can result in a reaction.
A disulfiram-alcohol reaction can occur up to 14 days after discontinuing disulfiram therapy.
 Alcohol & Sulfonylureas
Alcohol + Sulfonylureas (Gliclazide, Glipizide,
Glyburide, Tolazamide and Tolbutamide)

Altered gluconeogenesis, delayed absorption,

enhanced hepatic metabolism

Prolonged hypoglycemia

Coma
Diabetics should be encouraged to limit alcohol intake to
three or fewer drinks daily.
 Alcohol & CNS Depressants
Alcohol + CNS Depressants (Benzodiazepines (Clonazepam, Midazolam, Alprazolam, Diazepam,
Lorazepam), Barbiturates (Amobarbital, Aprobarbital, Mephobarbital, Pentopbarbital,
Phenobarbital), OTC (Antihistamine), cough suppressant (Dextromethorphan), narcotic pain killer
(Oxycontin, Vicodin, Percodan), sleeping pill, anti-anxiety, muscle relaxant, ketamine

Synergistic CNS effects

Fatal depression of CNS

Heart slows
Breathing slows
Over sedation
Coma
Death

CONTRAINDICATED
Warn patients that small amounts of alcohol combined with a CNS depressant may cause a marked reduction in psychomotor performance.
Risks associated with driving a car or operating dangerous machinery may be significantly enhanced after combined use of these agents.
A patient taking CNS depressant should be advised to avoid the use of alcohol.
 Alcohol & Opioids
Alcohol + Opioids (Morphine, Oxycodone,
Oxymorphone, Hydromorphone)

Additive central nervous system (CNS) and respiratory

depression

Increased risk of respiratory depression, hypotension,

profound sedation or coma

Contraindicated

Counsel patients on the potential for increased risk of CNS depression, including respiratory depression, hypotension,
profound sedation, and coma, when alcohol is ingested with opioids. Patients should be instructed to avoid alcohol
consumption while taking opioids.
 Alcohol & Antidepressants
Alcohol + Antidepressants (Amitriptyline, Clomipramine,
Imipramine, Desipramine, Trimipramine, Citalopram, Escitalopram,
Paroxetine, Venlafaxine, Desvenlafaxine)

Additive CNS effects

Enhanced CNS depression and impairment of

motor skills

Patients receiving antidepressants should be advised to avoid the use of alcohol

 Alcohol & Phenothiazines
Alcohol + Phenothiazines (Fluphenazine, Prochlorperazine,
Thioridazine, Trifluoperazine, Triflupromazine)

Additive CNS effects

EPS effects

Increased risk of central nervous system

depression

Concomitant administration of ethanol and phenothiazines has been reported to result in additive central nervous
system depression.
Alcohol triggers extrapyramidal side effects also.
Patients should be instructed to avoid alcohol consumption while taking phenothiazines.
 Alcohol & Acetaminophen
Alcohol increases CYP2E1 mediated acetaminophen metabolism

Accumulation of the hepatotoxic metabolite NAPQI

Depletion of Gluthatione

Increased risk of hepatotoxicity

Caution should be used with patients who drink 3 or more alcoholic beverages per day and take acetaminophen.
Chronic alcoholics should avoid the use of acetaminophen.
 Alcohol & Aspirin
Alcohol + Aspirin

Alcohol potentiates bleeding time prolongation

and gastrointestinal irritation

Increased gastrointestinal blood loss

Avoid ingestion of ethanol within 12 hours of aspirin ingestion.

 Alcohol & Anti Depressant (NDRI)
Alcohol + Bupropion

Alcohol further lowers the seizure threshold

Increased risk of seizures

Ingestion of ethanol should be minimized, and preferably avoided completely, in patients receiving
bupropion.
WARNING :
14 super common type of medications that can have very
dangerous reactions with alcohol (FDA,2014; NIAAA,2014):

1.OTC pain and fever meds (NSAID),

2. Prescription pain meds (Oxycodone,Meperidine, Hydrocodone),
3. Allergy and cold & flue meds (Benadryl,Claritin,Tylenol),
4. Cough meds (Robitusin,Codeine),
5. Antibiotics (Azithromycin,Flagyl,Nizoral),
6. Anxiety meds (Ativan,Klonopin,Valium,Xanax),
7. Depression meds (Prozac,Venlafaxine, Zoloft),
8. Attention and concentration meds (Methylphenidate),
9. Heartburn meds (Zantac,Reglan),
10. Sleep meds (Ambien,Sominex, Lunesta),
11. Blood pressure meds (Benzepril,Lopressor HCT, Norvasc,Losartan),
12.Diabetes meds (Glucotrol, Glynase, Micronase),
13.Blood clot meds (Coumadin),
14.Cholesterol meds (Atorvastatin, Crestor)
 Typical alcohol-drug interactions :
Short term use (Acute) :
Alcohol inhibits drug metabolism resulting in higher drug level
- Drug inhibit ADH Alcohol toxicity CNS Depressant
- Drug inhibit ALDH Acetyldehyde toxicity
- Drug inhibit CYP2E1 Prolong toxic effect of Alcohol
Chronic use (alcoholism) : Alcohol induces drug metabolism resulting in lower
drug level. Effect can last for several weeks after cessation of drinking
Drug metabolism induced by alcohol can transform drug into toxic metabolites and damage
organ (e.g., acetaminophen (Tylenol) cause liver damage)
Alcohol (CNS Depressant) may magnify the central nervous system effects of psychoactive \
medications / other CNS depressant depression of central brain stem
The absorption of drugs is increased due to increased gastric solubility of drugs and
gastrointestinal blood flow induced by alcohol.
Chronic use (Alcoholism) pathologic changes (liver disease and cardiac disease)
alteration organ function affect the action many drugs (alcoholic liver disease reduction
in protein binding and decreases of drug metabolism) (Sands et al,2012 ; W.Jone,2014)
 Conclusion
Most of the adverse alcohol-drug interactions are caused by inhibition of metabolism and
enhancement of the central depressant effects.

Acute alcoholic intoxication tends to inhibit drug metabolism which may lead to toxic
effects.

Chronic alcoholism results in enzyme induction which cause diminished therapeutic

efficacy of drugs.

Drugs and alcohol interaction : disulfiram-like reactions, hypoglycemia, increase the risk of
hepatotoxicity, seizures, GI bleeding, CNS depression, respiratory depression, coma

The patients should be advised to avoid alcohol ingestion to prevent most of the
interactions.
THANK YOU