Pharmacokinetics + Pharmacodynamics Flashcards
Pharmacokinetics is the study of:
Pharmacodynamics is the study of:
PK: study of factors determining the amount of drug at the receptor site (dose-concentration)
PD: study of mechanisms by which drugs produce their biological effects (dose-response)
What does knowledge of pharmacokinetics help with?
Helps choose most effective route, dosage and schedule and permits prediction of changes in concentration of a drug with time
Match the terms to their definitions:
1) Absorption
2) Distribution
3) Metabolism
4) Excretion
A) elimination of a chemically unchanged drug, or its metabolites, from the body.
B) aka biotransformation. Enzymatic conversion of a chemical entity (drug) into another.
C) movement of drug from site of administration into blood. generally involves crossing a BIOLOGICAL membrane. CRITICAL determinant of how rapidly the effects of a drug will be seen
D) movement of drug through the body and to its SOA generally via vascular system.
Absorption: movement of drug from site of administration into blood. generally involves crossing a BIOLOGICAL membrane. CRITICAL determinant of how rapidly the effects of a drug will be seen
Distribution: movement of drug through the body and to its SOA generally via vascular system.
Metabolism: aka biotransformation. Enzymatic conversion of a chemical entity (drug) into another.
Excretion: elimination of a chemically unchanged drug, or its metabolites, from the body.
*Elimination = the irreversible loss of drug from the body. two processes contribute to drug elimination: metabolism and excretion
What are the four factors absorption is dependent on?
1) Chemical and physical properties of the drug (larger + polar drugs have a diff time crossing membranes)
2) Surface area for penetration (greater SA = greater absorption)
3) Route of administration
4) pH at site of absorption (determines if drug will be polar or not)
(T/F) Membranes function as a barrier to the free movement of drug in and out of the bloodstream. Ability to cross membrane determines where and how long a drug will be present in the body.
True!
*crossing the membrane determined by polarity + size of drug
What are the three ways to cross a membrane?
1) channels and pores
2) transport systems
3) penetration of the membrane
Match the ways to cross a membrane to their descriptions:
1) Channels and pores
2) Transport systems
3) Penetration of the membrane
A) MOST COMMON mechanism for absorption (most drugs are too large or lack transport systems). Drug must be lipid soluble to penetrate the lipids.
B) Usually in ION FLOW, may be exploited for absorption of certain drugs. RARE mechanism of drug absorption. Only very small compounds (MW<200Da) can pass.
C) Large protein-mediated movement of drugs across a membrane. Structure-specific/selective (drug is similar to endogenous compounds). Can be passive or active transport.
Channels and pores: Usually in ION FLOW, may be exploited for absorption of certain drugs. RARE mechanism of drug absorption. Only very small compounds (MW<200Da) can pass.
Transport systems: Large protein-mediated movement of drugs across a membrane. Structure-specific/selective (drug is similar to endogenous compounds). Can be passive or active transport.
Penetration of the membrane: MOST COMMON mechanism for absorption (most drugs are too large or lack transport systems). Drug must be lipid soluble to penetrate the lipids.
Distinguish passive and active transport and the different types of active transport.
Passive transport: no energy required + drug moves WITH a concentration gradient
Active transport: energy required + drug moves AGAINST a concentration gradient
Primary active transport: ATP-dependent
Secondary active transport: coupled transport down a concentration gradient is used to fuel movement
(T/F) Many drugs are weak acids/bases. They exist as both ionized and unionized forms in a ratio that varies according the pH of the surrounding environment.
True!
Uncharged (unionized) is sufficiently soluble in membrane lipids to cross cell membranes.
Ionized (charged) is incapable of crossing membranes.
If pH = pKa then A- = HA. This means ____% of the drug is ionized.
50
(T/F) The pH at the site of absorption can vary greatly in the esophagus. Major impact on orally administered drugs.
False!
The pH at the site of absorption can vary greatly in the INTESTINE. Major impact on orally administered drugs.
HA <–> H+ + A-
BH+ <–> H+ + B
1) If pH < pKa, more _____ or _____
2) If pH > pKa, more _____ or ______
3) In the stomach (pH 1-3), would a weak base (pKa 8) or a weak acid (pKa 3.5) be absorbed more readily?
4) In the intestine (pH 7), would a weak base or a weak acid be absorbed more readily?
HA + BH+
A- or B
1) HA or BH+
2) A- or B
3) Weak base (pH<pKa): BH+, Weak acid (pH<pKA): HA. The acid would be absorbed more readily.
4) Weak base (pH<pKa): BH+, weak acid (pH>pKa): A-: Less of BH+; so weak base would be absorbed more readily (?)
What is enteric coating? Why is it used?
Enteric coating is a polymer barrier applied to oral drugs to prevent exposure to the stomach. Surface is stable at low pH but breaks down in more neutral/alkaline environments.
It is used because:
1) The high acidity of the stomach can lead to inactivation of many drugs.
2) Many drugs can also be damaging to the stomach lining.
If the pKa of a drug is 7.1 and the pH of the stomach is 2.5, what percent of the drug will be ionized when administered?
Can this drug be taken orally?
0.002% ionized!
The overwhelming majority of the drug is unionized and able to be absorbed in the stomach! Thus, it can be taken orally.
What are proteolytic enzymes? How can they be overcome?
Proteolytic enzymes in the digestive system inactivate drugs!
Example: insulin, liraglutide, “peptide drugs”
Emerging approaches such as nanoparticles, permeation enhancement and conjugation may enable use of oral peptide drugs!
A route of absorption is topical (local effect).
Describe it. Give examples. What are the barriers to absorption? What are the advantages and disadvantages?
Description: Drug administered externally directly at the site of action.
Examples: ear/eye drops, antibiotic creams (polysporin), sunscreens
Barriers to absorption: no barriers, drug reaches site of action immediately
Advantages: Easiest route. Drug administered = drug at site of action.
Disadvantages: Irritation can occur (formulation is little acidic; hypersensitivity). Limited applicability, SOA must be external.
A route of absorption is topical (systemic effect).
Describe it. Give examples.
What are the barriers to absorption?
What is the absorption pattern?
What are the advantages and disadvantages?
Description: drug administered externally, is absorbed through skin and enters bloodstream through dermal vessels.
Examples: nicotine, nitroglycerine, estrogen patches
Barriers to absorption: skin and adventitia around dermal blood vessels (arm vs heel)
Absorption pattern: generally slow + incomplete. best with low dose, low MW, lipid soluble drugs.
Advantages: convenience, sustained release reduces need for repeated dosing
Disadvantages: limited uses (few drugs will cross the skin at sufficient concentrations)
Match the three different types of skin absorption to their definitions:
1) Transcellular absorption
2) Intercellular absorption
3) Follicular absorption
A) drug enters via hair follicle. generally for small, non-polar compounds. follicular absorption is usually minimal.
B) drug crosses through cells (gets into the blood with the highest concentration). most common. generally for small, non-polar compounds
C) drug crosses around cells. less selective since drug does not cross cell membrane (minor contributor to drug absorption)
Transcellular absorption: drug crosses through cells (gets into the blood with the highest concentration). most common. generally for small, non-polar compounds
Intercellular absorption: drug crosses around cells. less selective since drug does not cross cell membrane (minor contributor to drug absorption)
Follicular absorption: drug enters via hair follicle. generally for small, non-polar compounds. follicular absorption is usually minimal.
(T/F) Entering the bloodstream does NOT mean that a chemical will be active once it does! A drug must be at a certain threshold to achieve its effects.
True!
A route of absorption is oral (po).
Describe it. Give examples.
What are the barriers to absorption?
What is the absorption pattern?
What are the advantages and disadvantages?
Description: Drug is swallowed and absorbed through the digestive system.
Examples: acetominophen, ACE inhibitors, statins
Barriers to absorption: Epithelial lining of GI tract. Capillary wall of blood vessels in GI system.
Absorption pattern: Slow + variable
Advantages: painless, east, economical, can be done at home + potential reversibility/arrest
Disadvantages: requires conscious and cooperative patient. potential for inactivation in stomach (acid/proteolytic enzymes). variability in absorption (first-pass effect)
A route of absorption is sublingual (SL).
Describe it. Give examples.
What are the barriers to absorption?
What is the absorption pattern?
What are the advantages and disadvantages?
Description: drug is placed beneath the tongue.
Examples: buprenorphine (suboxone), nitroglycerin, and nifedipine
Barriers to absorption: (thin) dermal layer in the tongue (highly vascularized)
Absorption pattern: rapid entry to blood stream
Advantages: rapid absorption, reversible, first pass effect avoided, may be used in unconscious patients
Disadvantages: unpleasant taste, irritation of mucous membrane, drug can be swallowed (altered PK)
A route of absorption is intravenous (IV).
Describe it. Give examples.
What are the barriers to absorption?
What is the absorption pattern?
What are the advantages and disadvantages?
Description: Drug is administered by injection directly to vein.
Examples: morphine, anesthetics
Barriers to absorption: none (100% gets absorbed)
Absorption pattern: N/A
Advantages: immediate, bypass first pass, emergency, compatible with unconscious patients, real time titration of dose possible, large volume of drug allowed, diluted irritant can be injected, blood plasma/fluids can be injected in conjunction with drug.
Disadvantages: irreversible (greater risk with dosing calculations), infection?, phlebitis (inflammation of blood vessels), infiltration of surrounding tissues, highly lipid soluble drugs not possible
A route of absorption is rectal (PR).
Describe it. Give examples.
What are the barriers to absorption?
What is the absorption pattern?
What are the advantages and disadvantages?
Description: Drug administered rectally. Solid: SUPPOSITORY. Liquid/gas: ENEMA.
Examples: Indomethacin (anti-inflammatory)
Barriers to absorption: drug is absorbed through rectal lining and enters enteric circulation (fairly superficial but not as much as sublingual)
Absorption pattern: slow, although more rapid than oral. Partial “first pass effect”
Advantages: compatible with unconscious patients, avoids nausea + vomiting, cannot be destroyed by stomach enzymes
Disadvantages: rectal, partial first pass effect
A route of absorption is subcutaneous (SC).
Describe it. Give examples.
What are the barriers to absorption?
What is the absorption pattern?
What are the advantages and disadvantages?
Description: Drug is administered under the skin
Examples: insulin
Barriers to absorption: capillary walls of dermal vessels (still better than oral)
Absorption pattern: slow
Advantages: absorption is slow + constant. compatible with highly lipid soluble drugs.
Disadvantages: limited volume. local inflammation/abscess formation. absorption dependent upon blood flow to region.
*45˚
A route of absorption is Intramuscular (IM).
Describe it. Give examples.
What are the barriers to absorption?
What is the absorption pattern?
What are the advantages and disadvantages?
Description: drug injected directly into muscle
Examples: vaccines
Barriers to absorption: capillary wall of muscle vessels
Absorption pattern: generally slow
Advantages: absorption is slow + constant. compatible with highly lipid soluble drugs.
Disadvantages: limited volume. local inflammation/abscess formation. absorption dependent upon blood flow to region.
*90˚
A route of absorption is Inhalation
Describe it. Give examples.
What are the barriers to absorption?
What is the absorption pattern?
What are the advantages and disadvantages?
Description: drug is taken in during breathing through lung
Examples: corticosteroids, nitrous oxide
Barriers to absorption: alveolar lining, lung capillary wall (blood vessels most superficial in lungs)
Absorption pattern: rapid
Advantages: rapid onset of action. certain drugs can be targeted to lung with lower system levels (bronchodilators)
Disadvantages: gaseous drugs better, technique can impact degree of drug delivery/absorption
Rank the routes of drug administrations displayed below in order, where 1 is the fastest.
IM/SC, IV, skin, SL, Inhalation, Ingestion, rectal
1) IV
2) Inhalation
3) SC
4) IM/SC
5) Rectal
6) Ingestion
7) Skin
Briefly describe the First Pass Effect.
A rapid inactivation of drug prior to entry into the systemic circulation.
Drugs absorbed in GI tract enter the portal circulation. Therefore, they are exposed to the liver (and its metabolizing enzymes) prior to distribution to the rest of the body.
It is a major consideration for drugs taken orally. They get metabolized before reach the SOA - PRE-SYSTEMIC METABOLISM!
Certain drugs (morphine, nitroglycerine, buprenorphine) are subject to such an extensive first pass effect that they must be given via alternative routes.
Describe Bioavailability. What can reduce it?
Bioavailability: fraction of unchanged drug that reaches the systemic circulation.
F = AUC dose absorbed/AUC dose administered
IV administation F=1!
The fraction will be reduced by incomplete absorption and by hepatic metabolism (1st pass effect). Or by factors like food/drug interactions, intestinal motility, efflux transporters etc.
For a 70kg male, the IV AUC of drug X from a 200 mg dose is 150 mg.hr/L. The oral AUC from a 200 mg dose is 13.2 mg.hr/L.
What is the bioavailability of drug X?
What other conclusions can we draw from these data?
F = AUC po dose absorbed / AUC IV dose administered
F = 13.2/150 = 0.088 or 8.8%
With such a low bioavailability, this drug would be better administered parenterally.
The oral bioavailability of drug Y is ~80%. The standard IV dose is 40 mg.
What dose would need to be administered ORALLY to achieve the same plasma concentration as the IV dose?
F = dose absorbed/dose administered
0.80 = 40mg/X
X = 50 mg
Speed of the drug distribution (equilibration with plasma) depends on the nature of the compartment it is distributing to.
Differentiate the two compartments.
1) Central compartments: highly perfused tissues, rapid equilibration. rapid clearance upon drug removal. HEART, LIVER, BRAIN, KIDNEY and BLOODSTREAM.
2) Peripheral compartments: organs with less or more variable perfusion. slower clearance upon drug removal. ADIPOSE TISSUE, SKELETAL MUSCLE.
*drug enters and leaves rapidly in 1 unlike 2
Movement of drug between compartments (distribution) may be rapid or slow.
What is the difference between single and multiple compartment distribution?
Single compartment distribution: Drug distribution between compartments is immediate (behave as one). Reductions in plasma concentrations due to metabolism/elimination.
Multiple compartment distribution: Drug distribution is slow. More common. Reduction in plasma concentrations first due to distribution to peripheral compartments and then due to elimination.
Certain drugs can partition selectively to individual compartments (i.e., lipophilic drugs in adipose tissues). This can impact on the AMOUNT OF DRUG NEEDED and on the CLEARANCE OF A DRUG.
