Define pharmacokinetics? What does ADME stand for?
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
What are pharmacodynamics?
The processes to determine the intensity of a drug's effect in relation to it's concentration. dose-response relationships
What are the major transport mechanisms for drugs to get to target cells?
Diffusion Filtration Endocytosis Ion-pair Facilitated Active
What are some factors that affect drug absorption?
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
What is meant by the following drug routes: -Enteral -Parenteral -Other
Enteral - drugs placed directly into GI tract, typically oral but includes buccal, sublingual, rectal Parenteral -IV, IM Other -Inhaled
What is the "first pass effect"?
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.
What is the definition of bioavailability?
Amount of a drug that reaches circulation unchanged (IV=100%) Determined by measuring the area under the drug concentration-time curve
Understand differences in peak concentrations and time to peak concentrations as it pertains to AUC on drug concentration-time graphs.
What are some factors that affect drug distribution?
Capillary/tissue membrane permeability
Tissue perfusion rate
Binding of drug to plasma proteins and tissues
Regional difference in pH
What is the definition of volume of distribution?
How is it calculated?
What does it indicate?
: 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)
What are some factors affecting Volume of Distribution of a drug?
Protein binding in circulation, lipid solubility of the drug
Body composition, Age, Sex, etc.
What is special about the blood brain barrier, what is required to cross it?
Has tight capillaries, requires specialized proteins or carriers to cross it.
Ex. L-type amino acid transported for L-dopa
How/where can drugs enter the CSF?
via the Choroid Plexus which is lined with fenestrated capillaries
With regards to placental barriers, do lipid or water soluble drugs cross faster?
Lipid move faster
Water move slower
How does redistribution work?
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.
What factors of Biotransformation (metabolism) aid in elimination?
Increased drug polarity or water solubility
What is a prodrug?
Is given in an inactive form but is activated by the body through metabolism.
Classic example is ACE inhibitors which undergo hydrolysis.
What are reactive metabolities and why are they of concern?
They are toxic metabolities or active metabolites in the body.
Tylenol/Acetaminophen is hepatoxic.
What happens in Phase 1 of drug metabolism?
Alter and create new funcitonal groups or cleave ester/amides to release masked functional groups (more receptive to conjugation)
What happens in Phase 2 of Metabolism?
Conjugation reactions couple the drug to an endogenous substrate (amino acid, acetic acid, glucurionic acid or sulfate) via a transferase, typically increases activity
Where are polar and nonpolar products of metabolism eliminated respectively?
Polar - urine
Nonpolar - biliary elimination
What is the importance of Cytochrome P450/P450 Reductase?
Microsomal enzymes which catalyze conjugation reactions.
Located on smooth surface of ER.
What is the major CYP Isoform in humans?
What are nonmicrosomal enzymes and what do they do (reaction types)?
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
Which type of enzymes (microsomal or nonmicrosomal) can undergo induction?
What are some basic examples of Inducing Agents?
Result of induction?
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
What are some methods by which enzymes can be inhibited?
What are some examples of inhibitors? Result of inhibitors?
Competition between drugs: ketoconazole
Mechanism based: erythromycin
Results in lower metabolism and higher drug levels in the body
How does genetic polymorphism affect Microsomal Enzymes and NonMicrosomal Enzymes respectively?
Overall affect of polymorphism?
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
Is the kidney more effective at eliminating polar compounds or highly lipid soluble compounds?
With regards to Urine pH and ion trapping which of the following pair:
Weak Acids/Weak Bases
Acidifcation promotes weak acid excretion
Alkalinization promotes weak base excretion
What is Clearance as it relates to drug elimination?
the theoretical volme of plasma from which a drug is removed per unit time
What factors can influence renal clearance?
a drugs Vd
degree of protein binding w/ drug
glomerular filtration rate
active tubular secretion
What is total clearance?
the sum of all clearances in the body
CL-hepatic + CL-renal + etc. = Clearance Total
Understand the process of Enterohepatic Recycling of Drugs
What is the difference between first-order and zero-order kinetics of elimination?
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)
Does Elimination Half-Life apply to first-order, zero-order, or both types of elimination kinetics?
Only First Order