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149 Cards in this Set
- Front
- Back
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Nonproprietary (generic) name is worth remembering, true or false?
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True
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Brand name is worth remembering, true or false?
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False
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Pharmokinetics involves?
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Absorption, Distribution, Biotransformation, Excretion
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Pharmodynamics involves?
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Receptor binding, Signal transduction, Biological effect
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Affinity is?
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Force of attraction between drug and receptor
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kd = k2/k1, true or false?
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True
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If kd is lower, then the drug has more affinity for the receptor, true or false?
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True
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Which dose-response curve is better?
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The Log scale is better (than arithmetic scale), because it straightens the line and is easier to mathematically analyze
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EC50 is?
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The conc. of drug that produces 50% of maximal response
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Emax is?
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Maximal effect produced by a drug
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Efficacy and Intrinsic activity are the same, true or false?
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False
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Efficacy is?
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The ability of a bound drug to change the receptor in a way that prodcues an effect (some drugs have affinity, but not efficacy)
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Kd is?
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Conc. of drug that occupies 50% of total number of receptors at equilibrium
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Potency is?
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Position of the dose-effect curve along the dose axis AND it is determined by affinity + intrinsic activity
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A more potent of two drugs is clinically superior, true or false?
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False
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If EC50=Kd, then there are no spare receptors, true or false?
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True
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If EC50 is less than Kd, then it suggests existance of spare receptors, true or false?
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True
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When all receptors need to be occupied for a full response then what relationship holds true?
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EC50=Kd
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Spare receptors do not increase the sensitivity of the system, true or false?
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False
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Spare receptors can bind (and internalize) extra ligand, preventing an exaggerated response if too much ligand is present, true of false?
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True
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An agonist is?
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Drug that binds to receptor and produces an effect (has affinity + intrinsic activity)
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A partial agonist is?
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Drug that has affinity, but less intrinsic activity, ie weaker signal (lower Emax/lower efficacy)
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An antagonist is?
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Drug that has affinity, but no intrinsic activity
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An antagonist can be competitve (reversible), which is the majority of drugs, and non-competitive (irreversible), which is the minority of drugs, true or false?
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True
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An agonist the same Emax as a partial agonist, true or false?
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False, an agonist has a higher Emax (higher efficacy) than a partial agonist
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A partial agonist acts like a antagonist in the presence of a full agonist (it provides some agonist activity and at the same time blocks the full effect of an agonist), true of false?
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True
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In the presence of competitive antagonist a higher dose of agonist is required to produce the same effect (or to produce Emax), true or false?
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True (Emax remains the same)
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In the presence of competitive antagonist, the EC50 of an agonist increases or stays the same?
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Increases (the curve shifts to the right). But, Emax remains the same
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In the presence of non-competitive antagonist a higher dose of agonist is required to produce the same effect (or to produce Emax), true or false?
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False (even a higher dose of agonist can not produce maximal effect, Emax is lowered)
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In the presence of non-competitive antagonist, the EC50 of an agonist decreases or stays the same?
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Decreases (and the Emax is lowered)
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Competitive antagonists change kd, true or false?
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True
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Noncompetitive antagonists change intrinsic activity, true or false?
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True
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Quantal dose response curve is when?
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Different doses of a drug are given to a population and a given response is recorded
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Name the two types of quantal dose response curves.
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Frequency distribution (like a bell-curve) and cumlative frequency (like a sigmoid curve, each bar represents ppl up to and including current dose)
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Equation for Therapeutic Index is?
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TD50 or LD50/ED50
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Larger the therapeutic dose then?
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The safer the drug
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Smaller the therapeutic dose then?
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The more dangerous the drug
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ED50 is?
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The effective dose in 50% of ppl
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TD50 is?
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The toxic dose in 50% of ppl
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LD50 is?
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The lethal dose in 50% of ppl
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Therapeutic window is?
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TD1 - ED80 >80
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The narrower the window then, the wider the window then?
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Narrower means more dangerous, wider window means safer drug
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Name the four types of signal transduction mechanisms?
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GIEN (G-protein coupled receptors (GPCRs), ion receptors, enzymes as receptors, nuclear receptors)
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GPCRs are also known as what type of receptors?
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Metabotropic receptors
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Ion receptors are also known as what type of receptors?
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Ionotropic receptors
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Put the signal transduction mechanisms in order from fastest to slowest.
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Ion receptors fastest
Enzyme receptors second fastest GPCR's third fastest Nuclear receptors slowest |
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Name the three pathways activated by GPCRs.
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Inositol triphosphate (IP3)
(elevates intracellular calcium) Diacyl glycerol (DAG) (activates protein kinase C) Cyclic adenosine triphosphate (cAMP) (activates protein kinase A) Also, hyperpolarizes cell membrane through activating potassium channels |
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Give a brief overview of nuclear receptors.
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Receptors are in cytosol. Agonist enters cell and binds to receptor. Drug-receptor complex enters nucleus and stimulates gene transcription and new proteins synthesized (takes hours to days)
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Give brief overview of enzyme receptor action.
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Pair of monomers (inactive) become activated by agonist to form diamer. Diamer interacts with tyrosine (phosphorylation rxn takes place). Receptor becomes active enzyme and activates other enzymes
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Give a brief overview of ion channel receptors and give two examples
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Agonist binds to receptor/ion channel, channel opens and specific ions pass across cell membrane.
Ex: Nicotinic acetylcholine receptor (depolarization and contraction of muscle), Gamma aminobutyric acid (GABA) receptor (inhibits neurotransmission) |
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Agonists tend to desensitize or sensitize receptors?
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Agonists desensitize/down-regulate receptors
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Antagonists tend to up-regulate or down-regulate receptors?
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Up-regulate/Sensitize
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Name and differentiate the two types of desensitization (down-regulation).
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Homologous desensitization (decreased receptor number)
Heterologous desensitization (decreased signal transduction) |
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List three properties that lead to better absorption.
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Non-ionized, smaller, lipid soluble drugs
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List three properties that lead to worse absorption.
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Ionized, larger, water soluble drugs
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What is the purpose of drug metabolism?
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Convert non-ionized drugs to the ionized form, so the ionized form can be excreted (not reabsorbed in the kidneys)
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Give a few reasons why some drugs are poorly absorbed.
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Destroyed by stomach acid or digestive enzymes
Polar Metabolized extensively |
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The pKa of a drug is defined as?
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The pH at which the drug is half ionized
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Most drugs are weak acids or weak bases, true of false?
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True
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An acid is better absorbed in an acidic medium, true or false?
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True (because it is in its non-ionized form)
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A base is better absorbed in a basic medium, true or false?
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True (because it is in its non-ionized form)
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An acid in basic medium is not as well absorbed, true or false?
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True (because it is in its ionized form)
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Ion trapping is when?
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At steady state, an acidic drug would accumulate on the more basic side of a membrane and a basic drug on the more
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Give a clinically significant situation pertaining to ion trapping.
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Basic drug (non-ionized) would transfer across from mother to fetus or breast milk (acidic sites) and would become ionized and accumulate (because ionized form can not cross membrane again)
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Give another clinically significant situation pertaining to ion trapping.
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Acidification (using ammonium chloride or ascorbic acid) or alkalinization (using sodium bicarbonate) of urine accelerates excretion (accelerates renal clearance) of basic or acidic drugs
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What is parenteral?
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Other than orally
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What is first pass metabolism?
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When metabolizing enzymes in the intestinal wall and liver process the drug and very little drug reaches the general circulation (so must give drug parenterally)
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Give an example where first pass metabolism is clinically relevant.
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When a drug is taken that inhibits those metabolizing drugs in intestinal wall and liver, other substances (ex: tyramine, which stimulates adrenergic receptors) that are usually metabolized by those enzymes are not metabolized and are absorbed and can have an effect (undesired effect in some cases)
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What is bioavailability?
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Fraction of an orally given drug that reaches the circulation
Bioavailability=(oral dose that reaches circulation/iv dose that would be in circulation)x100 |
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Displacement of a drug from plasma protein binding generally causes no change in its overall effect or adverse effects, true or false? Give a reason for an exception.
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True (except when a drug has a small volume of distribution (ie nowhere to go))
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If most drug is extravascular, then a change in free plasma drug conc. caused by displacement from plasma protein binding would be minimal, true or false?
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True
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If most drug is intravascular, then a change in free plasma drug conc. caused by displacement from plasma protein binding would have significant effects, true or false?
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True
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What is distribution?
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The reversible movement of a drug between body compartments
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Name the four factors affecting distribution.
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Blood flow, ionization, capillary permeability, plasma protein binding
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Name two organs in which capillaries are leaky (so distribution to these organs are higher).
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Liver and spleen
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Name an organ with capillaries that have tight junctions.
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Brain
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What kind of drugs cross brain capillaries?
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Lipophilic drugs
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The blood-brain barrier does not work properly in areas of inury, true or false? Give an example.
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True.
Ex: Tumors of the brain |
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If a tissue receives more blood, it receives more or less drug?
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More drug
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Put the following organs in order (from highest to lowest) in terms of how much blood they receive: lungs, fat, brain, skeletal muscle, brain, kidneys, liver.
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Brain, liver, kidneys, lungs, skeletal muscle, fat
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What is the adult blood volume?
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5L
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Lipophilic drugs distribute out of fluids and concentrate in fat, true or false?
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True
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Normally where is the drug concentration measured from?
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Blood
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What does the volume of distribution equal?
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Dose/Concentration
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If the concentration in the plasma is less (due to high concentration of a lipid soluble drug in fat stores) than the Vd will be very high, true or false?
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True
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A high Vd indicates that most of the drug is in the intravascular or extravascular compartment?
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Extravascular
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If the concentration in the plasma is high the Vd will be low, true or false?
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True
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What is the significance of a low Vd and give an example for why this could be?
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Means drug is in vascular compartment (because bound to plasma proteins).
Ex: when drug is large or charged |
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What is redistribution?
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A rapid rise in concentration of a drug (normally given through IV) in highly perfused organs (such as the brain and heart) followed by a fall in concentration in these organs as the drug is distributed to other organs (ex: fat and skeletal muscle)
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What is biotransformation?
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Chemical modification of drugs by enzymes to make them more polar (less lipid solbule) and more readily excretable by the kidneys
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Name four organs with high levels of metabolizing enzymes
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Liver, gastrointestinal wall, lungs, kidneys
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What are prodrugs?
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They are inactive and must be metabolized in order to become active.
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Name the two phases of biotransformation reactions.
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Phase I - Functionalization Reactions
Phase II - Conjugation Reactions |
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Describe Phase I biotransformation reactions.
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Involve oxidation, reduction, hydrolytic reactions. Makes the drug more polar, but not necessarily inactive
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Describe Phase II biotransformation reactoins.
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Involve glucuronidation, sulfation, acetylation reactions, most of these result in drug inactivation (drug becomes more water soluble and more easily excreted by the kidneys)
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Name a Phase I enzyme and describe it briefly.
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Microsomal cytochrome P450 monooxygenase family of enzymes. They transfer electrons from NADPH to an oxygen molecule and thus oxidize drugs.
These enzymes are not substrate specific (ie broad action), are located in the ER of the cell, metabolize the widest range of drugs |
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What is the most common cytochrome P450 polymorphism (CYP polymorphism) in Caucasians?
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2D6 (CYP2D6)
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CYP2D6 deficient people will be slow metabolizers of?
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Beta-adrenergic antagonists, neuroleptics, antidepressants, and codeine
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What drug is almost ineffective as an analgesic in CYP2D6 deficient patients?
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Codeine (because it must be metabolized by CYP2D6 to its more potent metabolite morphine for analgesic effect)
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Name two types of factors affecting drug biotransformation.
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Induction and Inhibition of enzymes
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Name the cytochrome P450 enzyme that is the primary enzyme for metabolism of about half of all drugs and is inhibited or induced by many drugs.
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3A4 (CYP3A4)
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Describe induction of enzymes.
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Induction causes expression of more CYP enzymes and faster elimination of drugs. So, lower expected drug levels can cause treatment failure.
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Give three examples of CYP enzyme inducers.
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Rifampin (antibiotic)
Barbituates St. Johns Wort (Herb) |
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Describe inhibition of metabolizing enzymes.
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Inhibition of CYP enzymes reduces the elimination of drugs. Higher than expected drug levels can cause drug toxicity
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Give three examples of CYP enzyme inhibitors.
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Grapefruit juice
Cimetidine (stomach acid inhibitor) Erythromycin (antibiotic) |
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Where are Phase II enzymes mostly located in the cell?
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Cytosol of cell
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Give an example of a Phase II enzyme and describe it.
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P-glycoprotein (a transport protein). It is an efflux pump (uses ATP) that moves compounds from inside to the outside of a cell.
It has a broad specificity. It is located at many sites (luminal surfaces). It is expressed more in certain tissues (ex: tumors) |
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What is the clinical significance of P-glycoprotein?
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It plays a role in drug resistance to cancer chemotherapeutic agents (because tumors express more P-glycoprotein).
Also, P-glycoprotein in the blood-brain barrier protects the CNS |
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Give an example of a drug that has an important relationship/dependance on P-glycoprotein and explain why.
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Digoxin relies on P-glycoprotein for elimination.
This is important because some drugs inhibit P-glycoprotein (so that it can not eliminate digoxin as it usually does) and can cause digoxin toxicity |
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What is enterohepatic recirculation?
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When a compound is conjugated in the liver, excreted in the bile, deconjugated in the intestine (by bacterial enzymes) and reabsorbed into the circulation
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Give the significance of enterohepatic recirculation and give an example.
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It prolongs the duration of action (half-life) of a drug (it stays in circulation longer and has an effect for longer).
Also, antibiotics remove intestinal bacteria, therefore no enzymes, therefore no deconjugation, therefore no recirculation or prolongation of a drug Ex: rifampin removes intestinal bacteria (decreasing enterohepatic recirculation) and it induces CYP3A4 enzyme so that a drug is metabolized even more, so a drug has even less effectiveness |
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What is clearance and what are clearance values good for?
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Clearance is the volume of blood from which a drug is irreversibly removed per unit of time.
Clearance values are useful to calculate maintenance dose of a drug |
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What is rate of elimination?
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The amount of drug removed by an organ or the whole body
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Clearance equals?
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Rate of elimination/concentration
(Cl=Dose/AUC) OR (in other words): Clearance = (Q(Ca-Cv))/Ca (where Q is bl. flow, Ca is arterial bl. conc. and Cv is venous bl. conc.) |
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Rate of elimination equals?
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Rate of elimination = Q(Ca-Cv)
(where Q is bl. flow, Ca is arterial bl. conc. and Cv is venous bl. conc.) |
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Renal clearance involves filtration that is a passive or active process?
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Filtration is a passive process
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The kidney does or does not filter protein-bound drug?
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The kidney does not filter protein-bound drug (only free drug is filtered)
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Drugs that are strong acids and bases or weak acids and bases are secreted (by an active process) by the renal tubules?
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Strong acids and bases are secreted
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A drug will be reabsorbed if it is polar or non-polar
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If a drug is non-polar (hydrophobic/lipid-soluble) then it will be reabsorbed
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Net removal of a drug equals?
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Net removal = filtered + secreted - reabsorbed
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How is glomular filtration rate (GFR)measured?
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GFR is measured by creatinine clearance
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Why is creatinine clearance used to measure GFR?
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Creatinine clearance is used to measure GFR because creatinine is produced endogenously (it does not have to be administered), it is freely filtered by the kidneys (so it is not bound to protein), it is not reabsorbed and is minimally secreted by renal tubules. Therefore, net removal equals filtered portion
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Most drugs are eliminated according to First or Zero Order Rate Process/Kinetics?
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Most drugs are eliminated according to First Order Kinetics
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What is First Order Kinetics?
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First Order Kinetics is when a constant fraction of drug is eliminated per unit of time (rate of elimination is proportional to the plasma conc., so higher plasma conc. then more drug is removed, lower plasma conc. then less drug is removed)
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The metabolic mechanism for most or few drugs will be saturated only at very high concentrations?
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The metabolic mechanism for most drugs will be saturated only at very high concentrations
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What is Zero Order Kinetics?
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Zero Order Kinetics is when a constant amount of drug is eliminated per unit of time (because that is the maximum rate of elimination for that pathway when metabolizing enzymes are saturated)
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What is half-life and what is its significance?
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Half-life is the time required for the blood concentration of a drug to be reduced by 50% (this applies to drugs that are eliminated by first order rate of elimination).
Significant because it takes about 5 half-lives for more than 90% of a drug to be effectively eliminated (and takes 5 half-lives to reach a steady-state concentration in the plasma) |
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What is therapeutic window?
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Therapeutic window is the difference between the minimum effective concentration (MEC) and the conc. that produces an adverse effect
(Window = TD1 - ED80 > 80) |
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For some drugs the therapeutic window is small (only a two- to three- fold difference), true or false?
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True
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What is loading dose?
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Loading dose is the dose of drug that would place the plasma conc. of drug in the therapeutic window with one or very few doses over a very short interval (it is larger than the maintenance dose and if loading dose is given repeatedly would produce toxic concentrations)
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Loading dose equals?
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LD = (Cp x Vd)/F
(where Cp is plasma conc., Vd is volume of distribution, and F is the fraction/percentage that is bioavailable) |
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What is maintenance dose?
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Maintenance dose is the dose needed to maintain the conc. within the therapeutic window when given repeatedly at a constant interval
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Maintenance dose equals?
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MD = (Cp x Cldrug)/F
(where Cp is plasma conc., Cldrug is clearance of drug, and F is the fraction/percentage of drug that is bioavailable) |
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Clearance and volume of distribution are dependant or independant variables?
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Clearance and volume of distribution are independant variables
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Clearance and Vd are used to determine?
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Clearance and Vd are used to determine half-life
t1/2 = (0.693 x Vd)/Cl (half-life is directly proportional to Vd, so higher Vd, then higher half-life, and higher Cl means lower half-life) |
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A higher Vd means a higher or lower half-life?
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A higher Vd means a higher half-life
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A higher Cl (clearance) means a higher or lower half-life?
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A higher Cl (clearance) means a lower half-life
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Drug dosing should aim for the target plasma conc., true or false?
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True
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The volume of distribution is useful in calculating?
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Loading dose
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Clearance is useful in calculating?
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Maintenance dose
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The time to reach steady state depends only on?
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Half-life
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Name the four stages of drug development.
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Preclinical (animal studies)
Clinical (Phase 1, Phase 2, Phase 3) Marketing Generic |
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What is QALY and what does it stand for?
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QALY stands for quality-adjusted life year and it takes into account both quantity and the quality of life generated by healthcare interventions
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What is interchangeability?
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Interchangeability is when a copycat drug has a Cmax (max. plasma conc.) and Tmax (time to reach max. plasma conc.) that is within 80% to 125% of an innovator
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Very young children have more or less cytochrome molecules? How does this affect their metabolizing of drugs?
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Very yound children have less cytochrome molecules (their enzymes are not completely activated yet), so they metabolize drugs to a lesser degree
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From what ages is clearance (metabolic activity) the greatest?
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From about 12 months of age through into puberty is when clearance (metabolic activity) is greatest (in adulthood it slightly lowers and stabilizes)
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Name some changes in elderly that affect drug metabolism?
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Reduced gastric acidity, gi mobility can lead to decreased absorption.
Increased body fat leads to increased Vd (of lipid soluble drugs). Reduced GFR leads to decreased clearance (of water soluble drugs). Reduced hepatic blood flow leads to decreased clearance |
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Pediatric dosing can be problematic because clearance may be increased or decreased?
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Children have increased clearance (after the age of one through into puberty)
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Geriatric dosing can be problematic because clearance may be increased or decreased?
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In geriatric patients clearance is decreased (because of increased Vd, reduced GFR, and reduced hepatic blood flow)
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