2017 Pharmacology - Concepts of Pharmacokinetics

Question 1

Define pharmacokinetics? What does ADME stand for?

Answer 1

It is the processes that determine the concentration of a drug and its time course of action. A-absorption D-distribution M-metabolism E-excretion

Question 2

What are pharmacodynamics?

Answer 2

The processes to determine the intensity of a drug’s effect in relation to it’s concentration. dose-response relationships

Question 3

What are the major transport mechanisms for drugs to get to target cells?

Answer 3

Diffusion Filtration Endocytosis Ion-pair Facilitated Active

Question 4

What are some factors that affect drug absorption?

Answer 4

Formulation of a drug Particle size pH of environment Concentration/dose Circulation to site of absorption Absorbing surface area (greatest in small intestine) Physiological factors (GI) -gastric emptying time, GI motility -presence of food

Question 5

What is meant by the following drug routes: -Enteral -Parenteral -Other

Answer 5

Enteral - drugs placed directly into GI tract, typically oral but includes buccal, sublingual, rectal Parenteral -IV, IM Other -Inhaled

Question 6

What is the “first pass effect”?

Answer 6

Some oral drugs are partially inactivated or eliminated during their first pass through the GI tract, decreasing the amount of drug in the body. Can be avoided or mitigated using other routes.

Question 7

What is the definition of bioavailability?

Answer 7

Amount of a drug that reaches circulation unchanged (IV=100%) Determined by measuring the area under the drug concentration-time curve

Question 8

Understand differences in peak concentrations and time to peak concentrations as it pertains to AUC on drug concentration-time graphs.

Answer 8

Question 9

What are some factors that affect drug distribution?

Answer 9

Capillary/tissue membrane permeability

Tissue perfusion rate

Tissue mass

Binding of drug to plasma proteins and tissues

Regional difference in pH

Transport mechanisms

Question 10

What is the definition of volume of distribution?

How is it calculated?

What does it indicate?

Answer 10

: the apparent volume of fluid in which a drug seems to be distributed in the body

Vd=Dose of drug/Peak plasma [Concentration]

It indicates the relative size of the body compartment containing the drug (TBW, ECW, ICW, Plasma)

Question 11

What are some factors affecting Volume of Distribution of a drug?

Answer 11

Protein binding in circulation, lipid solubility of the drug

Body composition, Age, Sex, etc.

Question 12

What is special about the blood brain barrier, what is required to cross it?

Answer 12

Has tight capillaries, requires specialized proteins or carriers to cross it.

Ex. L-type amino acid transported for L-dopa

Question 13

How/where can drugs enter the CSF?

Answer 13

via the Choroid Plexus which is lined with fenestrated capillaries

Question 14

With regards to placental barriers, do lipid or water soluble drugs cross faster?

Answer 14

Lipid move faster

Water move slower

Question 15

How does redistribution work?

Answer 15

It may terminate the action of some drugs (highly lipid soluble) even through they remain in the body. Because the drug goes elsewhere in the body (Thiopental, IV anesthetic) acts quickly in brain then distributes to muscle for metabolism/elimination.

Question 16

What factors of Biotransformation (metabolism) aid in elimination?

Answer 16

Increased drug polarity or water solubility

Question 17

What is a prodrug?

Answer 17

Is given in an inactive form but is activated by the body through metabolism.

Classic example is ACE inhibitors which undergo hydrolysis.

Question 18

What are reactive metabolities and why are they of concern?

Answer 18

They are toxic metabolities or active metabolites in the body.

Tylenol/Acetaminophen is hepatoxic.

Question 19

What happens in Phase 1 of drug metabolism?

Answer 19

Alter and create new funcitonal groups or cleave ester/amides to release masked functional groups (more receptive to conjugation)

Question 20

What happens in Phase 2 of Metabolism?

Answer 20

Conjugation reactions couple the drug to an endogenous substrate (amino acid, acetic acid, glucurionic acid or sulfate) via a transferase, typically increases activity

• acetylation
• glucornidation
• sulfation

Question 21

Where are polar and nonpolar products of metabolism eliminated respectively?

Answer 21

Polar - urine

Nonpolar - biliary elimination

Question 22

What is the importance of Cytochrome P450/P450 Reductase?

Answer 22

Microsomal enzymes which catalyze conjugation reactions.

Located on smooth surface of ER.

Question 23

What is the major CYP Isoform in humans?

Answer 23

CYP3A4

Question 24

What are nonmicrosomal enzymes and what do they do (reaction types)?

Answer 24

Enzymes not in microsomes

Responsible for hydrolysis, oxidation and some reduction reactions

Catalyze ALL Phase 2 conjugations except glucuronidation

ex. acetyl-, methyl-, sulfo-, GSH-transferases

Question 25

Which type of enzymes (microsomal or nonmicrosomal) can undergo induction?

Answer 25

Only Microsomal

Question 26

What are some basic examples of Inducing Agents?

Result of induction?

Answer 26

Phenobarbital , Phenytoin (anticonvulsant) , Rifampin (antimicrobial which induces all Cytochrome C450 isozymes)

Environmental chemicals - PAHs (tobacco smoke)

Results in higher metabolism and lower drug levels in the body

Question 27

What are some methods by which enzymes can be inhibited?

Answer 27

Competative

Noncompetative

Reversible

Irreversible

Question 28

What are some examples of inhibitors? Result of inhibitors?

Answer 28

Competition between drugs: ketoconazole

Mechanism based: erythromycin

Results in lower metabolism and higher drug levels in the body

Question 29

How does genetic polymorphism affect Microsomal Enzymes and NonMicrosomal Enzymes respectively?

Overall affect of polymorphism?

Answer 29

Microsomal - variant allels affect rates of drug metabolism by CYPs (codine, warfarin)

-poor, extensive, ultrarapid metabolizers

Nonmicrosomal - variant allels affect rates of conjugation by transferases

-fast vs slow acetylators

**People metabolize drugs at different rates and they may need different dosing based on that rate of metaboism

Question 30

Is the kidney more effective at eliminating polar compounds or highly lipid soluble compounds?

Answer 30

Polar

Question 31

With regards to Urine pH and ion trapping which of the following pair:

Acidification/Alkalinization

Weak Acids/Weak Bases

Answer 31

Acidifcation promotes weak acid excretion

Alkalinization promotes weak base excretion

Question 32

What is Clearance as it relates to drug elimination?

Answer 32

the theoretical volme of plasma from which a drug is removed per unit time

Question 33

What factors can influence renal clearance?

Answer 33

a drugs Vd

degree of protein binding w/ drug

glomerular filtration rate

active tubular secretion

passive diffusion

Question 34

What is total clearance?

Answer 34

the sum of all clearances in the body

CL-hepatic + CL-renal + etc. = Clearance Total

Question 35

Understand the process of Enterohepatic Recycling of Drugs

Answer 35

Question 36

What is the difference between first-order and zero-order kinetics of elimination?

Answer 36

First Order: constant fraction (say 50%) of a drug present in the body is eliminated per unit time (most drugs)

Zero-order: constant amount (1g) of drug is eliminated per unit time (ethanol)

Question 37

Does Elimination Half-Life apply to first-order, zero-order, or both types of elimination kinetics?

Answer 37

Only First Order