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195 Cards in this Set

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During which phase may a drug undergo disintegration and dissolution (depending on its dosage form and the route of administration)?
Pharmaceutical phase
What processes determine the concentration of a drug and its time course of action?
Pharmacokinetic processes
What 2 processes occur under the heading: Pharmacokinetic processes?
Absorption and distribution
What processes determine the intensity of a drug's effect in relation to its concentration, usually at the site of action?
Pharmacodynamic processes
What type of transport process do nonelectrolytes take?
Passive transport across the lipid bilayer at rates proportional to their lipid/water partition coefficients.
What is essential for a drug molecule to rapidly diffuse across cell membranes (when they use passive transport)?
Some water solubility (having hydrophilic groups)
What represents the pH at which there are equal proportions (i.e. 50%) of ionized and nonionized molecules?
pKa
What type of molecules (ionized vs. nonionized) are more lipid-soluble and can diffuse readily across cell membranes?
Nonionized
What type of molecules are usually unable to penetrate membranes by passive diffusion?
ionized molecules
What side of the membrane will the concentration of total drug be greater?
At equilibrium, the concentration of nonionized drug will be the same on both sides of the membrane, but the concentration of total drug will be higher on the side where the degree of ionization is greater.
What idea is defined by the idea that an acidic drug will accumulate on the more basic side of the membrane and a basic drug on the more acidic side of the membrane?
Ion trapping...drugs may be trapped in body fluids such as urine, whose pH differs from blood.
Is facilitated diffusion saturable or not saturable?
Saturable
What is a major determinant of a drug's dissolution rate?
The solubility of a drug
In the gastric lumen, will acidic or basic drugs be absorbed?
Acidic drugs will be mostly nonionized in the gastric lumen and consequently should be readily absorbed from the stomach. Basic drugs will be highly ionized in the stomach and will not be absorbed until they reach the small intestine.
What occurs when a drug is metabolized prior to entry into the systemic circulation?
First-pass effect: The drug is metabolized within the G.I. tract or during the drug's "first pass" through the liver.
What type of drugs avoid the first pass effect?
Drugs absorbed within the oral cavity...following sublingual administration. They gain access to the general circulation without first traversing the liver.
What are the parameters important in evaluating the bioavailability of the drug?
1. Peak height concentration
2. Time of peak concentration
3. Area under the serum concentration--time curve
What is the fraction of unchanged drug reaching the systemic circulation following administration by any route?
bioavailability...the fraction (%) of drug absorbed. IV administration provides 100% bioavailability.
What is a function of the extent of absorption of a drug and represents the overall systemic exposure of the drug?
Area under the curve
What is the movement of a drug from the systemic circulation (blood) into various tissues?
Distribution
What is the initial barrier to distribution of drugs outside the vascular compartment?
The capillary
What are the major determinants of the rate of transcapillary movement?
Molecular size
lipid solubility
Concentration gradient
With regards to plasma proteins, what do acidic drugs usually bind to?
Plasma albumin
With regards to plasma proteins, what do basic drugs typically bind to
alpha1-acid glycoprotein
What is a better index of the effective therapeutic level of the drug?
the concentration of free drug rather than the concentration of total drug
What decreases the effective concentration gradient of a drug, thereby slowing the rate of transfer across the capillary?
The binding of a drug to plasma proteins.
What may prolong drug availability and duration of action?
Extensive protein binding
Binding of drugs to plasma proteins is usually nonselective. What does this mean?
That different substances can compete for binding sites. Drugs can compete with endogenous substances for binding sites.
What is defined as the fluid volume in which a drug seems to distribute as if its concentration were uniform throughout the body?
apparent volume of distribution (Vd)
How is Vd calculated?
by dividing the total amount of drug administered by the plasma drug concentration after absorption and distribution are completed.
What is the approximate volume of total body water?
45 L (ex of drug that distributes in this volume: Ethanol)
What is the volume of extracellular water?
15 L...ex. Gentamicin (a larger water-soluble drug) distributes here.
What is the volume of blood plasma?
3 L...ex. Heparin (a highly protein-bound or charged molecule) distributes in this compartment.
What is the volume of fat?
14 -24 L...ex. Diazepam (a highly lipid-soluble molecule) distributes in this compartment
What is the volume of bone?
5 L...ex. Fluoride (certain ions) distribute in this compartment.
What is the principal route into and out of the CNS for drugs?
Intracellular or transcellular transport (i.e. directly through the endothelial cell membrane).
What type of drugs move more readily through the placenta?
Most lipid-soluble drugs readily move from mother to fetus; Water-soluble drugs move more slowly. Transfer of highly polar or ionized drugs across the placenta is limited.
Due to the pH of fetal blood, what type of drugs are more likely to be involved in ion trapping in the fetal blood?
Since the pH of fetal blood is slightly more acidic than that of maternal blood, weakly basic drugs may undergo ion trapping in the fetal circulation.
What is referred to as the removal of a drug from the tissues where it exerts its effects to other tissues that are not involved in the pharmacologic response?
Redistribution
What is a chemical change in the drug molecule referred to?
biotransformation
Where is the main site of biotransformation in the body?
Liver
What are converted to active moieties by metabolic processes?
prodrugs
What do Phase I (functionalization) reactions in drug metabolism consist of?
Oxidative and reductive reactions that alter and create new functional groups and hydrolytic reactions that cleave esters and amides to release masked functional groups.
What do Phase II (conjugation/synthetic) reactions in drug metabolism consist of?
The drug or a metabolite is couple to an endogenous substrate, such as an amino acid, acetic acid, glucuronic acid or sulfate. Attachment of these hydrophilic groups usually makes the drug more polar and less active.
What are metabolism of most drugs mediated by?
Microsomal enzymes located on the smooth surface of endoplasmic reticulum.
What is the most predominant cytochrome P450 isoform in human drug metabolism?
CYP3A4
What microsomal enzyme is likely to be involved in the greatest number of drug-drug interactions?
CYP3A4
What microsomal enzyme whose relative abundance in the liver is low is the second most CYP isoform in human drug metabolism?
CYP2D6
Which microsomal enzyme metabolizes several clinically important drugs, such as phenytoin and warfarin, which have narrow therapeutic indices?
CYP2C9
Which conjugation reaction do nonmicrosomal enzymes not catalyze?
glucuronidation (They catalyze all other conjugation reactions.)
What occurs when prior administration of an agent accelerates drug biotransformation by increasing the total quantity of microsomal enzymes?
Enzyme induction
What occurs when compounds induce their own metabolism?
auto induction
What type of enzymes cannot be induced?
Nonmicrosomal enzymes
What can occur when addition of a drug with greater affinity for the enzyme inhibits metabolism of the primary drug in a competitive manner?
Enzyme inhibition
What is the most common route of drug excretion?
Through the kidney
What type of compounds are eliminated more efficiently from excretory organs (excluding the lungs)?
Polar compounds are eliminated more efficiently than substances with high lipid solubility.
What type of drugs does glomerular filtration remove all of?
All unbound drugs of low molecular weight, but charged molecules are usually filtered at slower rates than uncharged compounds.
What is an important limiting factor in the renal excretion of drugs?
The extent to which substances diffuse back across the tubular membranes and re-enter the circulation.
What is the volume of plasma from which all the substance is removed in a unit of time called?
renal clearance CLr
What type of drug will have a clearance that corresponds to the GFR?
A drug that is completely filtered by the glomeruli, but neither reabsorbed nor secreted. (Like creatinine.)
What type of drug will have a clearance that corresponds to the renal plasma flow?
A drug that is completely removed by active tubular secretion, during a single transit through the kidney.
For any drug not inactivated by metabolism, what is usually the main factor that determines its duration of action?
The rate of renal elimination
What is the equation of bioavailability (F)?
F = (AUCoral)/(AUCiv) x (IVdose)/(ORALdose)
What is the apparent volume of distribution used mainly for?
intravenously administered drugs
What is the equation for volume distribution (Vd)
Vd = Dose (mg/kg)/Plasma concentration (mg/L)
How do you estimate plasma clearance (Clt)?
(the rate of drug elimination)/(plasma drug concentration)
How do you calculate an organ's extraction ratio?
E = (Cin - Cout)/Cin
What relates to a constant fraction of the drug present in the body eliminated per unit of time?
First-order kinetics
A complete plasma disappearance curve obtained after intravenous administration of a drug will show 2 distinct phases. What are these 2 phases?
An initial distribution phase, then a prolonged elimination phase
What type of kinetics relates to a consistent amount (regardless of plasma concentration) eliminated per unit of time?
Zero-order kinetics
How many half-lives does it take to reach steady state?
5 (5 half lives are needed to eliminate medications.)
What is the equation used to estimate half life?
k = 0.693/t1/2
What is the equation for creatinine clearance?
CrCl = 140 - age x (IBW/72) x serum creatinine (multiple by 0.85 if a female).
What is the equation for IBW?
Men: 50 + 2.3 (height in inches - 60)
Women: 45.5 + 2.3 (height in inches - 60)
What is the equation for adjusted body weight? Use if patients are >20% of IBW
ABW = IBW + 0.4 (TBW - IBW)
How do you convert pounds to kilograms?
Divide by 2.2
What is an antibiotic that has extensive gram positive bacterial coverage?
Vancomycin
What is described as how tightly a ligand binds to a receptor?
Affinity
What is described as the strength of a single drug-receptor complex in evoking a response of a tissue?
Efficacy
What type of ligands bind to receptors and mimic the effect of an endogenous compound?
an agonist
What type of ligands bind to receptors without evoking change in second messengers, but the binding prevents the interaction of any agonist with the receptor?
an antagonist
What is the type I receptor?
Ligand-gated ion channels
What is the type II receptor?
G-protein coupled receptors (metabotropic)
What is the type III receptor?
Tyrosine kinase linked receptors
What is the type IV receptor?
transcription factors
What type of ligand does not have intrinsic activity but may induce a physiological response due to blocking an action?
an antagonist
What type of bonds are stronger than hydrogen bonds but weaker than covalent bonds?
Hydrophobic bonds
What is the weakest bond?
van der Waals
What is the strongest bond?
Covalent bonds
How is the intrinsic activity of a ligand defined?
maximum response to a test agonist divided by maximum response to a full agonist through the same receptor
What is information encoded in the chemical structure of a drug?
Efficacy
What is the stimulus that is communicated to the cell dependent on?
1. The proportion of receptors occupied
2. The efficacy of the agonist
What is the assumption made at equilibrium regarding drug-receptor interactions?
The response (observed as a biological/physiological effect resulting from the drug-receptor interaction) is related to the number of receptors occupied by the drug, which is based on the law of mass action.
What is seen in the dose-response curve?
The magnitude of response produced by a drug is a function of the amount of drug administered.
What can dose-response curves NOT measure?
Affinity of agonist drugs for their receptors because the response evoked is generally not directly proportional to receptor occupancy.
Why can't drug concentration at the receptors be known exactly?
Due to inactivation of the agonist by uptake into tissue or degradation.
Many full agonists elicit maximal responses at very low receptor occupancies. When this occurs, what are the cells said to possess?
Spare receptors
What type of response are quantal relationships based on?
Based on a response being present (all) or not present (none)...all or none criteria
What type of dose-response curve estimates the number of responders of a population (percentage) at each specific dose of an agonist?
Quantal relationship
What type of curve is presented as cumulative frequency (the percentage of total responders up to and including that dose) plotted on the Y-axis versus the log dose of the agonist plotted on the X-axis?
Quantal relationships
When is a maximum response obtained in a graded response curve?
Once the addition of more agonist does not evoke additional increase in response.
What type of curve is used to indirectly estimate drug binding?
a graded response curve
What is defined as the dose of drug required to produce a given level of response, generally 50% of maximum response?
Potency
What type of drugs will produce the same response at a lower dose than a less potent drug?
The more potent drugs
When will dose-response curves be parallel between 2 drugs?
If the two drugs bind to and stimulate the same receptor and the same tissue is used.
What does potency depend on?
1. The affinity
2. The efficacy
of a drug for a given receptor
What does it mean when the dose-response curve is shifted to the right?
The drug is less potent.
What does it mean when a dose-response curve is shifted to the left?
The drug is more potent.
How can you tell if 2 drugs likely occupy the same receptor (when 1 is an agonist and the other is an antagonist)?
If increasing the concentration of agonist stimulates a response from the tissue while the concentration of the antagonist is kept constant. Thus, the blockade provided by the antagonist can be overcome by increasing the amount or concentration of the agonist.
With what type of antagonism is the shift parallel and the maximum effect not diminished?
Reversible competitive antagonism
With what type of antagonism is there a decrease in maximum effect even when there is an increase in agonist concentration?
Irreversible competitive antagonism
What is the efficacy of a partial agonist?
Between 0 and 1.
What type of drugs do not bind at maximum efficacy?
Partial agonists
What type of antagonism exists when there is no change in antagonist occupancy of receptors when additional agonist is added?
Irreversible (Non-Equilibrium) Competitive antagonism
When does irreversible competitive antagonism occur?
With antagonist drugs that form covalent bonds with the receptor.
What occurs when the antagonist binds to some site on the receptor that is not part of the agonist binding site and blocks the sequence of events that leads to the response evoked by the agonist?
Non-competitive antagonism
What occurs when a receptor exists in an active state without being bound by an agonist, which results in a basal level of response?
The receptor is constitutively active.
What is the ligand that binds to the receptor while in the receptor state, shifts the equilibrium from the activated state to the resting state, when receptors are constitutively active?
Inverse agonist
What type of agonist reduces the level of constitutive activation of the receptor and the basal level of response?
Inverse agonists
What does an antagonist do to the constitutive level of activity in the presence of an agonist or an inverse agonist?
The antagonist restores the system towards the constitutive level of activity.
What is the physiological function of receptors?
To bind the appropriate endogenous ligand to propagate the regulatory signal of the ligand inside the target cell (this is message propagation or integration).
What can receptor activation do?
1. Stimulate signal transduction pathways
2. Change catalytic activity of enzymes (results in signal amplification).
3. Change the levels of cytoplasmic second messengers
What results in an effect that is diminished following continued or subsequent exposure to the same concentration of drug?
Desensitization...also referred to as down-regulation or refractoriness.
When does desensitization generally occur?
In response to prolonged exposure to an agonist.
What is the mechanism for desensitization?
Through conformational changes that occur in the receptor which 1. alters the binding of the ligand to the receptor or 2. decreases the coupling of the agonist-receptor complex to their signaling mechanism
What can happen with prolonged exposure to a ligand?
a decrease in the number of receptors in the cell membrane.
What generally follows chronic reduction of receptor stimulation?
Supersensitivity
What is the result of supersensitivity?
The response to the agonist at the same concentration is increased.
What forms the membrane spanning domains of the receptors?
Hydrophobic alpha-helical regions of the protein comprising approximately 20 amino acid residues
What type of receptors have a whole complex that contains 16 to 20 membrane-spanning segments surrounding a central ion channel?
Receptors coupled directly to ion channels
What type of receptors control the fastest (with regards to time) synaptic events?
Type 1: Ligand-Gated Ion Channels
With what type of receptor does an agonist act on the receptor in the postsynaptic membrane to transiently increase the permeability of the membrane to a particular ion by opening a channel?
Type 1: Ligand-Gated Ion channels
What type of receptors are made of an oligomer of several subunits which come together to form a channel?
Type 1: Ligand-Gated Ion channels
What type of receptor comprises most of the receptors that are familiar to pharmacologists?
Type 2: G-protein coupled receptors
What type of molecular structure comprises the Type 2: G-protein coupled receptor?
1. Single polypeptide chain of 400 to 500 amino acid residues
2. 7 transmembrane alpha-helices that span the cellular membrane
3. Extracellular N-terminus and Intracellular C-terminus that vary in length
4. 3 Intracellular loops with the third loop that is relatively long, is a highly variable region and couples to the G-protein
How many subunits is the G-protein made up of?
3 subunits: alpha, beta and gamma
In the resting state, what does the G-protein exist as?
An unattached αβϓ trimer with GDP occupying a binding site on the α subunit
What happens to the G receptor when receptor occupation by an agonist occurs?
A conformational change in the receptor which causes the receptor to acquire a high affinity for binding the αβϒ trimer (with GDP still occupying the alpha-subunit binding site). The alpha subunit then releases GDP which is replaced by GTP.
What happens when GTP binds to the alpha subunit?
The alpha subunit dissociates from the beta-gamma subunit
Once the alpha subunit dissociates from the beta gamma subunit, what does the beta gamma subunit do?
It can then bind to effector (various enzymes or ion channels) to activate or inhibit these effectors.
What does the alpha subunit with bound GTP do?
Activates or inhibits various targets or effectors (enzymes or ion channels).
What terminates the function of the alpha-subunit?
Dephosphorylation of GTP to GDP by the intrinsic GTPase activity of the alpha-subunit.
Why is the activation of the effector self-limiting?
Since GTP is dephosphorylated to GDP by the alpha-subunit, an action which is increased by the binding of the alpha-subunit to the effector.
Why does the amplification of signaling occur?
Since several G-protein molecules can be activated which, in turn, remain associated long enough to the effector to produce many molecules of product.
G-protein targets adenylate cyclase. What does activation of adenylate cyclase give rise to?
Intracellular cyclic AMP (cAMP) from ATP
What does inhibition of adenylate cyclase give rise to?
Decreases the formation of cAMP.
What regulates the activity of protein kinases which catalyze the phosphorylation of other enzymes to activate or inactivate them.
cAMP
What is hydrolyzed by phosphodiesterase to terminate its activity?
cAMP
What enzyme that when activated degrades phosphatidylinositol triphosphate to DAG and IP3 which both function as second messengers?
Phospholipase C
What causes the release of calcium from intracellular stores?
IP3
What evokes many cellular responses resulting from the regulation of the activity of various enzymes and ion channels, and the activation of contractile proteins?
Calcium
What activates protein kinase C (a membrane bound protein) of which 13 different types exist with distinctly different cellular distributions?
DAG
What kind of channels can G proteins interact directly with to cause them to open or close?
Ion channels (such as potassium channels)
What type of receptors are involved in direct control of protein phosphorylation?
Tyrosine Kinase-Linked receptors
What receptors have a large extracellular ligand-binding domain connected via a single alpha-helix to the intracellular domain?
Tyrosine Kinase-Linked receptors
What does ligand binding to tyrosine kinase-linked receptors generally lead to?
a kinase cascade...dimerization of pairs of receptors
What is defined as the dose which causes death in 50% of exposed animals?
LD50
What is defined as the dose where 50% of subjects show the response?
ED50
How do you figure out the therapeutic index of a drug?
TI = LD50/ED50
How do you figure out the standard safety margin?
SSM = (LD1 - ED99)/ED99 x 100
What type of toxic reactions are usually reversible with no long term effects?
Pharmacological
What type of toxic reactions are measurable and can be irreversible?
Pathological
What type of toxic reactions cause damage to the DNA and can be transferred to the next generation?
Genotoxic
If you alkalinize the urine, what type of compounds can you get rid of?
Acidic compounds such as phenobarbital and salicylates.
If you acidify the urine, what type of compounds can you get rid of?
Basic compounds such as amphetamine
What is the antidote for acetaminophen?
Acetylcysteine
What is the antidote for anticholinesterases?
Atropine
What is the antidote for antimuscarinic agents?
physostigmine
What is the antidote for ethylene glycol?
Ethanol
What is the antidote for arsenic?
Dimercaprol (BAL)
What is the antidote for copper?
Penicillamine
What is the antidote for gold?
BAL or penicillamine
What is the antidote for lead?
Calcium disodium edetate (CaEDTA) or penicillamine
What is the antidote for Mercury?
N-acetylpenicillamine or BAL
What is the antidote for iron?"
Deferoxamine
What is the antidote for methanolol?
ethanol
What is the antidote for narcotics?
Naloxone
What is the antidote for organophosphates?
Atropine + Pralidoxime (2-PAM)
For first order reactions, What is Km relative to the substrate concentration?
Very large
Does the concentration of a drug eliminated by first order kinetics ever reach zero?
No because a drug eliminated via first order kinetics decreases exponentially.
Are first-order reactions saturable?
No. They are not saturable.
For saturation kinetic reactions, what is the substrate concentration relative to Km?
The substrate concentration is very large.
Are saturation kinetic reactions saturable?
Yes.
For saturation reactions, what is the velocity capacity-limited by?
The Vmax. If plasma drug concentrations exceed the Vmax, further dose increases will result in disproportionate and "unexpectedly" high plasma drug concentrations.
In the US, who can approve or deny a drug for general use when phase III trials are completed and the sponsor believes that efficacy and safety have been adequately demonstrated?
The Food and Drug Administration (FDA)
Who monitors the adverse reactions of drugs following marketing?
Committee on Safety of Medicines
When can a clinical trial be initiated?
Only when an IND is approved by the FDA.
Why don't the majority of drugs that enter phase I and II not go on to phase III?
Either because of toxicity occurring or because the pharmaceutical therapeutic benefit did not occur in humans.
What is the most rigorous and widely used control?
the concurrent control
What does the concurrent control group receive?
They receive placebo and is observed simultaneously with the group given the experimental drug.
What is the purpose of phase I?
Determine biologic activity and metabolism in humans (takes 9 to 24 months).
What is the purpose of phase II in clinical trials?
Determine potential usefulness, pharmacologic profile and dosage range...this takes 12 to 24 months.
What is the purpose of phase III in clinical trials?
Determine the efficacy for selected indications and rates of common adverse events. This takes 12 to 36 months.
What provides a useful measure to compare the bioavailability of drugs administered by different routes?
the area under the curve (AUC)
How do you calculate loading dose (X0)?
It is calculated by multiplying the desired concentration by the Volume of distribution.