Week 1: Pharmacodynamics and Pharmacokinetics Flashcards
Alignment of a drug with its receptor is aided by various bonding forces. Which bonding forces play a predominant role in this alignment?
-Van der Waals
-Hydrophobic
-Hydrogen
-Ionic
-Covalent
The dosage range of a drug that provides safe effective therapy with minimal adverse effects is?
Therapeutic window
Volume of distribution of a mathematical calculation which equals:
Vd= Dose of drug/Plasma
concentration of drug
What the BODY does to a drug once administered
The study of the changes in the concentration of a drug during the process of ABSORPTION, DISTRIBUTION, METABOLISM, and ELIMINATION from the body (ADME)
Pharmacokinetics
What a DRUG does to the body
The study of the biochemical, physiologic, and molecular effects of drugs on the body and involves receptor binding
Pharmacodynamics
The extent to which a drug reaches its effect site after its introduction into the body; differs based on the route of administration
Bioavailability
Factors affecting bioavailability of a drug (6)
-Solubility
-Molecular weight
-pH and pKa
-Blood flow
-Age/sex/pathology
-Temperature
Quick tell-tale for bioavailability
Blood flow to region med is administered
ex: Lungs have good blood flow = good bioavailability
What is essential for the delivery of drugs to various tissues?
The vascular system
Which drugs enter organs, muscles, and fats and bind to receptors?
Unbound drugs
What are most drugs salts of?
Weak acids
Weak bases
As an acid or base, drugs exist in solution as?
Ionized form
Nonionized form
Is an ionized form of a drug water or lipid soluble?
Water soluble; unable to easily penetrate lipid cell membranes
Is a nonionized form of a drug water or lipid soluble?
Lipophilic; diffuses across cell membranes like blood-brain/gastric/placental barriers
ex: propofol (very fast acting medication
What are acid and bases degree of ionization at a particular site determined by?
-pKa = dissociation constant
-pH gradient across the membrane
The negative log of the equilibrium constant for the dissociation of the acid or base
The pH at which 50% of the drug is ionized, 50% is nonionized
pKa = dissociation constant
A med had a pKa of 7.3. pH is 7.3. If inject med IV, how much of drug is ionized? nonionized?
50% ionized, 50% nonionized
What is quantitatively the most abundant plasma protein?
Albumin
What two other proteins bind basic drugs?
- Alpha 1-acid glycoprotein
-Beta globulin
_______ drugs are not free to act on receptors, and therefore influences how a drug is distributed
Protein-bound
______ protein binding prevents drug from leaving blood to enter tissues
(High or low)
High
High protein binding results in ______ plasma concentrations
(High or low)
High
If a drug is highly lipid soluble, it tends to be ______ protein bound
(Highly, not as)
Highly
Can adding more drug “overcome” protein binding?
Yes, because the number of protein binding sites for drugs is FINITE
Bond is usually weak and can dissociate as
-plasma concentrations of drug declines
-a second drug that bind to the same protein is introduced
May occur when drug administered ORALLY or RECTALLY
Occurs in the intestinal wall or liver prior to drug entering systemic circulation
First-pass hepatic metabolism
-Venous drainage from most portions of GI tract enter portal circulation
-Less bioavailability
A protein or other substance that binds to an endogenous chemical or a drug
Leads to a chain of events which ultimately results in an effect
Receptor
Drug response occurs from a low concentration
Sensitivity
Produced by structurally similar chemicals
Selectivity
The response from a given set of receptors is always the same because the cells themselves determine the response
Specificity
Receptors have 3 common properties
Sensitivity
Selectivity
Specificity
Drug response equation
D + R <—-> (DRC) <—–> TR
D= drug
R= receptor
DRC= drug receptor complex
TR= tissue response
Complete saturation of available receptors with drug molecules is not necessary for a desired tissue response to be elicited
(True or false?)
True
d/t sensitivity
Spare Receptor Concept
ex: acetylcholine and its receptor at the neuromuscular junction; less than 1% of the cell surface binds drug to receptor protein to achieve tissue response
Degree of attraction between a drug and its receptor on the cell’s surface
Affinity or potency
ex: different agonists can produce the same maximal response (efficacy) but at differing concentrations; the most potent drug of a series requires the lowest dose
ex: High affinity/potency = less drug
ex: Low affinity/potency = more drug; increase concentration gradient
A drug’s capacity to produce an effect
Efficacy
ex: Propofol has a high efficacy for sleep
ex: Reglan has a low efficacy for nausea, but high efficacy as a prokinetic
Which is safer, a wide or narrow therapeutic index?
Wide
Narrow = higher risk of giving a lethal dose
Are similar in molecular structure to their corresponding agonist drugs
They have receptor affinity, but lack intrinsic activity or efficacy
Pure antagonists
Second major type of antagonist drugs
Have receptor protein affinity and intrinsic activity, but often only a FRACTION of the potency of the pure agonist
Agonist-Antagonists
ex: Nalbuphine (mixed narcotic agonist-antagonist)
Involves two agonist drugs that bind to different receptors
Both drugs bind to specific unrelated receptor proteins and initiate a protein conformational shift with elicited individual tissue response
These responses however generate OPPOSING forces; won’t see as dramatic of a change
Physiologic Antagonism
ex: isoproterenol-induced vasodilation and norepinephrine-induced vasoconstriction
Occurs when a drug’s action is blocked and no receptor activity is involved
Chemical Antagonism
ex: Protamine is a positively charged protein that forms an ionic bond with heparin, thus rendering it inactive
ex: Sugammadex encapsulates rocuronium, rendering it inactive
Useful for predicting serum concentrations and changes in drug concentrations in other tissues
Depict the body as theoretic spaces with calculated volumes
Compartment models
Two compartments of the two-compartment model
First compartment = central compartment
-Intravascular fluid
-Highly perfused tissues (heart, lungs, brain, liver, kidneys)
-Vessel rich group; 75% CO
Second compartment = peripheral compartment
-Vessel-poor group; 25% CO
-Muscle, fat, bone
Single-compartment model is not sufficient to describe the action of many drugs, including ______ ______ anesthetic drugs
Lipid soluble
Proportional expression that relates the AMOUNT OF DRUG in the body to the SERUM CONCENTRATION
Calculated by dividing the dose of the drug administered intravenously by the plasma concentration before elimination occurs
Volume of distribution (Vd)
Formula for Volume of distribution (Vd)
Vd = Dose of drug/Plasma concentration of drug
A _____ Vd (>0.6 L/kg) implies that drug is widely distributed and likely ______ soluble
(Large or small)
(Water or lipid)
Large, lipid
A _______ Vd (<0.4 L/kg) implies drug is largely contained in the plasma and likely ______ soluble
(Large of small)
(Water or lipid)
Small, water
Enzyme-catalyzed change in chemical structure of agent
Metabolism
Main organ of metabolism
Liver
Other metabolism pathways
Plasma
Lungs
GI tract
Kidneys
Heart
Brain
Skin
Increased enzyme activity created by enzymatic stimulation over a period of time
System can therefore break down more agent that uses same enzymatic system for biotransformation (metabolism)
Leads to reduced half-lives (drug doesn’t work as long)
Enzyme induction
ex: Alcohol
Drug is cleared at a rate proportional to the amount of drug present in the plasma
Most drugs administered in therapeutic doses follow this
First-Order Kinetics
A constant amount of drug is cleared regardless of the plasma concentration
ex: alcohol
Drugs exceed body’s ability to excrete or metabolize them; enzyme system is saturated
Zero-Order Kinetics
Another name for metabolism
Biotransformation
Phases of metabolism
PHASE I: Oxidation, reduction, hydrolysis;
usually form more chemically reactive products, which can be pharmacologically active, toxic, or carcinogenic; often involve a monooxygenase system in which cytochrome P-450 plays a key role
PHASE II: Conjugation of a reactive group
usually leads to inactive and polar products that are readily excreted in urine
Do all drugs need to go through both Phase I and Phase II of metabolism?
Many drugs already possess an appropriate functional group for conjugation and do not need to be modified by a prior phase I reaction to be conjugated; allows them to be metabolized quicker
Time necessary for the plasma content of a drug to drop to half its prevailing concentration after a rapid bolus injection
Elimination Half-Life
Amount of drug remaining is related to what?
The number of half-lives elapsed
When is a drug regarded as fully eliminated?
When approximately 95% has been eliminated
Usually occurs in 4-5 half-lives
Time to halving of the blood concentration after termination of drug administered by an infusion designed to maintain a constant concentration
Accounts for continuous infusions or repeated dosing-induced changes in drug behavior (repeated small boluses)
Context-Sensitive Half-Time
The volume of plasma completely cleared of drug by metabolism and excretion per unit of time
Clearance
What properties govern clearance
Properties of the drug and the body’s ability to eliminate it:
-Directly proportional to the dose
-Inversely related to the agent’s half-life and concentration in central compartment
Two main organs for clearance
Hepatic
Renal
Formula for clearance
Clearance = Q X E
Q= blood flow to organs
E= Extraction ratio/ability to extract drug from bloodstream
Drug is cleared at a constant PERCENTAGE; dosage INDEPENDENT; a constant fractions of total drug is metabolized in a set time period; greatest amount og drug eliminated per unit time occurs when concentration highest
First-order kinetics
Drug is cleared in a CONSTANT amount regardless of plasma concentration
Zero-order kinetics
