PRELIM 02 - Pharmacokinetics Flashcards
Refers to any set of physical properties whose value determine the pharmacokinetic characteristics or behavior of the drug
Pharmacokinetic parameters
Absorption (Pharmacokinetic parameter)
Bioavailability
Distribution (Pharmacokinetic parameter)
Volume of distribution
Metabolism and excretion (2 pharmacokinetic parameters) (HC)
Half-life, Clearance
An organelle is that semipermeable; follows the fluid mosaic model
Cell membrane
A double layer of amphiphilic phospholipids; found in the cell membrane
Lipid bilayer
Proteins that span the cell membrane
Integral proteins
Proteins that are attached to the cell membrane; modules function of integral proteins
Peripheral proteins
Refers to spontaneous movement of molecules across a concentration gradient; no energy required
Diffusion/Passive transport
Refers to transport of molecules against a concentration gradient; requires energy
Active transport
Diffusion through the cell membrane or between cells; major process for transport of most drugs (Types of diffusion)
Simple diffusion
2 types of simple diffusion (TP)
Transcellular, Paracellular
Most drugs that undergo transcellular diffusion through the lipid bilayer are __________, __________, and __________ (HUN)
Hydrophobic, Unionized, Nonpolar
Done by carrier proteins; saturation may occur (Types of diffusion)
Facilitated diffusion
Glucose, and vitamins B1, B2, and B12 undergo __________ diffusion
Facilitated
Transport that is carrier-mediated and is accompanied by an energy-producing process
Active transport
Moves substances by using energy produced by ATP hydrolysis; pumps coupled to ATPase (Types of active transport)
Primary active transport
Moves substances by using kinetic energy from the concentration gradient established by primary active transport (Types of active transport)
Secondary active transport
5-fluorouracil, methyldopa, levodopa, methotrexate, and iron salts undergo __________ transport
Active
Transport the involves vesicles and requires energy
Vesicular transport
Engulfment by the cell membrane of particles larger than 500 nm (Types of endocytosis)
Phagocytosis
Polio and other vaccines undergo __________ (Types of endocytosis)
Phagocytosis
Engulfment of small droplets of extracellular fluid by membrane vesicles (Types of endocytosis)
Pinocytosis
Vitamins A, D, E, K undergo __________ (Types of endocytosis)
Phagocytosis
Receptors on cell surfaces bind with ligands to form ligand-receptor complexes on cell surfaces (Types of endocytosis)
Receptor-mediated endocytosis
The material internalized by the membrane domain is transported through the cell and secreted on the opposite side (Types of endocytosis)
Transcytosis
Refers to the movement of solvent from a less concentrated solution to a more concentrated solution through pores
Osmosis
Refers to the movement of small molecules with the solvent during osmosis
Solvent drag
Water, sugars, and urea undergo __________ and __________ (SO)
Solvent drag, Osmosis
Transport wherein oppositely charged molecules interact and form a neutral complex
Ion-pair transport
Quaternary ammonium compounds and sulfonic acids undergo __________ transport
Ion-pair
Refers to the process of movement of unchanged drug from the site of administration to systemic circulation
Absorption
Effects that involves the metabolism of drug before it reaches the circulation
First pass effect
Intestinal metabolism is due to __________ enzymes (mainly CYP3A4)
CYP450
Primary site of drug metabolism
Liver
A measure of the extent to which the drug reaches the systemic circulation following administration by any route
Bioavailability (F)
Compares the amount of the active drug reaching the systemic circulation following extravascular administration with the amount of the same drug following intravenous administration (Types of bioavailability)
Absolute bioavailability
Compares the amount of the active drug reaching the systemic circulation following administration of a test formulation with the amount of the same drug following administration from a reference formulation (Types of bioavailability)
Relative bioavailability
A measure that compares the bioavailability of multisource drug products with the innovator drug product
Bioequivalence
Drug products that contain the same active drug substance; marketed by more than one pharmaceutical manufacturer; examples include generic drug products
Multisource drug products
Drug products that are marketed as new chemical entities
Innovator drug products
Means that there is no clinically significant difference in bioavailability
Bioequivalent
Bioavailability and bioequivalence testing may be __________ or __________ (II)
In vivo, In vitro
Refers to the maximum concentration of drug in the plasma
Peak plasma concentration (Cmax)
Unit of peak plasma concentration (Cmax)
mcg/mL
Refers to the time for a drug to reach peak plasma concentration after administration
Time of peak concentration (Tmax)
Unit of time of peak concentration (Tmax)
Hours
Refers to the total integrated area under the plasma drug concentration-time profile
Area under the curve (AUC)
Unit of area under the curve (AUC)
mcg-h/mL
Refers to the minimum concentration of drug in the plasma required to produce the therapeutic effect
Minimum effective concentration (MEC)
The level of plasma drug concentration below MEC
Subtherapeutic level
Refers to the minimum concentration of drug in the plasma that produces adverse or unwanted effects
Minimum toxic concentration (MTC) or Maximum safe concentration (MSC)
The time required for the drug to start producing pharmacologic response
Onset of action
F=1 by definition (Route of administration)
Intravenous
0.75 < F < 1 (2 routes of administration) (SI)
Subcutaneous, Intramuscular
0.05 < F < 1 (Route of administration)
Oral ingestion
Bioavailability is complete (F=1); distribution is rapid (Route of administration)
Intravenous (IV)
The rate of absorption via simple diffusion is constant and slow to provide a sustained effect (Route of administration)
Subcutaneous (SC)
Drugs can be in aqueous solutions (absorbed rapidly) or in specialized depot preparations (absorbed slowly) (Route of administration)
Intramuscular (IM)
A drug is injected directly into an artery to localize its effect in a particular tissue or organ (Route of administration)
Intra-arterial (IA)
Produces local and rapid effects of drugs on the meninges or cerebrospinal axis (Route of administration)
Intrathecal
Access to the circulation is rapid by this route because the lung’s surface area is large (Route of administration)
Inhalational
It achieves a local and direct effect (Route of administration)
Topical
This route is most often used for the sustained delivery of drugs (Route of administration)
Transdermal
It is the safest and most common, convenient, and economical method of drug administration (Route of administration)
Oral (PO)
Venous drainage from the mouth is to the superior vena cava, bypassing the portal circulation (Route of administration)
Sublingual (SL)
Approximately 50% of the drug that is absorbed from the rectum will bypass the liver (Route of administration)
Rectal
pH range of the stomach
pH 1-3.5
pH range of the small intestine
pH 6-7.5
According to this theory, the unionized form of an acidic or basic drug, if sufficiently lipid soluble, is absorbed but the ionized form is not
pH partition theory
The higher the surface area, the __________ the extent and rate of absorption
Greater
Most drugs are absorbed in the __________ because of its large surface area and gradually changing pH
Small intestine
Refers to the distribution of the drug into interstitial and intracellular fluids
Distribution
A __________ is not a real physiologic or anatomic region but is considered a tissue or group of tissues that have similar blood flow and drug affinity
Compartment
The body is a single homogenous compartment; most drugs follow this model (Types of compartment models)
One-compartment model
Its subtypes include central compartment and tissue compartment (Types of compartment models)
Two-compartment model
Includes the blood and highly perfused lean organs such as the heart, brain, liver, lung, and kidneys (Types of two-compartment models)
Central compartment
Includes the slowly perfused tissues such as muscle, skin, fat, and bone (Types of two-compartment model)
Tissue compartment
Refers to the measure of the apparent space in the body available to contain the drug
Volume of distribution (Vd)
Humans are ___________% water
60%
The Vd of the plasma compartment for a 70 kg man or 6% of body weight is __________ L
4
Drugs with ___________ are too large to move out through the endothelial slit junctions and are effectively trapped within the plasma compartment
Very large molecular weight
The Vd of the extracellular fluid for a 70 kg man or 20% of body weight is __________ L
14
In extracellular fluid, drugs with low molecular weight and are __________ can move through the endothelial slit junctions of the capillaries into the interstitial fluid
Hydrophilic
The Vd of the total body water for a 70 kg man or 60% body weight is __________ L
42 L
In total body water, drugs with low molecular weight and are __________ can move into the interstitium through the slit junctions
Hydrophobic
Small water-soluble molecules: eg, ethanol (Fluid compartment in the body)
Total body water
Larger water-soluble molecules: eg, gentamicin (Fluid compartment in the body)
Extracellular fluid/water
Larger protein molecules: eg, antibodies (Fluid compartment in the body)
Plasma compartment
Highly lipid-soluble molecules: eg, diazepam (Fluid compartment in the body)
Fat
Certain ions: eg, lead, fluoride (Fluid compartment in the body)
Bone
Refers to the volume of blood that circulates in the cardiovascular system and reaches different organs and tissues in the body per unit of time
Blood flow
Unit of blood flow
mL/min
Refers to the amount of xenobiotic that can be stored or distributed in a tissue that depends on the mass of tissue or size of organ
Tissue size
Refers to the distribution of a compound in a region of the body that depends on the blood flow to that region
Tissue perfusion
Refers to the diffusion of drug into extravascular tissues
Tissue diffusion
Are proteins that are neutral molecules and are highly lipophilic
Lipoproteins
Are proteins that are acidic/weakly acidic compounds in ionized form with moderate or marked lipophilicity
Albumin
Are proteins that are ionized, basic compounds with moderate lipophilicity
α-1-acid glycoprotein (AGP)
Phenytoin, salicylates, phenylbutazone, disopyramide, and penicillins bind to ___________
Albumin
Propanolol, saquinavir, imipramine, quinidine, and lidocaine bind to ____________
α-1-acid glycoprotein (AGP)
Chlorpromazine binds to ___________
Lipoproteins
Happens when drugs with the same binding site compete for interaction
Drug displacement
Refers to a barrier composed of tight junctions of endothelial cells of cerebral capillaries; drug distribution is highly regulated and limited here
Blood-brain barrier (BBB)
Cells that form a solid envelope around the brain capillaries
Astrocytes
Most antibiotics like __________ cannot penetrate the blood-brain barrier (BBB)
Penicillins
One must use ___________ for parkinsonism instead of dopamine
Levodopa
A barrier that is not effective as the blood-brain barrier (BBB)
Placental barrier
Many drugs such as ethanol, sulfonamides, barbiturates, gaseous anesthetics, and some antibiotics cross the placental barrier by __________
Simple diffusion
Nutrients for fetal growth such as glucose, amino acids, minerals, some vitamins, purines, and pyrimidines cross the placental barrier by __________
Carrier-mediated/Energy requiring process
Drugs such as thalidomide, phenytoin, isotretinoin, testosterone, and methotrexate show teratogenic effects during the __________, which is the stage where fetal organs develop
1st trimester
Refers to the conversion of drugs into more hydrophilic metabolites for elimination and termination of biological and pharmacological activity
Metabolism/Biotransformation
Primary organ for drug metabolism
Liver
Lungs, kidneys, intestine, placenta, adrenals, and skin are organs that perform __________ metabolism
Extrahepatic
Are enzymes that are different from the enzymes that metabolize food
Drug metabolizing enzymes
Enzymes that metabolize the majority of drugs; catalyze oxidation, reduction, hydrolysis, and glucuronidation reactions (Types of drug metabolizing enzymes)
Microsomal enzymes
Microsomes (fragments that contain microsomal enzymes) are derived from __________
Rough endoplasmic reticulum
Enzymes that include those that are present in the cytoplasm and those attached to the mitochondria but not to the RER (Types of drug metabolizing enzymes)
Non-microsomal enzymes
2 phases of metabolism
Phase I, Phase II
A polar functional group is introduced/unmasked on the otherwise lipid-soluble substrate; include oxidation, reduction, and hydrolysis (Phases of metabolism)
Phase I
Products of Phase I metabolism
Primary metabolites
A flavoprotein; contains FMN and FAD; a monooxygenase in Phase I metabolism
NADPH CYP450 oxidoreductase
A hemeprotein; a monooxygenase in Phase I metabolism
Cytochrome P450 (CYP450)
Represents a superfamily of heme containing enzymes; involved in Phase I metabolism
Cytochrome P450 (CYP450)
A member of the oxidoreductase family; present in high concentrations in the liver and kidney; involved in metabolism of alcohols (Other Phase I enzymes)
Alcohol dehydrogenase
Metabolize aldehydes to less reactive forms (Other Phase I enzymes)
Aldehyde dehydrogenase
Deamination of diamines not monoamines (Other Phase I enzymes)
Diamine oxidase (Histaminase)
Metabolism of purine bases and hypoxanthine to xanthine and finally to uric acid (Other Phase I enzymes)
Xanthine oxidase (XOD)
Catalyze the hydrolysis of a large number of structurally diverse esters, aides, thioesters, and carbamates in humans (Other Phase I enzymes)
Carboxylesterases (CES)
Hydrolyze the peptide bonds of proteins and peptides (Other Phase I enzymes)
Peptidase (Protease/Proteinase)
Small polar endogenous compounds are covalently attached to the unchanged drug or products of Phase I metabolism; involves conjugation or synthetic reactions (Phases of metabolism)
Phase II
Enzymes involved in Phase II metabolism
Transferases
Refers to the increased drug metabolizing ability of the enzymes by drugs and other substances
Enzyme induction
The agent that brings about enzyme induction
Inducers
Most inducers are __________ with long elimination half lives
Lipophilic
Includes several drugs and pesticides (Types of inducers)
Phenobarbital type inducers
Includes 3-methyl cholanthrene and cigarette smoke (Types of inducers)
Polycyclic hydrocarbon type inducers
Carbamazepine, meprobamate, cyclophosphamide, and rifampicin are capable of __________ or __________ (AS)
Auto-induction/Self-induction
Result from interaction at the enzymatic site, the net outcome being a change in enzyme activity (Type of enzyme inhibition)
Direct inhibition
Structurally similar compounds compete for the same site (Type of direct inhibition)
Competitive inhibition
A structurally unrelated compound interacts with the enzyme at a different site from the drug being metabolized (Type of direct inhibition)
Noncompetitive inhibition
Metabolic products compete with the substrate for the same enzyme (Type of direct inhibition)
Product inhibition
Involves decrease in enzyme content (Type of indirect inhibition)
Repression
Ethionine, puromycin, and actinomycin D results in __________
Decreased synthesis
CCl4, CS2, and disulfiram results in __________
Increased degradation
Involves nutritional deficiency or hormonal balance (Type of indirect inhibition)
Altered physiology
Metabolism is __________ related to volume of distribution (Vd)
Inversely
The microsomal enzyme system is not fully developed up to __________ months
2
__________ is well developed in newborns (e.g. sulfate conjugation of paracetamol)
Sulfation
__________ is not developed in newborns (e.g. chloramphenicol in newborns lead to kernicterus and gray baby syndrome)
Glucuronidation
Infants _________ months to __________ year old have similar profile as neonates in metabolizing drugs with improvement as age advances and as enzyme activity increases
2 months - 1 year old
Children that are __________ to __________ years old metabolize several drugs faster than adults
1-12
In the __________, liver size is reduced, microsomal enzyme activity is decreased, and hepatic blood flow declines; overall metabolism is slow
Elderly
A __________ protein diet decreases metabolizing activity
Low
A __________ protein diet increases metabolizing activity
High
__________ alcoholism decreases enzyme activity
Acute
__________ alcoholism increases enzyme activity
Chronic
____________ disease leads to increased half life of drugs
Liver
__________ disease leads to decrease of glycine conjugation of salicylates, oxidation of vitamin D, and hydrolysis of procaine
Kidney
__________ and __________ leads to decreased blood flow to the liver and decreased metabolism (CM)
Congestive heart failure (CHF), Myocardial infarction (MI)
__________ leads to decreased UDPGA and glucuronidation
Diabetes
Refers to the removal of the drug from the body either as the unchanged drug or as a metabolite
Excretion
Principal organ of excretion
Kidneys
Basic unit of the kidneys
Nephron
3 steps in renal excretion (GTT)
Glomerular filtration, Tubular reabsorption, Tubular secretion
A nonselective, unidirectional process whereby most compounds, ionized or unionized, are filtered
Glomerular filtration
Refers to the volume of blood that is filtered per unit time
Glomerular filtration rate (GFR)
Glomerular filtration rate (GFR) is around __________% of renal blood flow
20%
Normal glomerular filtration rate
125 mL/min
A carrier mediated process which requires energy for transport of substances against a concentration gradient
Tubular secretion
Tubular secretion occurs primarily in the __________
Proximal tubule
Happens with endogenous substances that are needed by the body such as electrolytes, glucose, vitamins, amino acids, and uric acid (Types of tubular reabsorption)
Active tubular reabsorption
Happens with exogenous substances; driven by the concentration gradient established by back diffusion of water, sodium, and inorganic ions (Types of tubular reabsorption)
Passive tubular reabsorption
Clearance is __________ proportional to plasma drug concentration
Directly
Clearance is __________ related to volume of distribution
Inversely
Example of acidic drug
Penicillin
Example of basic drug
Gentamicin
Example of very weakly acidic, nonpolar drug (pKa >8)
Phenytoin
Example of very weakly basic, nonpolar drug (pKa <6)
Propoxyphene
Example of a strongly acidic drug (pKa≤2)
Cromoglycic acid
Example of a strongly basic drug (pKa≥12)
Guanethidine
Example of acidic drugs with pKa 3-8
NSAIDs
2 examples of basic drugs with pKa 6-12 (MT)
Morphine analogs, Tricyclic antidepressants
__________ causes hypertension, DM, hypovolemia, pyelonephritis, and buildup of nephrotoxic agents
Renal impairment
Function that can be determined by measuring the GFR
Renal function (RF)
Is exogenous and tedious; used to determine renal function (RF)
Inulin
Is endogenous and is the most widely used to determine renal function (RF)
Creatinine
Involves the measurement of serum creatinine
Creatinine clearance
Bile is synthesized in the __________
Liver
Bile is stored in the __________
Gallbladder
Bile is secreted in the __________
Duodenum
Rate of elimination is convenient because it is constant (Types of elimination)
Zero-order elimination
Rate of elimination changes with respect to drug plasma concentration (Types of elimination)
First-order elimination
Refers to the factor that predicts the rate of elimination in relation to the drug concentration
Clearance (CL)
Unit of clearance
Volume/time
Clearance of drug by several organs is __________
Additive
Refers to the time required to change the amount of drug in the body by one-half during elimination
Half-life (t1/2)
