Download Mechanisms of drug interaction

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There is a different types of drug interactions:
1-drug-drug interaction
2-drug-food interaction
3-drug-lab test interaction
4-drug-disease interaction
-In general we can classify these interactions depending on the mechanism of action into 2 types:
A. Pharmacodynamic interactions
 If the effect changes the time or the magnitude of response.
 This type of interaction occurs mainly between 2 drugs have the same pharmacological effect or
antagonize each other.
B. Pharmacokinetics interactions
 If ADME (Absorption, Distribution, Metabolism, and Elimination) change the net effect of the drug.
-Not all of these interactions are harmful, they can be beneficial sometimes.
DRUG-FOOD INTERACTIONs:

It can be a pharmacodynamic or pharmacokinetic interaction.
-How can food affect the pharmacokinetic of the drug?

→Food can affect the metabolism of the drug and increase its concentration.
Ex:
Grape fruit that inhibits CYP enzyme thus increase the concentration of the drug in blood stream.
(Harmful)

→ Food can affect the absorption of the drug and decrease its concentration.
Ex:
Tetracycline and fluoroquinolones can chelate with divalent and trivalent cations (Mg+2, Ca+2, Fe+3)
from milk and dietary products and supplementations which decrease the efficacy of medication.
(Harmful)
-Absorption extent → Food can affect the drug absorption by affecting the Extent like tetracycline and
.
fluoroquinolones.
-Absorption rate → food can affect the drug absorption Rate by delaying it and it can be detected by TP
(peak of drug)
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If T peak occurs:
-After 1 hour → ↑ rate of absorption (rapid)
-After 3 hours → ↓ rate of absorption (slow)
-Do I care about delaying the onset of action of a drug?
Depending on the drug; if it was a single dose drug or if I need a rapid effect (analgesic) then I care about
having a rapid absorption, so the drug should not be taken with food-that affect its absorption rate-.
Ex:
hypnotic drug peak occurs after 30 min of administration so if the patient takes it before 30 min of sleep
after a big meal-that affect the rate of absorption but not the extent- the absorption would be delayed and it
may needs 3 hours for absorption and making the proper response.
On the other hand chronic medications response, wouldn’t be affected by slow absorption rate resulted
from food.
 → Interaction between warfarin and vitK.
Decrease the efficacy of warfarin> pharmacodynamic interaction. (harmful)
 → interaction diuretic and salts food.
Salts food increase the Na and water in the body, while diuretic increase Na and water excretion>
pharmacodynamic interaction antagonize each other.(harmful)
Drug-disease interaction:
Not very common term, the most common term is contraindication. Ex: use of nonselective B-blocker with
asthma.
Contraindications:
1. absolute contraindication
Impossible to take the drug in specific situations because ALWAYS risk outweighs the benefit.
2. relative contraindication
A drug which is contraindicated BUT it can improve the condition. (Benefit outweighs the risk)
Mainly found in lexi as precautions; For example use with caution in coronary heart disease. And if you have
another option you better use it.
Ex:
NSAIDs with HTN, they aren't absolute contraindicated, if there is a benefit from using NSAIDs in patients
with HTN we can use them but with great caution.
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Mechanisms of drug interaction
1- Pharmaceutics interactions
It's also called incompatibilities which Occur outside the body unlike pharmacokinetics and
pharmacodynamics which take place inside the body. Mainly occur between parental indications;
Ex:
ceftriaxone (powder) it should be dissolve in solution to give it as injection. There are solutions
which it is compatible with and others incompatible with (not stable chemically or physically) like
calcium containing fluids (ringer lactate)
Ceftriaxone+ ringer lactate (Ca++) → precipitate (outside body)
2- Pharmacodynamic interactions:
Where the effects of one drug are changed by the presence of another drug at its site of action or at
another site.
Mainly they have the same pharmacological effect or they antagonize each other. No effect on
ADME.
Types of pharmacodynamic interactions:
A-additive
1+1=2
2 drugs have the same pharmacological effect
 Antihypertensive drug (1) decrease the BP 20mmhg and drug (2) decrease BP 20mmhg.
Total decrease in BP is 40mmhg (beneficial)
 Alcohols with benzodiazepine both have CNS depressant effect
ALCOHOL(X) +BENZODIAZEPINE(Y) → X+Y (harmful)

Combination of erectile dysfunction drugs such as (sildenafil, vardenafil, tadalafil) with
nitrates (isosorbide mononitrate) both are vasodilators and cause hypotension. (harmful)
B-synergistic
1+1>2
 Combination of sulfonamides antibiotic (sulfamethaxazole) and dihydrofolic acid reductase
inhibitors such as (trimethoprim) brand name trimoxazole → net effect is synergistic killing
of bacteria, they work at different sites of action. (beneficial)

Combination of beta lactam( works on cell wall synthesis) AND Aminoglycoside (works on
protein synthesis) results in synergistic bacterial killing. (beneficial)
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C-potentiating 1 + 0 > 1
 2 drugs with different pharmacological effect but one of them enhance/improve the action
of the second drug.
 During operation skeletal muscle relaxant is used for anesthesia, and the presence of
opioids (no skeletal muscle relaxation effect) will potentiate the effect of skeletal muscle
relaxant so the dose of it should be decreased.
Ex:
Patients who use clonidine (as antihypertensive drug, no anesthetic effect) during operation
they need small dose of anesthetic drug. (Beneficial, it could be harmful if patient takes aagonist and doctor didn’t know)
D-antagonistic 1 + -1 = 0
 2 drugs antagonize each other. Ex: b-agonist with b-blocker.
3- Pharmacokinetic interactions:
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ADME interactions.
More common than pharmacodynamic interactions.
Drug Absorption change is due change in absorption rate (t peak) OR extent.
The rate of absorption is important mainly in single dose drugs AND rapid effect. While
chronic medications won't be affected significantly because they reach steady state.
So for single rapid effect, drug should be taken on empty stomach, if they would be delayed
by food and extent will not change.
What are causes that change drug absorption?
1. ph change (change in ionization percentage)
2. Complexation(chelation)
3. Intestinal motility; rate/extent.
4. Transporter; some drugs need carrier to be absorbed.
If 2 drugs were given, one of them needs carrier to be absorbed, and the other blocks this
carrier, the absorption of the first drug will be affected.
1. Ph:
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Most of drugs are weak acids/bases and ph affects the fraction of ionized and
nonionized form.
For dissolution the drug should be ionized, and for absorption drug should be nonionized.
Drugs need acidic media to be absorbed such as (iron, B12, calcium, folic acid) so when it's
taken with other drugs that increase the stomach ph, its absorption will decrease. Drugs
increase the stomach ph such as (PPI, antacids, histamine receptor antagonist) this is a
pharmacokinetic interaction. (Absorption)
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Ex:
Different forms of calcium include: calcium carbonate -absorption extent depends on acidic
media- efficacy will be affected when it's given with PPI or antacids. (Harmful)
Calcium acetate –absorption doesn’t depend on acidic media- we can give it with PPI or antacids.
2. Complexation (chelation) AND adsorption:
Chelation:
A complex mainly between the drug and cations (divalent and trivalent), which form a ring around
the drug. This complex will precipitate and couldn't be absorbed. A pharmacokinetic interaction
affects absorption extent and decreases the efficacy. But if drug absorption increased this will affect
the safety.
Ex:
-Tetracycline with Ca+2/Fe+3(supplementation)
-Flouroquinolone with Ca+2/Fe+3
-Levothyroxine with Fe3+; should be separated (4-6) H.
-Ca+2 with Fe+3; form complexation that affect absorption.

If the effect was on metabolism; I can't separate between them.
Adsorption:
It happens on the surface.
Ex:
Charcoal is used for drug intoxication; which binds to the outer surface of the drug and
prevents its absorption. (Beneficial)
Ex:
Dyslipidemic Drugs (cholestyramine, cholestipol) which cause acid bile sequestrant, they have a large
size, and medication will adsorb on their surface such as (digoxin, warfarin, levothyroxin,
furosemide, mycophenolate) a pharmacokinetic interaction affects absorption and decreases
efficacy.
3. Intestinal motility
 Drugs decrease intestinal motility such as anticholinergic drugs (Tricyclic antidepressant, 1st
generation antihistamin, phenothiazines, oxybuytnin, tolterodine)

↓motility ↑contact time ↓rate of absorption ↑t peak ↑extent (drug should be acid
stable and enzymatically stable in GIT) this will affect safety.
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If Drug is unstable in GIT (it's better to cross GIT quickly) like b lactam(sensitive to acidity)
and was given with anticholinergic drug, the b lactam will be degraded ↓ extent
↓absorption rate ↑t peak
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Drugs increase intestinal motility such as laxatives, erythromycin, metocolpramide

↑motility ↓contact time ↑rate of absorption ↓t peak
versa)
↓extent (drug is stable, and vice
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4. Transporter

Not all drugs absorbed by passive diffusion, some of them need mediators.

Such as p-glycoprotein which is found in the surface of mucosa that effluxes the drug out of
the intestinal cell to the GI lumen and decreases the drug absorption.
So if we give a drug orally (substrate for pgp) with pgp inhibitor, the absorption of the drug
increases.
But If we give the drug with pgp inducer (increases the expression of pgp) the absorption of
the substrate decreases.

There is another pgp in the kidney; which increases the secretion of the drug in urine. If it
was given with pgp inhibitor the blood levels of the drug increases.
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And another one in the brain; which efflux the drug out of it. If it was given with pgp
inhibitor the drug effect in the brain increases.
Digoxin/diltiazme/amiodarone/statins →pgp substrates
Amiodarone/ carvediolol/ dilitiazem → pgp inhibitors
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Ex:
-Verapamil(substrate+ inhibitor) + carvedilol (pgp inhibitor)
Carvedilol inhibits pgp and increases the absorption of verapamil (pharmacokinetic interaction) thus
increase the risk of bradycardia and hypotension (pharmacodynamic interaction) drug interaction
needs therapy modification.
-Amiodarone(substrate+inhibitor) + digoxin(substrate)
Amiodarone inhibits pgp so the digoxin concentrations increase.
Done by:
Raghad qamareldeen
Zain obeidat
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