BPCK

PYQ

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3 MARKS O RF E

SOLVED
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EM O

Q
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SOMEONE FROM RCB

Set1
a) What are displacement interactions? Give Example.
b) Explan in short about an active transport of drug.
c) What is the difference between absolute & effective surface area? How
it can be improved for hydrophobic drug.
d) What are the limitations of pH - partition Hypothesis?
e) Discuss briefly factors affecting gastric emptying of drug.
f) Define the term biotransformation. List the factors affecting
biotransformation of drug.
g) Write in short about non renal route of Excretion.

Set2
a) Discuss the significance of protein binding of drugs.

B
b) Write a note on facilitated diffusion.
c) What is multi compartment model?

C
d) Explain with significance the study parameters used in bioavailability
determination.

R
e) What is the effect of particle size on the rate of drug dissolution?
f) The absorption rate of paediatric and geriatric differ from that of adults,

M
why?
g) Define bioavailability, absolute bioavailability and relative bioavailability

Set3

O R
a) What is pinocytosis and Phagocytosis? Give example.
b) Explain in short about Facilitated diffusion.
F
c) What is the rate-limiting step in bioavailability?
d) Explain binding of drug to Human Serum Albumin
E
e) What is Gastric emptying? Explain influence of food on drug absorption?
N

f) What is an active transport?

g) What is the effect of protein binding on the action of the durg?
O

Set 4
E

a) Define bioequivalence, pharmaceutical equivalence and therapeutic

M

equivalence.
b) What is the influence of G1 pH on drug absorption?
O

c) Write a short note on bio-waivers.

d) Explain clearance, renal clearance and renal clearance ratio.
S

e) Name and define the pharmacokinetic processes involved in the

termination of drug action.
f) What are limitations of pH - partition hypothesis?
g) What are the advantages of administrating a drug by constant rate i.v.
infusion over oral administration?

Set 1
a) What are displacement interactions? Give Example.

Displacement interactions occur when one drug displaces another drug that is bound to
plasma proteins, especially albumin. Many drugs bind reversibly to plasma proteins, and
only the unbound (free) fraction of the drug is pharmacologically active. When two
highly protein-bound drugs are administered together, they may compete for the same
binding site, leading to an increase in the free (active) concentration of one of the drugs.
This can potentially enhance the pharmacological or toxic effects of the displaced drug.

Example: Warfarin is a highly protein-bound anticoagulant. If a patient taking warfarin is

administered another highly protein-bound drug like sulfonamides or aspirin, it may
displace warfarin from the albumin binding sites. This displacement increases the free
concentration of warfarin in plasma, potentially leading to excessive anticoagulation

B
and a risk of bleeding.

C
Displacement interactions are significant in drugs with:

R
 Narrow therapeutic index
 High plasma protein binding (>90%)

M
 Low volume of distribution

These interactions are clinically relevant and must be considered when co-

O
administering multiple drugs, especially in elderly or polypharmacy patients.
RF
b) Explain in short about active transport of drug.
E
Active transport is a carrier-mediated process in which drugs are transported across
biological membranes against their concentration gradient (i.e., from a region of lower
N

concentration to a region of higher concentration), utilizing energy, typically in the form

of ATP. This mechanism is selective and saturable, involving specific carrier proteins.
O

Active transport shows:

E

 Saturation kinetics (Michaelis-Menten type)

M

 Specificity for drug structure

 Competition between structurally similar molecules
O

A classic example is the absorption of levodopa via the large neutral amino acid
S

transporter (LAT1) in the intestine. Levodopa, used in Parkinson's disease, mimics the
structure of amino acids and utilizes this transporter to cross the intestinal membrane
actively.

Active transport is also crucial in the renal tubular reabsorption/secretion of drugs and
in crossing the blood-brain barrier.

c) What is the difference between absolute & effective surface area? How can it be
improved for hydrophobic drug?

Absolute surface area refers to the total surface area of a solid drug particle as
measured by instruments like BET surface area analyzer using nitrogen adsorption
techniques. It is the maximum measurable area, including all crevices and pores.

Effective surface area, however, is the portion of the surface area that is actually
available for drug dissolution in the gastrointestinal fluids. It may be lower than the
absolute surface area due to factors like particle aggregation or poor wetting in
aqueous media, especially for hydrophobic drugs.

Improving effective surface area for hydrophobic drugs:

 Micronization: Reduces particle size, increasing surface area.

 Surfactants: Improve wetting and dispersion in GI fluids (e.g., sodium lauryl
sulfate).

B
 Solid dispersions: Incorporate drug into a hydrophilic carrier to enhance
dissolution.

C
 Nanonization: Producing nanoparticles for enhanced dispersion and absorption.

R
This increases the dissolution rate per Noyes-Whitney equation and improves
bioavailability.

O M
d) What are the limitations of pH-partition Hypothesis?

R
The pH-partition hypothesis explains drug absorption based on the drug’s ionization in
different pH environments of the GI tract. It suggests that only the non-ionized
F
(lipophilic) form of a drug can passively diffuse across biological membranes.
E
Limitations include:
N

1. Oversimplification: Ignores transporter-mediated mechanisms (e.g., active

transport, facilitated diffusion).
O

2. Membrane characteristics: Fails to account for differences in membrane

permeability.
E

3. Drug solubility: Doesn’t consider aqueous solubility or drug precipitation.

4. Gastric emptying and motility: Physiological factors affecting drug residence
M

time are not included.

5. Presence of food and enzymes: Influence drug absorption but are not
O

considered.
6. Drug metabolism and degradation: The hypothesis assumes all absorbed drug
S

remains unchanged.

Thus, while useful conceptually, it cannot fully predict in vivo absorption profiles.

e) Discuss briefly factors affecting gastric emptying of drug.

Gastric emptying rate affects the rate and extent of drug absorption, especially for
drugs absorbed in the small intestine. Factors that delay gastric emptying may slow the
onset of drug action, while those that accelerate it can lead to faster absorption.

Key factors include:

  Meal type and size: High-fat and high-protein meals delay gastric emptying.
 Osmolality: Hyperosmolar solutions delay emptying.
 Viscosity: Viscous formulations slow gastric transit.
 Volume: Moderate volumes promote, while very large volumes may delay
emptying.
 Drugs: Anticholinergics (e.g., atropine), opioids (e.g., morphine) delay emptying;
prokinetics (e.g., metoclopramide) accelerate it.
 Disease states: Diabetes mellitus, hypothyroidism may delay gastric emptying.
 Emotional state: Stress and anxiety can alter motility patterns.

These factors influence drug dissolution, onset of action, and therapeutic efficacy.

B
f) Define the term biotransformation. List the factors affecting biotransformation of

C
drug.

R
Biotransformation refers to the chemical modification of drugs by the body, typically via
enzymatic reactions, transforming lipophilic drugs into more hydrophilic metabolites for
easier excretion. This primarily occurs in the liver via microsomal enzymes (e.g.,

M
cytochrome P450 system).

O
Phases of biotransformation:



R
Phase I: Functionalization reactions (oxidation, reduction, hydrolysis)
Phase II: Conjugation reactions (glucuronidation, sulfation, acetylation)
F
Factors affecting biotransformation:
E
1. Genetics: Polymorphisms in CYP enzymes.
N

2. Age: Neonates and elderly have slower metabolism.

3. Sex: Hormonal differences influence enzyme levels.
O

4. Liver function: Hepatic impairment reduces metabolism.

5. Enzyme induction/inhibition: e.g., rifampin induces CYP450; ketoconazole
E

inhibits it.
6. Diet: Grapefruit juice inhibits certain enzymes.
M

7. Drug interactions: Co-administered drugs may compete for the same enzyme.
8. Disease states: Infections, cancer, and inflammation can alter enzymatic activity.
O

Understanding biotransformation is crucial for predicting drug action duration and

S

toxicity.

g) Write in short about non-renal route of excretion.

Apart from renal (urinary) excretion, drugs and their metabolites can be eliminated via
non-renal routes, especially when they are poorly excreted in urine due to size, polarity,
or protein binding.

Major non-renal routes include:

1. Biliary excretion: Drugs secreted into bile (e.g., rifampin, digoxin) enter the
 intestine and may undergo enterohepatic recycling.
2. Pulmonary excretion: Volatile drugs (e.g., anesthetics like isoflurane) are
eliminated via exhalation.
3. Salivary excretion: Small, lipophilic drugs may be excreted into saliva (e.g.,
lithium).
4. Sweat and Sebum: Minor route; drugs like rifampin may discolor sweat.
5. Lactation: Lipid-soluble drugs may pass into breast milk (e.g., diazepam).
6. Skin and hair: Drugs/metabolites may deposit in keratinous tissues, useful for
forensic analysis.

These routes can be significant in drug toxicity (e.g., drugs excreted in breast milk
affecting infants) or drug testing (e.g., hair analysis).

BC
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EM OS

Set 2

a) Discuss the significance of protein binding of drugs.

Protein binding refers to the reversible interaction between a drug and plasma proteins
such as albumin (for acidic drugs), α1-acid glycoprotein (for basic drugs), and
lipoproteins. Only the free (unbound) drug is pharmacologically active, can cross
membranes, be metabolized, or excreted.

Significance of protein binding:

1. Distribution: Protein-bound drugs have limited tissue distribution due to large

size and poor membrane permeability. The extent of binding affects volume of
distribution (Vd).
2. Pharmacological activity: Only unbound drug exerts therapeutic effects. Highly
bound drugs have prolonged effects due to slow release.
3. Elimination: Only free drugs are filtered in kidneys and metabolized in liver.
Hence, binding reduces clearance and prolongs half-life.
4. Drug interactions: Co-administered drugs may compete for the same binding
sites, displacing each other and increasing the free drug concentration (risk of

B
toxicity).
5. Disease impact: Conditions like liver disease (hypoalbuminemia) can alter

C
binding capacity, affecting drug levels.
6. Dosage adjustments: Highly protein-bound drugs may require careful monitoring

R
and dose adjustments in renal or hepatic impairment.

M
Examples: Warfarin (~99% bound), diazepam, and phenytoin. Understanding protein
binding is crucial for dose calculations and avoiding drug interactions.

O R
b) Write a note on facilitated diffusion.
F
Facilitated diffusion is a passive transport mechanism in which drugs move across
biological membranes along their concentration gradient (high to low), but with the help
of specific carrier proteins. Unlike simple diffusion, this process is saturable and
E
selective, but it does not require energy (ATP).
N

Characteristics:
O

 Selective: Transporters recognize specific molecules (e.g., sugars, amino acids).

E

 Saturable kinetics: Follows Michaelis-Menten kinetics; transport rate plateaus at

high drug concentrations.
M

 Inhibitable: Can be competitively inhibited by structurally similar substances.

 Temperature sensitive: Since it involves conformational changes in the carrier
O

protein.
S

Examples:

 Glucose transport via GLUT proteins

 Transport of vitamin B12 or certain amino acids
 Certain drugs like gabapentin and levodopa use facilitated diffusion transporters
in the intestine.

Facilitated diffusion helps in the efficient absorption of some drugs which would
otherwise have poor lipid solubility, enhancing their bioavailability.

c) What is multi-compartment model?

The multi-compartment model describes the distribution and elimination of a drug from
the body in two or more kinetic compartments rather than assuming the body as a
single unit (as in one-compartment model). This model offers a more realistic
representation of how drugs behave in different tissues.

Types:

1. Two-compartment model:
o Central compartment: Blood and highly perfused organs (e.g., liver,
kidney).
o Peripheral compartment: Poorly perfused tissues (e.g., fat, muscle).
o After IV injection, the drug rapidly distributes in the central compartment,
then slowly equilibrates with peripheral tissues.

B
2. Three-compartment model: Adds another peripheral compartment, often used in
complex pharmacokinetics (e.g., anesthetics).

C
Importance:

R
 Explains biphasic plasma concentration curves (distribution and elimination

M
phases).
 Aids in accurate dosing, especially for drugs with large Vd or delayed tissue
binding.


O
Essential for modeling plasma vs tissue kinetics in clinical pharmacokinetics.
R
Example: Digoxin exhibits a two-compartment behavior. Understanding this helps avoid
F
toxicity by allowing enough time for tissue distribution before measuring plasma levels.
E
d) Explain with significance the study parameters used in bioavailability determination.
N

Bioavailability is the rate and extent to which an active drug ingredient is absorbed and
O

becomes available at the site of action or in the systemic circulation. Several

pharmacokinetic parameters are used to assess it:
E

1. Cmax (Maximum plasma concentration): Reflects rate of absorption.

M

o Higher Cmax = faster onset of action.

2. Tmax (Time to reach Cmax): Indicates the speed of absorption.
O

o Delayed Tmax may mean slow absorption or delayed gastric emptying.

3. AUC (Area Under the Curve): Represents the total drug exposure over time.
S

o Most accurate measure of extent of absorption.

o Calculated using trapezoidal rule from plasma concentration vs time
graph.

Significance:

 AUC is used to compare two formulations (e.g., generic vs innovator drug).

 These parameters help determine bioequivalence, dosing frequency, and
formulation optimization.
 Important in designing modified-release dosage forms.

Example: Comparing AUC and Cmax of oral vs IV dosage can reveal absolute
bioavailability.
e) What is the effect of particle size on the rate of drug dissolution?

Particle size plays a crucial role in the dissolution rate of solid drug formulations.
According to the Noyes-Whitney equation, the rate of dissolution (dC/dt) is directly
proportional to the surface area (A) of the drug particle:

dCdt=DA(Cs−C)h\frac{dC}{dt} = \frac{DA (C_s - C)}{h}

Where:

 A = Surface area of the drug

 Cs = Saturation solubility

B
 h = Diffusion layer thickness

C
Smaller particles → larger surface area → faster dissolution rate

R
Implications:

M
 Enhances bioavailability of poorly soluble drugs.
 Crucial for BCS Class II drugs (low solubility, high permeability).

O
 Micronization and nanonization are pharmaceutical techniques used to reduce
particle size.

R
Helps in rapid onset of action for drugs intended for fast relief.
F
Example: Griseofulvin and fenofibrate show improved absorption upon particle size
reduction.
E
However, extremely small particles may aggregate or show poor flow properties,
N

requiring stabilization techniques.

O

f) The absorption rate of pediatric and geriatric differ from that of adults, why?
E

The rate of drug absorption differs in pediatric and geriatric populations due to
M

physiological and anatomical differences compared to healthy adults.

O

Pediatric Considerations:
S

 Gastric pH: Higher in neonates (alkaline), affecting drug ionization and solubility.
 Gastric emptying: Delayed, leading to slower absorption.
 Enzyme activity: Immature metabolic enzymes and transporters can alter
absorption.
 GI surface area: Smaller, influencing extent of absorption.
 Microbiota: Underdeveloped, affecting drug metabolism (e.g., digoxin).

Geriatric Considerations:

 Reduced blood flow to GI tract.

 Decreased GI motility and gastric secretions.
 Altered enzyme activity and changes in pH may affect drug dissolution and
 solubility.
 Polypharmacy and disease states (e.g., diabetes, renal impairment) also affect
absorption kinetics.

Hence, both populations may show delayed onset, lower bioavailability, or

unpredictable plasma concentrations, necessitating dose adjustments.

g) Define bioavailability, absolute bioavailability, and relative bioavailability.

Bioavailability is the fraction (%) of an administered drug dose that reaches the
systemic circulation in an unchanged form. It reflects both the rate and extent of
absorption.

BC
1. Absolute Bioavailability (Fabs):

R
 Compares the bioavailability of a drug given orally (or other extravascular routes)
with that of the same drug given intravenously (IV).

M
Fabs=AUCoral×DoseIVAUCIV×Doseoral×100F_{abs} = \frac{AUC_{oral} \times
Dose_{IV}}{AUC_{IV} \times Dose_{oral}} \times 100

2. Relative Bioavailability (Frel): O

A drug given IV is 100% bioavailable.
RF
 Compares the bioavailability of a test formulation (e.g., generic) to a reference
E
formulation (e.g., innovator brand).
N

Frel=AUCtest×DoserefAUCref×Dosetest×100F_{rel} = \frac{AUC_{test} \times

Dose_{ref}}{AUC_{ref} \times Dose_{test}} \times 100
O

Importance:
E

 Ensures therapeutic equivalence.

M

 Helps in dosage form development.

 Affects drug approval and regulatory submissions.
O

Example: If AUC of oral dose is 80% of IV dose, absolute bioavailability is 80%.

S

Set 3

a) What is pinocytosis and phagocytosis? Give example.

Pinocytosis and phagocytosis are forms of endocytosis, where cells engulf substances from
their surroundings by invaginating their membrane.

1. Pinocytosis ("cell drinking"):

o It is a non-specific process where small solute molecules or fluids are engulfed
into small vesicles.
o The vesicles then transport these substances into the cytoplasm.
 oIt plays a role in drug absorption when drugs are large, lipid-insoluble, or polar
and cannot cross via diffusion.
o Example: Fat-soluble vitamins (like vitamin A and D) absorption in the intestine.
2. Phagocytosis ("cell eating"):
o It involves the engulfment of large particles, such as bacteria or cellular debris,
by specialized cells like macrophages.
o This is important more in immune response than in drug absorption.
o Not a major route for drug absorption, but can be important in delivery of
particulate drug carriers like liposomes or nanoparticles.

Significance in pharmacy:

 These mechanisms allow for uptake of macromolecular drugs (like insulin in special
formulations).

B
 Nanocarriers are often designed to utilize pinocytosis or phagocytosis for targeted
delivery.

R C
b) Explain in short about Facilitated diffusion.

M
Facilitated diffusion is a carrier-mediated, passive transport process where drugs move across
biological membranes down their concentration gradient with the assistance of specific carrier
proteins.

Characteristics:

 O
No energy required (ATP-independent).
RF
 Selective: Only specific substances are transported.
 Saturable: At high concentrations, all carrier proteins become fully occupied.
E
 Subject to inhibition by similar substrates or inhibitors.
 Influenced by temperature due to the conformational changes of the carrier.
N

Examples in drug transport:

O

 Transport of glucose by GLUT proteins.

E

 Levodopa, used in Parkinson’s disease, is absorbed via amino acid transporters.

 Gabapentin uses L-amino acid transporters.
M

Clinical significance:
O

 Useful for transporting hydrophilic drugs that cannot diffuse passively.

 Important consideration in formulation design and drug absorption enhancement.
S

c) What is the rate-limiting step in bioavailability?

The rate-limiting step is the slowest step in a sequence of events involved in drug absorption
and bioavailability, which determines how fast the drug reaches systemic circulation.

Possible rate-limiting steps:

1. Disintegration of dosage form – Important for solid oral forms like tablets.
2. Dissolution of drug – Especially for poorly soluble drugs (BCS Class II).
3. Permeability across membranes – Crucial for hydrophilic drugs.
4. Gastric emptying – Delays overall absorption.
Among these, the dissolution step is often the rate-limiting for poorly water-soluble drugs,
while membrane permeability may limit absorption of poorly permeable drugs.

Example:

 Griseofulvin and digoxin exhibit dissolution-limited absorption.

 For peptides like insulin, enzymatic degradation and membrane passage are limiting.

Understanding the rate-limiting step helps optimize drug formulations (e.g., by using solubilizers,
particle size reduction, or permeation enhancers) to improve bioavailability.

d) Explain binding of drug to Human Serum Albumin.

B
Human Serum Albumin (HSA) is the most abundant plasma protein and plays a crucial role in

C
binding a variety of acidic and neutral drugs. It acts as a carrier, facilitating distribution and
regulating free drug concentration.

R
Binding Sites:

M
 Site I (warfarin binding site): Binds warfarin, salicylates.
 Site II (benzodiazepine binding site): Binds diazepam, ibuprofen.

Significance of HSA binding:


O R
Only free (unbound) drug is active pharmacologically and available for metabolism or
F
excretion.
 Binding affects:
o Distribution (low free drug = low tissue penetration)
E
o Duration of action (prolonged for highly bound drugs)
o Drug interactions (displacement may cause toxicity)
N

o Clearance (bound drug not filtered in kidneys)

O

Examples:
E

 Warfarin: ~99% bound – small increase in free drug can cause bleeding.
 Phenytoin: Binding reduced in uremia, leading to toxicity.
M

Diseases like hypoalbuminemia (seen in liver or kidney disease) reduce protein binding,
O

increasing free drug levels and necessitating dose adjustments.

S

e) What is gastric emptying? Explain influence of food on drug absorption.

Gastric emptying is the process by which the contents of the stomach are transferred into the
small intestine. It is a critical factor influencing the rate and extent of drug absorption, as most
drugs are absorbed in the small intestine.

Factors affecting gastric emptying:

 Food (especially high-fat meals): Delays gastric emptying.

 Liquids: Empty faster than solids.
 Meal size and caloric content
 Drug properties: Certain drugs (e.g., anticholinergics) delay emptying.
  Pathological conditions: Diabetes, stress, pain.

Effect of food:

 Delayed gastric emptying slows the rate of absorption.

 Some drugs require an empty stomach for optimal absorption (e.g., levothyroxine,
tetracyclines).
 Enhanced absorption may occur for lipophilic drugs in presence of fats (e.g.,
griseofulvin, ritonavir).
 Food may also interact with drugs physically or chemically, affecting bioavailability.

Therefore, timing of meals relative to drug dosing is important in clinical practice to ensure
consistent absorption and therapeutic efficacy.

BC
f) What is an active transport?

R
Active transport is a type of carrier-mediated transport where drugs or molecules are moved
against their concentration gradient (from low to high concentration) using energy (ATP).

M
Features:

O
 Energy-dependent (ATP required)
 Selective and saturable
 Can transport against concentration gradient
R
 Involves specific carrier proteins or transporters.

F
Subject to competitive inhibition.

Examples:
E
 L-Dopa is transported by amino acid transporters in the gut.
N

 Folic acid and 5-fluorouracil use active transport in the intestine.

 P-glycoprotein (P-gp): An efflux pump that actively transports drugs out of cells (e.g., in
O

intestines, BBB), limiting absorption and enhancing excretion.

E

Clinical relevance:
M

 Active transport is key in drug absorption, especially for polar, large, or essential
nutrients.
O

 Overexpression of efflux transporters (e.g., P-gp) may reduce drug efficacy (e.g., in
cancer resistance).
S

g) What is the effect of protein binding on the action of the drug?

Protein binding significantly affects the pharmacokinetics and pharmacodynamics of a drug.

Drugs bind reversibly to plasma proteins (mainly albumin), forming a bound fraction and a free
(unbound) fraction.

Only the free drug:

 Crosses biological membranes

 Binds to receptors to produce pharmacological effects
 Is available for metabolism and renal excretion
Effects of protein binding:

1. Duration of action: High binding → prolonged action (slow release from protein
complex).
2. Volume of distribution (Vd): Lower for highly protein-bound drugs.
3. Drug interactions: Displacement by other drugs may increase free drug levels, causing
toxicity.
4. Clearance and half-life: Bound drug is not cleared easily, prolonging half-life.

Example:

 Warfarin (99% bound): A small change in binding can significantly raise free drug levels,
increasing bleeding risk.
 Phenytoin: High protein binding; dosage must be adjusted in hypoalbuminemic patients.

BC
In diseases like renal failure, liver disease, or during co-administration of multiple drugs,
monitoring protein binding becomes crucial to avoid adverse effects.

R M
O RF E
Set 4
O N

a) Define bioequivalence, pharmaceutical equivalence and therapeutic equivalence.

E

1. Pharmaceutical Equivalence: Two drug products are said to be pharmaceutically

M

equivalent if:

 They contain the same active ingredient(s),

O

 In the same dosage form,

 With the same route of administration,
S

 And the same strength or concentration.

However, they may differ in excipients, shape, release mechanisms, or packaging.

Example: Two 500 mg paracetamol tablets from different manufacturers are

pharmaceutically equivalent.

2. Bioequivalence: Two pharmaceutical equivalents are bioequivalent if:

 Their rate and extent of absorption (i.e., bioavailability) are not significantly
different when administered in the same molar dose under similar conditions.
This is demonstrated through pharmacokinetic parameters:

 Cmax (peak plasma concentration),

 Tmax (time to reach Cmax),
 AUC (area under the plasma concentration-time curve).

3. Therapeutic Equivalence: Two drugs are therapeutically equivalent if they are:

 Pharmaceutically equivalent, and

 Bioequivalent, and
 Expected to have the same clinical effect and safety profile when administered
to patients under the same conditions.

BC
Clinical Importance:

R
 Ensures interchangeability between brand-name and generic drugs.
 Avoids therapeutic failure or toxicity due to variability in drug absorption.

O M
b) What is the influence of GI pH on drug absorption?
R
The Gastrointestinal (GI) pH affects the ionization and solubility of drugs, which in turn
influences their absorption across biological membranes.
F
pH along GI tract:
E
 Stomach: pH 1–3 (acidic)
N

 Small intestine: pH 5–8 (slightly alkaline)

 Colon: pH 6–7.5
O E

Effect on drug ionization: Based on the Henderson-Hasselbalch equation, the degree of

M

ionization depends on:

 Drug’s pKa, and

O

 GI pH.
 Weak acids (e.g., aspirin): Absorbed better in acidic pH (stomach).
S

 Weak bases (e.g., diazepam): Absorbed better in alkaline pH (intestine).

Only the non-ionized form of a drug can diffuse across membranes and be absorbed.

Clinical Implications:

 pH-altering drugs like antacids, H₂-blockers, or proton pump inhibitors can affect
drug absorption.
o Example: Ketoconazole (a weak base) requires acidic pH for absorption.
 Enteric coatings are used to protect acid-labile drugs (e.g., omeprazole) or to
prevent stomach irritation.
Understanding pH influence helps in drug formulation and predicting drug interactions.

c) Write a short note on bio-waivers.

A biowaiver is a regulatory approval allowing the waiving of in vivo bioequivalence

studies, based on in vitro data and other scientific justifications.

Criteria for granting a biowaiver:

 Applies primarily to oral, immediate-release solid dosage forms.

B
 Drug must be a Class I or III drug under the Biopharmaceutics Classification
System (BCS).

C
BCS Classification:

R
 Class I: High solubility, high permeability
 Class III: High solubility, low permeability

O M
Requirements:



R
Rapid or very rapid in vitro dissolution (e.g., >85% in 30 minutes).
Similar dissolution profile between test and reference products.
F
 Drug should not have a narrow therapeutic index.
EN

Advantages:
O

 Reduces time and cost in generic drug development.

 Minimizes the need for clinical trials.
EM

Examples:
O

 Biowaiver allowed for generic paracetamol (Class I).

 Not suitable for drugs like warfarin (narrow therapeutic index).
S

Biowaivers promote fast-tracked access to generics while maintaining quality and

efficacy standards.

d) Explain clearance, renal clearance and renal clearance ratio.

1. Clearance (Cl): It is the volume of plasma from which a drug is completely removed
per unit time. It represents the efficiency of elimination.

Cl=Rate of eliminationPlasma drug concentration\text{Cl} = \frac{\text{Rate of

elimination}}{\text{Plasma drug concentration}}
It can be total body clearance or organ-specific clearance (e.g., renal, hepatic).

2. Renal Clearance (Clr): It is the volume of plasma cleared of the drug by the kidneys
per unit time.

Clr=(U×V)P\text{Clr} = \frac{(U \times V)}{P}

Where:

 U = drug concentration in urine

 V = urine flow rate
 P = plasma concentration

BC
3. Renal Clearance Ratio (R): This is the ratio of a drug’s renal clearance to that of inulin

R
or creatinine (which are filtered but neither secreted nor reabsorbed).

R=ClrdrugClrinulin/creatinineR = \frac{Clr_{drug}}{Clr_{inulin/creatinine}}

M
 If R = 1 → drug is only filtered.

O
 R > 1 → drug is secreted.
 R < 1 → drug is reabsorbed.

Clinical significance:
RF E
 Helps determine elimination route and adjust doses in renal impairment.
 Example: Penicillin (R > 1, actively secreted), urea (R < 1, reabsorbed).
O N

e) Name and define the pharmacokinetic processes involved in the termination of drug
action.
EM

The termination of drug action depends on how the drug is eliminated from the body,
governed by key pharmacokinetic processes:
O

1. Absorption – Entry of drug into systemic circulation.

2. Distribution – Reversible transfer of drug between blood and tissues.
S

3. Metabolism (Biotransformation) – Chemical alteration of the drug, mainly in the

liver, converting lipophilic drugs into more water-soluble forms.
4. Excretion – Removal of unchanged drug or metabolites via urine, bile, sweat, etc.

Key terminators of drug action:

 Metabolism: Inactivates drugs or converts them into active/inactive metabolites.

 Excretion: Eliminates drug/metabolites, mainly through the kidneys (renal
clearance) or liver (biliary excretion).
 Redistribution: In lipophilic drugs (e.g., thiopental), movement from the brain to
muscle/fat terminates action.
Clinical examples:

 Propranolol: Metabolized extensively in liver.

 Aminoglycosides: Excreted unchanged by kidneys.

Understanding these helps optimize dosage regimens and minimize drug toxicity.

f) What are limitations of pH-partition hypothesis?

The pH-partition hypothesis states that non-ionized, lipophilic drugs are best absorbed

B
across membranes, while ionized forms are poorly absorbed.

C
Limitations:

R
1. Neglects Carrier-Mediated Transport:

M
o The hypothesis assumes only passive diffusion, ignoring facilitated or
active transport mechanisms.
2. Ion Trapping:

O
o Some ionized drugs can still accumulate in tissues (e.g., weak bases in
acidic compartments like the stomach), not explained by the hypothesis.
R
3. Lipid Solubility Matters:
o Non-ionized form must still be sufficiently lipid-soluble to permeate
F
membranes.
4. Surface Area and Permeability:
E
o Small intestine absorbs even weak acids despite higher pH due to large
surface area and permeability, contradicting the hypothesis.
N

5. Stability in GI Tract:
o Acid-labile drugs may degrade in the stomach even if non-ionized.
O E

Conclusion: The hypothesis is a simplified model that works for many passive diffusion
M

cases, but real-world absorption is influenced by transporters, enzymes, and

physiochemical interactions.
O

g) What are the advantages of administering a drug by constant rate i.v. infusion over
S

oral administration?

Constant rate intravenous (IV) infusion allows a drug to be delivered continuously into
systemic circulation, maintaining stable plasma concentrations.

Advantages over oral administration:

1. Bypasses First-Pass Metabolism:

o Direct entry into bloodstream avoids hepatic metabolism, improving
bioavailability.
2. Controlled Plasma Levels:
 o Maintains steady-state concentration (Css), reducing peaks and troughs
that may cause toxicity or subtherapeutic effects.
3. Rapid Onset:
o Faster therapeutic effect, useful in emergency settings (e.g., dopamine,
lidocaine).
4. Predictable Pharmacokinetics:
o Less influenced by food, GI pH, motility, or enzyme degradation.
5. Drug Titration Possible:
o Dosage can be adjusted easily based on therapeutic response.
6. Suitable for Unconscious or Vomiting Patients:
o Ideal when oral route is not feasible.

B
Limitations:

C
 Invasive, needs sterile technique and medical supervision.

R
 Risk of infection, thrombosis.
 Not convenient for long-term outpatient therapy.

M
Despite limitations, constant IV infusion is crucial for precise dosing, especially in
critical care or when a narrow therapeutic window exists.

O RF E
O N
EM OS