DRUG INTERACTIONS AND

BIOAVAILABILITY
By
Parth D. Mair (Que Pharma Pvt. Ltd., Wadhwan)
At:
CCPER, WADHWAN

1 Drug Interactions & Bioavailibility

 Contents
 What is Drug Interactions
 Type of Drug Interactions
 Drug-Drug Interactions
 Pharmacokinetics Drug Interactions
 Pharmacodynamic Drug Interactions
 Drug- Food Interactions
 Drug – Environmental Chemicals Interactions
 Bioavailability
 Factors affecting Bioavailabity
 BCS Classification

2 Drug Interactions & Bioavailibility

 What is Drug Interaction?
 Drug Interaction can be considered as a situation in which
the effects of on drug are altered by prior or concurrent
administration.

 This principle of interaction can be expanded to food,

nutritional supplements, diseases etc which alters the effects
of drugs.
 Drug Interactions are either due to pharmacokinetic or
pharmacodynamic effect.

3 Drug Interactions & Bioavailibility

 Types of Drug Interactions
 Drug – Drug Interactions
 Drug – Food Interactions
 Drug – Environmental Chemicals Interactions
 Drug- Disease Interactions
 Drug – Laboratory test Interactions

4 Drug Interactions & Bioavailibility

 Drug- Drug Interactions
 When one drug alters the effect of another drug which has
been administered concurrently during a therapy or multiple
therapies
 Drug- Drug Interactions can be caused by various reasons-
- Multiple Pharmacological Effects : Almost all drugs exhibit
effect on more than one physiological system. (E.g.
Tamsulosin, used for treatment of enlarged prostate, is also
an alpha-blocker and should not be used with another alpha-
blocker like Prazosin.

5 Drug Interactions & Bioavailibility

 - Multiple Prescribers : It is common for patient to consult
different Doctors for different ailments
( e.g. A patient regularly consulting a cardiologist for heart
ailments may visit a dermatologist for skin disease.
Atorvastatin, a lipid lowering agent, has been advised by the
cardiologist and itraconazole, an antifungal agent, has been
prescribed by Dermatologist for fungal infection.
Atorvastatin + Itraconazole can increase Skeletal muscle
damage & has potentiality to cause heart failures.)

6 Drug Interactions & Bioavailibility

 - Use of Non-Prescription Medicines – (E.g. Commonly used
laxatives and Antacids can cause decrease efficacy of certain
antibiotics).
- Patient Non Compliance – Adherence to directions by the Dr
or the pharmacist is needed to ensure optimum efficacy of
drugs.
- Drug Abuse – Codeine is a drug that has been abused since
long. Use of SSRIs such citalopram or fluoxetine along with
codeine can cause fatal interactions.

7 Drug Interactions & Bioavailibility

 Mechanism of Drug Interactions
 Pharmacokinetic Interactions
- Interactions in which one drug alters the Absorption,
Distribution, Metabolism and Excretion (ADME) of another
drug
 Pharmacodynamic Interactions
- Interactions in which drugs having similar or opposing
pharmacological effects are administered concurrently, one
of which alters the sensitivity or responsiveness of the tissues
for the other drug.

8 Drug Interactions & Bioavailibility

 Pharmacokinetic Interactions
 Alteration in GI Absorption
This type of interaction involve change in absorption pattern in
terms of total absorption amount or time for absorption.
Various mechanisms are responsible for change in absorption
such as-
- Alteration of pH (e.g. Unionized form of drug is more
absorbed as compared to that of ionized form. Ketoconazole
requires acidic medium to get absorbed. So concurrent use of
antacids, such as PPI (Rabeprazole/Pantoprazole,etc) or H2
receptor antagonists (Ranitidine) should be avoided in order
to achieve optimum efficacy)

9 Drug Interactions & Bioavailibility

 - Complexation & Adsorption – (e.g. metal ions such as iron,
calcium, aluminum or magnesium has the ability to form
complexes with various drugs. Aluminum and Manesium
containing anatacid (Like Digene or Gelusil)forms complex
complex with Levofloxacin even when they are administered
2-3 hours apart)
- Alteration of GI Motility/ Gastric Emptying – (e.g. some
drugs alter the gastric emptying time, either increase or
decrease, resulting change in time for absorption. Laxatives
tends to speed up gastric emptying resulting in reduction in
time available for absorption.

10 Drug Interactions & Bioavailibility

 - Alteration of GI Flora – (e.g. The GI flora plays an important
role in aiding absorption or converting drug into inactive
form. Digoxin, highly potent drug) is metabolized by the GI
flora to inactive form in patients with normal flora. But
concurrent administration of anitibiotics disturbs these flora
and results in higher amount of active Digoxin available for
absorption)

11 Drug Interactions & Bioavailibility

  Alteration of Distribution
This involves change in distribution pattern of one drug due to
another drug. The mechanism involves change in protein binding
characteristics of drugs either by competitive displacement or non
competitive displacement.
- The drugs that are highly protein bound (>90%) along with small
volume of distribution are the ones which are affected the most.
- E.g. Phenytoin is a highly protein bound drugand when valproic
acid is administered concurrently, free phenytoin level increase in
serum and results in increase in occurrence of adverse reactions.

12 Drug Interactions & Bioavailibility

  Stimulation of Metabolism
- Drug Metabolism occurs primarily in the liver and it involves
oxidation, reduction, hydrolysis and conjugation reactions.
- Cytochrome P-450 enzymes are the most important group of
enzymes for metabolism of drug.
- An increase or decrease in enzyme activity influenced by one drug
can alter metabolism of another drug.
- E.g. 1. Atorvastatin is metabolized by CYP3A4 enzyme which is
stimulated by Phenytoin.
- E.g. 2. Pyridoxine accelerates decarboxylation of Levodopa to
dopamine in peripheral tissues and less amount of Levodopa
crosses BBB.

13 Drug Interactions & Bioavailibility

  Inhibition of Metabolism
-Situation where one drug inhibits metabolism of another drug
by inhibiting the metabolic enzyme.
- E.g. Atorvastatin is metabolized by CYP3A4 enzyme which is
inhibited by Atorvastatin resulting in increased serum
concentration of Atorvastatin.
- E.g. Clarithromycin inhibits CYP3A enzymes responsible for
metabolism of simvastatin , thus can lead to myopathy.

14 Drug Interactions & Bioavailibility

  Alteration of Excretion
Situation where one drug alters the excretion of another drug
or its metabolite.
- Alteration of Urinary Ph : change in urine pH changes the
amount of drug reabsorbed from the urine. An acidic pH of
urine increases the reabsorption of Aspirin form urine and
prolongs its effect.
 Alteration of Active transport – Probenecid inhibits tubular
secretion of Penicillins and increase its serum concentration
by 2-4 folds

15 Drug Interactions & Bioavailibility

 Pharmacodynamic Interactions
 Drugs having opposing pharmacological activity
- Interactions result from using two drugs that have mutually
opposing pharmacological actions.
- E.g. thiazide diuretics increase the blood glucose level. When
it is prescribed with anti-diabetic drugs, their efficiency goes
down.
 Drugs having Similar Pharmacological effect
- When two drugs have similar Pharmacological effects, they
provide additive effects when administered concurrently
- E.g. When alcohol is taken CNS depressants, the resultant
additive action can be lethal in many cases.

16 Drug Interactions & Bioavailibility

 - In a psychiatric therapy, often an antipsychotic drug like
Chlorpromazine is co-prescibed with Trihexyphenidyl to
reduce extrapyramidal effects. Also in many patients a
tricyclic antidepressant Amitryptiline is also prescribed. All 3
drugs have anticholinergic activity and will result in high
occurrence of side effects like dry mouth, constipation,
blurred vision, etc.
- Antihypertensives should not be accompanied by Tricyclic
anti depressants as it will lead to orthostatic hypotension.

17 Drug Interactions & Bioavailibility

  Alteration in Electrolyte Concentration
- Concurrent administration of two drugs may result in
electrolyte imbalance, i.e. sodium and potassium imbalanace.
- Use of lisinopril along with potassium sparing diuretics such
as amiloride elevates the serum potassium level causing
hyperkalemia.
- Prolonged use of Thiazide diuretics can cause potassium
depletion resulting in hyper sensitization of heart towards
Digoxin.

18 Drug Interactions & Bioavailibility

  Interactions at Receptor Sites
- Many drugs act via same receptor sites resulting in increased
pharmacological response.
- MAOI drugs such moclobemide used within 14 days of
Amitryptiline may induce severe side effects like convulsions,
tremors and Vascular collapse

19 Drug Interactions & Bioavailibility

 DRUG – FOOD INTERACTION
 There is an alteration in effect of drug due to concurrent
intake of certain type of Food or nutrients
 Food may delay the absorption of drug , increase time for
absorption of drugs or compete for absorption of drugs.
 Levofloxacin should not be administered with milk as the
calcium in milk may form complex leading to decreased
bioavailability
 Food decreases the absorption of Azithromycin.
 A fatty meal along with Itraconazole enhances its
bioavailability.

20 Drug Interactions & Bioavailibility

  Any kind of food may reduce absoprtion of Alendronate
markedly.
 Acarbose should be administered with the first bite to obtain
optimum effectiveness
 MAO inhibitors and tyramine containing food should be
avoided as it results in spike in blood pressure.
 Grapefruit Juices enhances the bioavailability of Statins.

21 Drug Interactions & Bioavailibility

 DRUG – ENVIRONMENTAL CHEMICAL
INTERACTION
 Smoke and alcohol are found to be interacting with drug to
alter its effect.
 Smokers have increased hepatic enzyme activity.
 Therapeutic activity of drugs such as diazepam and
olanzapine is reduced to increase metabolism through hepatic
enzymes in smokers.
 There is a high risk of cardiac toxicity in women who smoke
and are on oral contraceptives.
 Similarly alcohol enhances sedative properties of CNS
depressants.

22 Drug Interactions & Bioavailibility

 BIOAVAILABILITY
 Bioavailability is the fraction of administered drug that
reaches the systemic circulation.
 Bioavailability is expressed as the fraction of administered
drug that gains access to the systemic circulation in a
chemically unchanged form.

 For example, if 100 mg of a drug are administered orally

and 70 mg of this drug are absorbed unchanged, the
bioavailability is 0.7 or seventy percent.

23 Drug Interactions & Bioavailibility

 DETERMINATION OF BIOAVAILABILITY
 Bioavailability is determined by comparing plasma levels
of a drug after a particular route of administration (for
example, oral administration) with plasma drug levels
achieved by IV injection in which all of the agent rapidly
enters the circulation.

 When the drug is given orally, only part of the

administered dose appears in the plasma.

24 Drug Interactions & Bioavailibility

  By plotting plasma concentrations of the drug versus
time, we can measure the area under the curve (AUC).

 This curve reflects the extent of absorption of the drug.

[Note: By definition, this is 100 percent for drugs
delivered IV.]

 Bioavailability of a drug administered orally is the ratio of

the area calculated for oral administration compared
with the area calculated for IV injection

25 Drug Interactions & Bioavailibility

 FACTORS THAT INFLUENCE BIOAVAILABILITY
 First-pass hepatic metabolism:
 When a drug is absorbed across the GI tract, it enters the
portal circulation before entering the systemic circulation.

 If the drug is rapidly metabolized by the liver, the amount of

unchanged drug that gains access to the systemic circulation
is decreased.
 Many drugs, such as propranolol or lidocaine, undergo
significant biotransformation during a single passage through
the liver.

26 Drug Interactions & Bioavailibility

  Solubility of the drug:

 Very hydrophilic drugs are poorly absorbed because of their

inability to cross the lipid-rich cell membranes.

 For a drug to be readily absorbed, it must be largely

hydrophobic, yet have some solubility in aqueous solutions.
 This is one reason why many drugs are weak acids or weak
bases. There are some drugs that are highly lipid-soluble, and
they are transported in the aqueous solutions of the body on
carrier proteins such as albumin.

27 Drug Interactions & Bioavailibility

  Chemical instability:

 Some drugs, such as penicillin G, are unstable in the pH of the gastric

contents. Others, such as insulin, are destroyed in the GI tract by
degradative enzymes.

 Nature of the drug formulation:

 Drug absorption may be altered by factors unrelated to the chemistry of

the drug. For example, particle size, salt form, crystal
polymorphism, enteric coatings and the presence of
excipients (such as binders and dispersing agents) can influence the
ease of dissolution and, therefore, alter the rate of absorption.

28 Drug Interactions & Bioavailibility

  Contents of the gastrointestinal tract (fluid volume and pH,
diet, presence or absence of food, bacterial activity, and
presence of other drugs).
 Rate of gastrointestinal tract transit (influenced by disease,
physical activity, drugs, emotional status of subject, and
composition of the gastrointestinal tract contents).

29 Drug Interactions & Bioavailibility

BIOPHARMACEUTICAL CLASSIFICATION SYSTEM [BCS]

• The Biopharmaceutical Classification System was first developed

by in 1995, by Amidon et al & his colleagues.

• Definition:
“The Biopharmaceutical Classification System is a scientific
framework for classifying a drug substance based on its aqueous
solubility & intestinal permeability & dissolution rate”.

• To saved time fast screening is required so drug substances are

classified on basis of solubility and permeability. This
classification is called Biopharmaceutical Classification System.

30 Drug Interactions & Bioavailibility

 FACTOR AFFECTING ON BCS
The Biopharmaceutical Classification System has been developed to
provide a scientific approach to allow for to prediction in vivo
pharmacokinetics of oral immediate release (IR) drug product by
classifying drug compound based on their,

1. SOLUBILITY

2. PERMEABILITY

3. DISSOLUTION

31 Drug Interactions & Bioavailibility

The Biopharmaceutics Classification System (BCS)
(as defined by the FDA after Amidon)

32 Drug Interactions & Bioavailibility

 Class I
• Ideal for oral route administration.
• Drug absorbed rapidly.
• Drug dissolved rapidly.
• Rapid therapeutic action.
• Bioavailability problem not expected for immediate
release drug product.
• e.g. Metoprolol , Propranolol, Diltiazem.

33 Drug Interactions & Bioavailibility

 CLASS II
• Oral route for administration.

• Drug absorb rapidly.

• Drug dissolve slowly.

• Bioavailability is controlled by dosage form and rate of

release of the drug substance.

• e. g. Nifedipine, naproxen.
34 Drug Interactions & Bioavailibility
 CLASS III
• Oral route for administration.

• Drug absorbance is limited.

• Drug dissolve rapidly.

• Bioavailability is incomplete if drug is not release or

dissolve in absorption window.

• e. g. Cimitidine, Metformin,Insulin.

35 Drug Interactions & Bioavailibility

 CLASS IV
• Poorly absorbed by orally administration.

• Both solubility & permeability limitation.

• Low dissolution rate.

• Slow or low therapeutic action.

• An alternate route of administration may be needed.

• e. g. Taxol, Chlorthiazole, Cefexime Trihydrate.

36 Drug Interactions & Bioavailibility

 CLASS BOUNDARY
•HIGHLY SOLUBLE

• The highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5.
• The volume estimate - a glassful (8 ounce)

•HIGHLY PERMEABLE

• When the extent of absorption in humans is determined to be > 90% of an administered

dose.

•RAPIDLY DISSOLVING

• When > 85% of the labeled amount of drug substance dissolves within 30 minutes using
USP apparatus I or II in a volume of < 900 ml buffer solutions.

37 Drug Interactions & Bioavailibility

 THANK
YOU!
38 Drug Interactions & Bioavailibility