Pharmacology Cell Membrane and Drug Disposition

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Questions and Answers

What determines the degree of ionization of acidic drugs in an environment?

The pH of the environment (correct)

The molecular size of the drug

The temperature of the environment

The route of administration

Which factor is NOT associated with the extent of absorption of drugs taken orally?

Altered gastric motility

Splanchnic blood flow

Liver enzyme activity (correct)

Particle size and formulation

What is the primary route through which drugs must pass to reach systemic circulation after being absorbed?

Via the portal circulation to the liver (correct)

Through interstitial fluid

Directly into the bloodstream

Through the lymphatic system

What is the Vd (volume of distribution) of a drug related to?

The concentration of the drug in blood or plasma Signup and view all the answers

What is the definition of bioavailability?

The proportion of drug concentration reaching systemic circulation Signup and view all the answers

What is primarily responsible for drug metabolism in the human body?

Liver Signup and view all the answers

Which statement is true regarding the distribution of drugs across the placental barrier?

Fetal blood levels are usually lower than maternal levels. Signup and view all the answers

What does the Phase-1 reaction of drug metabolism primarily involve?

Reduction, oxidation, and hydrolysis Signup and view all the answers

Which enzyme system is involved in Phase-1 metabolism?

Cytochrome P450 system Signup and view all the answers

How do lipophilic compounds typically exit the body?

Through metabolism via liver enzymes Signup and view all the answers

Which of the following groups can be conjugated during Phase-2 metabolism to enhance solubility?

Glutathione Signup and view all the answers

Which factor could decrease the activity of glucuronidation in neonates?

Reduced enzyme activity Signup and view all the answers

What is the primary function of CYP3A4 in drug metabolism?

Metabolizing a wide range of substrates Signup and view all the answers

What distinguishes fast acetylators from slow acetylators?

Genetically determined acetylation rates Signup and view all the answers

Which of the following drugs is known to inhibit the CYP3A4 enzyme?

Cimetidine Signup and view all the answers

Study Notes

Cell Membrane

Molecules cross cell membranes in four main ways: diffusion through lipids, diffusion through pores, carrier protein combination, and active transport.

Ionization Constant (pKa)

pKa is the pH where 50% of a drug is ionized.
Ionized drugs are poorly absorbed and unionized forms are more lipid soluble and rapidly absorbed.
Acidic drugs are less ionized in acidic environments and basic drugs are less ionized in basic (alkaline) environments.

Drug Disposition

Divided into four processes: absorption, distribution, metabolism, and excretion.

Bioavailability

The proportion of a drug that reaches systemic circulation following administration.
IV doses have 100% bioavailability.

Factors Affecting Bioavailability

Extent of absorption: Oral administration often results in incomplete absorption.
- Factors affecting GI absorption: altered gastric motility, splanchnic blood flow, particle size and formulation.
First-pass metabolism: After absorption, drugs pass through the liver via portal circulation, where they can be metabolized.

Volume of Distribution (Vd)

The ratio of the amount of drug in the body to the concentration of the drug in blood or plasma.
Vd = amount of drug in body / C (concentration)
The higher the Vd, the lower the plasma concentration, and vice versa.

Factors Controlling Distribution of Drugs

Blood flow
Molecular size
pKa
Plasma and tissue protein binding (only unbound drug exerts pharmacological effects).

Special Barriers to Distribution

Placental: Most drugs cross the placental barrier, but fetal blood levels are usually lower than maternal levels.
Blood-Brain: Permeable to lipid-soluble or very small drug molecules.

Drug Elimination

Drug metabolism: Enzymatic conversion of one chemical entity to another, mainly occurring in the liver.
Drug excretion: Elimination of drugs either unchanged or metabolized.

Drug Metabolism

Lipophilic compounds are not excreted by the kidney and need to become more soluble to be excreted.
Metabolism often occurs in the liver via the CYP450 system.
Metabolism can result in the formation of active metabolites (e.g., diazepam to nordiazepam).
Prodrugs lack activity until they undergo bioactivation (e.g., clorazepate to desmethyldiazepam).

Phases of Metabolism

Phase I Reactions (Catabolic): Oxidation, reduction, and hydrolysis reactions.
- Occur mainly in the smooth ER of liver, GI tract, lungs, and kidneys.
- Include NADPH cytochrome reductase and the CYP450 system.
- Require O2 and NADPH.
- Multiple CYP families vary by substrate specificity and sensitivity to inhibitors and inducers.
Phase II Reactions (Conjugation): Conjugation with other groups to increase solubility.
- Glucuronyl, sulfate, methyl, acetyl, glycine, and glutathione are commonly used groups.
- May follow a Phase I reaction or occur directly.
- Acetylation is genetically determined (fast vs. slow acetylators).
- Glucuronidation is inducible and reduced in neonates.

Renal Excretion

Glomerular Filtration Rate (GFR): Depends on the molecular weight of the drug and its extent of binding to plasma proteins.
Tubular Secretion: Transfer of drug molecules by two independent carrier systems (one for acidic compounds and one for basic compounds).
- Transports drugs against a concentration gradient, effectively reducing plasma concentration to zero (e.g., penicillin).
Diffusion across the renal tubules: Renal tubules can be freely permeable, allowing for equal drug concentrations in plasma and renal tubules.

Renal Clearance

Volume of plasma containing the amount of substance removed by the kidney per unit time.
CL = Rate of elimination / Plasma concentration (Cp).
Total body clearance (CL) = Renal clearance (CLR) + Extra-renal clearance (CLER).

Ionization and Renal Clearance

Ionization increases renal clearance of drugs.
Both ionized and non-ionized forms are filtered, but only free unbound drug is filtered.
Only non-ionized forms undergo secretion or active/passive reabsorption.
Ionized forms are trapped in the filtrate.

Drug Elimination Kinetics

First-order kinetics (un-saturable): Amount of drug removed is directly proportional to its concentration in plasma.
Zero-order kinetics (saturable): Drugs are removed at a constant rate regardless of plasma concentration levels (enzyme-dependent process with limited capacity).
- Example: Ethanol

Half-Life (t½)

Time required to eliminate 50% of the drug concentration.
t½ = Vd x 0.7 / CL.
Determines the time needed to reach steady state (occurs after 5 t1/2).

Clinical Significance of Half-Life

Reaching stable plasma drug concentrations.
Keeping drug levels below toxic levels but above the minimum effective level.
Determining the time needed to reach steady-state plasma concentrations (occurs after 5 t1/2).

Steady-State Plasma Concentration

The steady level of drug in plasma achieved when the rate of administration equals the rate of elimination.
Reached after 5 t1/2.
If the dose is changed, the new steady state is reached after another 5 t1/2.

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Description

Explore the essential concepts of cell membrane dynamics and drug disposition in this quiz. You'll learn about how drugs cross membranes, the significance of pKa, and the processes of absorption, distribution, metabolism, and excretion. Test your understanding of bioavailability and the factors that affect it.