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255 Cards in this Set
- Front
- Back
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What is any chemical agent that affects living organism
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a drug
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What is the systematic study of drugs?
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pharmacology
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What is the study of the time course of absorption, distribution, and excretion of drugs.
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pharmacokinetics
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What is the study of the biochemical and physiological effects of drugs and their mechanisms of action
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pharmacodynamics
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What is toxicology
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Deals with adverse effects of drugs: Prevention, recognition and treatment of drug poisoning
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What does pharmacy involve?
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The preparation and dispensing of drugs -- now changing to “pharmaceutical care”.
DRUG EXPERTS TO PHYSICIANS PATIENT COUNSELING |
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Why does each drug have at least three names?
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There is the chemical name, the brand name and the generic name. There may be multiple brand names.
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Describe the risk to benefit ratio
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benefit from any drug therapy must be balanced by its potential risks
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What is selectivity
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ability of drug to produce its desired effects with minimal undersired effects
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Why should you "neither be the first to use a new drug nor the last to discard the old?"
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because only a fraction of new drugs represent a SIGNIFICANT advance.
Less is known about the newer drug safety and usefulness. |
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Are adverse rxns predictable?
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Yes and no. To hypersensitivity not predictable
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Are drug interactions therapeutic or toxic?
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Both
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What term refers to the absorption, distribution, biotransformation and excretion of drugs in the intact organism
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pharmacokinetics
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A relationship in pharmacokinetics is believed to exist between what and what?
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Between the pharmacological or toxic response and the plasma drug concentration
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The plasma concentration of drug will be related to what?
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the concentration of drug at its sites of action
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What is the ultimate drug concentration at the site of action dependent upon?
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on the dose administered, the extent and rate of its absorption, distribution, binding in tissues, biotransformation, and excretion
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What are the physicochemical factors in transfer of drugs across membranes?
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permeability
lipid solubility for passive transfer. |
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What is passive diffusion directly proportional to?
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The concentration gradient and the lipid: water partition coefficient of the drug (lipid solubility)
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What is the most common mode of drug transfer?
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passive transfer--by either passive diffusion or bulk flow
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What is the difference between passive diffusion and bulk flow?
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passive diffusion is between smaller molecules, while bulk flow deals with larger molecules.
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What are some forms of specialized transport?
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active transport and facilitated transport and phagocytosis and exocytosis
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What is the definition of the lipid: water partition coefficient?
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ratio of the concentration
of the drug in water and a nonpolar organic solvent (e.g. oil, ether, chloroform, etc.) |
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What is true of drugs with a LARGE lipid: water partition coefficient?
Are these ionized? |
They will readily undergo passive diffusion.
No non-ionized, non-electrolyte |
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Are most drugs strong or weak acids and bases?
Are they ionized or non-ionized? |
Weak! and are present in both non-ionized and ionized species.
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Do ionized or non-ionized have an easier time getting across the cell membrane?
How are ionized drugs dispensed? |
non-ionized, they are lipid soluble
As salts |
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In the stomach is aspirin ionized or non-ionized? What about in the plasma membrane?
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non-ionized
ionized in the plasma membrane |
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What does an acidic pH favor?
What does a basic pH favor? |
absorption of weak acids
absorption of weak bases |
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What factors affect rate of absorption?
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solubility, concentration gradient, area, thickness, permeability, blood circulation, route of administration.
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What is Fick's law of diffusion?
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flux = (C1-C2)x area x permeability /thickeness
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What are the main routes of administration?
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enteral, paraenteral, respiratory, topical
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What types of enteral routes of administration are available?
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oral, sublingual, rectal
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What is advantageous about oral drugs?
disadvantageous? |
convenient, economical, safe
cannot be used in unconscious or uncooperative patients or those with emesis absorption may be incomplete due to metabolism in gut or liver, or just slow to absorb |
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What is the major site of absorption?
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small intestine
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If gastric emptying time (GET)decreases what will that do to absorption?
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increase absorption
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What is intestinal transit time (ITT)?
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time drug is in small intestine
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What does food do to drug absorption?
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decreases drug absorption because it forms complexes
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What factors affect the rate of GI absorption?
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1. passive diffusion
2. small intestine does most of the absorption 3. GET 4. ITT 5. food 6. Formualtion factors 7. destruction of drugs--1st pass effect, gastric pH, enzymes |
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What has been done to some pills to make them easier on the stomach? What problem can this cause?
What is another special oral dosage form? What are the advantages? |
added enteric coating leads to large variability in absorption.
controlled release! Advantage--better compliance take once a day, controlled release. |
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What are the advantages and disadvantages of sublingual drugs?
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avoids first pass
disadvantages--taste, irritation, small amts administered |
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What are the forms of rectal admin? Advantages and disadvantages?
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enema and suppositories
advantage--can use during emesis, unconscious, avoids 1st pass effect and gastric acid disadvantage--unpleasant, absorption is irregular and incomplete |
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name some examples of paraenteral administration.
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intravenous, intraarterial, subcutaneous, intrathecal, intramuscular
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What are the advantages of paraenteral administration? Disadvantages?
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Advantages--rapid and predictablie absorption, acurate dosage, avoid gastric acid, can use in emesis, unconscious, uncooperative
disadvantages--asepsis must be maintained, less safe, painful, self medicating is difficult, expensive |
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Can you use a depot preparation in IV or intramescular?
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depot preparations or in oil provide slow and even absorption. They CAN be used in intramuscular, but NOT in intravenous
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Do drugs that enter thru the respiratory tract undergo 1st pass?
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No they don't go through the liver.
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What is necessary for topical drugs?
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must be in an oily solution to penetrate the cell membranes.
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How do transdermal pathceds maintain their delivery systems?
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use a rate controlling membrane to allow only minimal amts of drug to skin
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What are the three factors affecting teh rate and extent of drug distribution into tissues?
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regional blood flow, permeability of membrane barriers to the drug, extent of plasma protein and tissue binding, regional difference in pH, presence of transport mechanisms.
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Rate the following in ease of permeability: capillary endothelium, cell membrane, blood brain barrier, placenta
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EASIEST capillary endothelium then a tie between teh cell membrane and placenta because lipid soluble drugs pass freely in both and finally blood brain barrier because tight junctions restrict most drugs. Only HIGHLY LIPID SOLUBLE drugs pass blood brain barrier
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What are many drugs bound to?
What do acid drugs bind to? What about basic drugs? |
plasma proteins.
Acidic drugs bind to albumin and basic drugs bind to alpha 1 acid glycoprotein |
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Are drugs bound to plasma proteins reversibly?
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yes highly reversible.
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Will drugs bound to plasma proteins pass through the glomerulus? The liver? The renal tubules?
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No to the glomerulus because they're too big.
Yes to the liver and renal tubules |
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What is an example of a drug that binds to a plasma protein?
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warafin--anticoagulent drug
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Name 4 drug reservoirs and name a drug for each category.
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1. plasma protein (warafin)
2. bone (tetracycline) 3. cellular reservoirs--tissues skeletal mm, heart, liver (lidocane for heart) 4. fat (thiopental) |
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How is the volume of distribution calculated?
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Vd= total amt of drug in body/conc of drug in plasma
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What is Vd
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The amt of fluid required to contain all of the drug in the body at the same conc as in the plasma
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What is the total amount of fluid in the body?
How much is in the plasma? the interstitial fluid? intracellular fluid? |
40L total
5L in plasma 10-15 in interstitial fluid 20L intracellular fluid |
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What does it mean if Vd is large?
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most of drug is in the tissues
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What does it mean if Vd is small?
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most of drug is in the plasma, bound to a plasma protein
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What are the 3 main steps in termination of drug action?
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1. redistribution
2. drug metabolism 3. drug and metabolite excretion |
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When is redistribution most important?
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When a drug is administered by IV to brain or cardiovascular
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How long does it take for thiopental (Pentothal) to reach the brain?
How long does it take to diffuse out of the brain? |
within a minute of injection
Very short time too. |
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What is biotransformation? What does it accomplish?
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drug metabolism of lipid soluble weak acids and bases, which wouldn't be readily excreted from the body.
it 1. increases water solubility. makes more polar metabolites which are not lipid soluble and/or 2. inactivates drug (but not always) |
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What is the major site of drug metabolism? What are the minors?
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Major: liver
Minor: kidney, lungs, GI tract, skin |
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What are the consequences of the first pass effect?
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enzymes in liver metabolize oral drugs. This leads to a HIGH extraction ratio, LOW plasma levels, VARIABILITY IN PLASMA LEVELS BETWEEN PATIENTS---must adjust patients to the dosage
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How can thiopental be utilized if it is in the brain for such a short time?
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repeat dosage
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What is thiopental (Pentothal) used for?
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used as anethesia
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What does biotransformation do?
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Either: increases water solublity (makes cmpds more polar) or inactivates the drug
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What are microsomal enzymes?
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Enzymes whihc do metabolism in the lipophilic membranes of the SER
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What do microsomal enzymes metabolize?
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metabolize xenobiotics--foreign cmpds
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Name the two types of very important biotransformational rxns that microsomal enzymes are involved with.
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oxidations and glucuronide conjugations
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What are non-microsomal enzymes?
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Drugs that do biotransformation, but are foundoutside the SER, like cyotsol, mitochondria, lysosomes etc
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Are most conjugation rxns microsomal?
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No, except for glucuronide conjugations, most are non microsomal
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What are the 4 ways that biotransformation can alter a drug?
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1. active drug to inactive metabolite
2. active drug to active metabolite 3. inactive drug to active metabolite 4. active drug to TOXIC metabolite (OD) |
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What is a prodrug?
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Like #3 above--inactive drug that prodices an active metabolite.
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Why might a prodrug be advantageous? What are some examples?
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produrgs may improve bioavilability (absorption) ad, mask adverse rxns, alter drug solubilty , improve selectivity
ex. levodopa (Dopar) for parkinsons, methydopa(Aldomet) and enalapril (Vasotec) for hyptertx |
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What happens in a Phase I drug rxn? Phase 2?
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Phase I-- convert the drug to more solubel polar metabolite by adding a polar group---OH, -SH, -NH2
Phase 2 rxns are conjucations (conjugates are usually polar) make drug more stable and easily excreted. uaually pharacologically inactivated |
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What are MFO's and what do they include?
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Mixed function oxidase system; type of phase I rxn microsomal. Involves cytochrome P450, NADPH, O2
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Is substrate specificity high or low for cytochrome P450?
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low, a whole family of isoenzymes allows for broad substrate specificity--NONSPECIFIC enzyme
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What are two of the most common P450's? What can induce these?
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2D6 and 3A4
none for 2D6 3A4, 2C9 and 2A6 induced by barbituates smoking induces 1A2 |
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How does cytochrome P450 work to oxidize a drug?
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start w/ parent, complex w/ P450, need NADPH to give up electron in order for flavoprotein to give e to drug-P450 complex, thus reduce complex, add 02, eliminate h20, product R-OH is oxidized and more polar/soluble
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What are some kinds of Type 1 Microsomal OXIDATIONS?
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OXIDATION--cytochrome P40 dependent or N or S oxidation, alphiphatic and aromatic HYDROXYLATION, N, O or S DEALKYLATION, DEAMINATION, DESULFURATION
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What are some types of NON-microsomal oxidations?
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alcohol dehydrogenase, aldehyde dehydrogenase, monoamineoxidase (MAO)--breakdown NE and E
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What are the 3 main types of Phase I rxns?
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oxidation, reduction, hydrolysis
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Is Phase I reduction microsomal or non-microsomal?
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It is both and less common than oxidation
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What types of Phase I hydrolysis rxns are there?
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esterases and amidases
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How are drug conjugates (PhaseII) formed?
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combine drug or metabolite with ENDOGENOUS substance like glucoronic acid, sulfate, glycine, acetate
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What is the family of enzymes that do glucouronide conjugations?
Are glucuronides active or inactive? |
Uridine diphosphate (UDP)-glucuronlytransferases
the MOST important in humans--especiall for phenols, alcohols, carboxylic acids, adn amines type of MICROSOMAL ENZYME!! Glucuronides are inactive and polar--excreted in urine and bile rapidly! |
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Name 6 types of conjugations.
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1. Glucuronides--only one that is microsomal
2-6 non-microsomal 2. acetylation 3. sulfate conjugation 4. glycine conjugation 5. glutathione conjugation 6. methylation |
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Does a drug undergo Phase 1 or Phase 2 or both?
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Depends on drug. Some will do both, some will do only one or the other depending on what modification is necessary to excrete
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Name three causes of drug interactions.
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1. drug inhibition
2. microsomal enzyme induction 3. individual differences in metabolism |
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What is the consequence of enzyme inhibition?
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The original drug is not metabolized as quickly as it should, because of introduction of a second drug. Could cause therapeutic or toxic effects.
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Give some examples of enzyme inhibition.
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ethanol and barbiturate
cimetidine and warafin ketoconazole and terfenadine |
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What happens if wafafine is given with cimetidine(Tagamet)(antiulcer)?
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increase warafin because of decreased elimination increase anticogulent and bleeding. Must monitor drug levels
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How do induced enzymes change cytochrome P450?
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Changes to different cytochrome P450's that have different molecular weights.
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What does induction cause?
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Greater rate of biotransformation, decreased level of drug
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What are the consequences of microsomal enzyme induction?
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tolerance, increased reactive intermediates, drug interactions
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When phenobarbitol is taken with warafin what complications arise?
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induction--increase levels of warafin b/c of increased metabolism
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What is the term meaning physiologic and genetic factors?
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pharmacogenetics
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What are factors of pharmacogenetics?
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genetic variation, age, nutrition, hormones, disease
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What are the main processes in elimination of drugs and metabolites?
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1. glomerular filtration
2. active tubular secretion 3. passive tubular reabsorption |
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Where does active tubular secretion take place? Passive tubular reabsorption?
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active tubular secretion--in proximal tubule, passive tubular reabsorption in proximal and distal tubule
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Is glomerular filtration active or passive? saturable or non saturable?
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passive AND nonsaturable
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What is the amount of drug entering the tubular lumen by fitration dependent on?
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1. plasma concentration
2. plasma protein binding (don't go thru!) 3. glomerular filtration rate (blood flow) |
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Is tubular secretion active or passive?
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Active
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What is secreted from the proximal tubule? Selective or non-selective? Does plasma protein binding effect rate of secretion?
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weak organic acids and bases NON-SELECTIVE
Plasma protein binding doesn't affect tubular secretion because only FREE drugs pass through the glomerulus and thus the renal tube. |
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When does competition for tubular transport occur?
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When organic ions have a similar charge
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What is a well known drug interaction w/ penicillin? Is this adverse?
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probenecid and penicillin are competitive inhibitors. thus probenecid taken in conjuntion with penicillin allows penicillin to stay in circulation longer and it is not excreted out. Both are weak ACIDS.
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What is probenecid used for now?
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Used in treatment of resistant gonorreha, gout, cancer. Previously used in conjuntion with expensive penicillin to increase utilization.
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Why is pH important in passive tubular reabsorption? How are acidic drugs removed? Basic?
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Especially important in drug poisioning. for an acid drug--alkalinize urin with Na+HCO3- to exrete acids.
Ex. salicylate. Basic drugs--acidify the urine with NH4+Cl- to speed exretion of weak base. Ex. amphetamine. |
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How is ion trapping used in drug excretion?
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Ion trapping--trap in ionized form for enhanced secretion. happens in passive tubular reabsorption w/ acids and bases
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Give an example of a drug that undergoes active secretion an dreabsorption
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probenecid
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Are water soluble drugs excreted or reabsorbed? Lipid Soluble?
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water soluble are excreted. Lipid soluble are reabsorbed, eventually will undergo Phase I drug metabolism
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What other mode of excretion is available besides renal?
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biliary and fecal excretion
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What is the flow of drug and metabolites in enterohepatic circulation?
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plasma to liver to bile to gut. from here ca be reabsorbed in the plasma OR excreted via feces
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What can enterohepatic circulation result in?
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long duration of action of a drug.
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What can grapefruit juice do to microsomal enzymes?
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-inhibit activity
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Define pharmacodynamics.
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study of biochemical and physiological effects of drugs and their mechanisms of action
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Who was responsible for the concept of drug receptors and when?
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-JN Langley and Paul Ehrlich
-1900s |
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What occurs when drug binds receptor?
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-initiates a chain of biochemical events (ie conformational ∆) leading to the drug’s observed effects
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Where are the receptors located?
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-on surface of cell
-within the cell |
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What types of proteins are drug receptors and what types of drugs interact?
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-regulatory proteins: NT and hormones
-enzymes:dihydrofolate reductase (methlotrexate) -transport proteins: Na-K ATPase (digitalis) -Structural proteins:Tubulin (anti cancer) |
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What are the different cholinoceptors and what activates them?
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-nicotinic: Nn-ganglia, Nm-mm
-muscarinic: M1, M2-for heart. M3 and up ACTIVATED BY Ach and similar drugs. |
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Describe adrenoceptors. What are they dependent on?
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-actvated by catecholamines: norepinephrine, epinephrine
-α1, α2, β1, β2 location dependent |
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Give 4 ex. of drug receptors
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cholinoceptors, adrenoreceptors, histamine receptors, Na-K ATPase
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What is the structure of nicotinic Ach Receptor?
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Has 4 subunits, 2 alpha, 1 beta, 1 gamma. Ligand gated membrane channel--allows for influx of Na
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What is the serpintine receptor and example of? What is extracellular and intracellular? What binds to each?
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serpentine receptor snakes across the membrane 7 times--type of adrenergic receptor.
EXTRACELLULAR--n terminal binds to NE, E, ACH INTRACELLULAR--c terminal binds to G protien stimulate cAMP |
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What are some features of receptors
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made of protein, one or more subunits, MW 45-200 Kdaltons, usually reversible drug binding,non specific effects, SATURABLE, agonist activation leads to signal transduction, may need more than one drug to activate receptor, magnitude dependent on degree of binding
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Name the four chemical bonds in drug action and a brief description.
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-Ionic bonds: electrostatic inx
-Van der Waal’s: weak bonds when atoms are close together -Hydrogen: bonds b/c H+, O2, N atoms; maintains tertiary structure -Covalent: strong, irreversible, least common |
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What is the strength of each of the chemical bonds?
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In kcal/mole:
Vander Waals--0.5; Hydrogen--2-5; ionic--5; Covalent--100 |
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Describe the classical receptor theory.
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intensity of drug effect/response (intensity) is proportional to the fraction of receptors occupied by the drug.
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What is the law of mass action?
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-rate of formation of drug-receptor complex is proportional to the concentration of drug and receptor
1:1 type of response. increase drug conc. increase contact increase effect |
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What is the equation for drug effect? What is this similar to?
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Effect = Emax [D]/Kd + [D]
Kd is dissociation constant similar to michaelis-menton eq |
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What is Kd equal to?
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Kd = [D] [R]/[DR]= k1/k2
reactants over products Where D + R = (k1, k2) DR = (k3)EFFECT |
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Explain what spare receptors are.
What % of receptors is commonly neccessary for max. response? |
all receptors do not need to be used to reach maximal response.
1-2% of receptors are needed in most drugs |
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What is affinity?
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propensity of a drug to bine with receptor; measured by 1/Kd or k1/k2
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What is intrinsic activity?
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i.e., EFFICACY--ability of drug to initiate response after binding to receptor agonist
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what is an agonist? What is its k3? ex?
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drug with both affinity to receptor and intrinsic activity; interaction with receptor and elicits response (k3 = 1)morphine
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What is an antagonist? What is its k3? ex?
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drug with affinity to receptor without response; competes against agonist (k3 = 0)naloxone
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What is a partial agonist? What is its k3? ex?
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drug with affinity to receptor, with partial/weak activity (k3 < 1)
nalorphine |
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What is an allosteric modulator? ex?
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binds at DIFFERENT site from agonist. Can increase (allosteric activator) or decrease (allosteric antagonist)agonist activity.
Ex. Valium (increase GABA effect) |
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What occurs after the binding of a drug to receptor?
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-conformational change leads to trigger chain of events leading to a pharmacological response
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Explain what receptor-effector coupling refers to.
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transduction process b/t occupancy of receptors and drug response
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What is the efficiency of occupancy-response coupling determined by?
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-initial conformational change in receptor
-biochemical signaling |
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Name the five major transmembrane signaling mechanisms.
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-steroids
-ion channels -transmembrane tyrosine kinase -JAK-STAT -G protein-coupled receptors |
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What is a characteristic of steroid receptor? Where are they found? What do they do?
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lipid soluble--found in cytoplams and nucleus. Modulate gene expression in the cell NUCLEUS.
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Where are ion channels found? What do ion channels do? Ex?
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In the membrane. Permit ion diffusion when open. Ex. Ach on nicotinic ach receptor.
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Where are transmembrane tyrosine kinase receptors located? How do they work? Ex?
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cell membrane NOTE: tyrosine intracellular. phosphorylate tyrosine proteins, form a dimer, agonist binds extracellularly, activates substrates. Ex. Insulin and epidermal growth factors
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Where are JAK-STAT cytokine receptors found? How do they work? Ex.
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Found in the membrane--JAK intracellular binds to STAT's. Binds agonist to receptor on OUTSIDE, dimerization, phosphorylate JAK, phosphorylate STAT to induce protein transcription. Ex. interferons, interleukins--CYTOKINES
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What does the nicotinic ach receptor accomplish?
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let na in, contract skeletal mm.
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What type of receptor do cAMP messengers use? Ca-Phosphoinositide Signaling Pathway (C pathway)?
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cAMP--alpha 2 and beta
C pathway--alpha 1 |
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What happens when a serpintine receptor binds to a drug?
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activates G protein, adenylyl cylase activates cAMP (inhibited by phosphodiesterase), protein C protein dependent kinase activate
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What happens when phospholipase C is activated?
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IP3 and DAG are activated
IP3 stimulates release of Ca+2 to form calmodulin complex and activate calmodulin enzymes. DAG activates protein kinase C, phosphorylates substrate activates enzymes etc. |
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What drugs use G protein coupling?
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NE, Ach on muscarnic receptor
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What does andrenergic mean?
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uses epinephrine as the 'messenger'. Adrenergic stimulation is what is involved in the 'flight or fight' response
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What is the importance of structure-activity relationship?
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-affinity and intrinsic activity of drug related to chemical structure
-relatively minor modifications in molecule may result in major physiological changes, ie stereospecificity, specific functional groups |
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What is a catecho group? What are some catecholamines?
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Catecho group is a benzene ring with OH groups in 3 and 4 position.
NE, E, Isoproterenol, propranolol are catecholamines |
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What are the differences between NE, E, Isoproterenol, propranolol ? Describe their receptors. Which is an antagonist?
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NE-catechol group, amino side chain α>β receptors. i.e. more potent at alpha receptor
EPINEPHRINE--same as NE, but w/ methyl group on amine α=β; levo>dextro ISOPROTERENOL--same as NE but isopropyl group on end; β rec. PROPRANOLOL-- similar but with other benzyl group and isopropyl group; antagonist by blocking receptor |
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What are the effects of NE, E, Isoproterenol, propranolol?
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NE--autonomic system, symp NT
Epi--adrenaline (adreno medulla) Isoproterenol--heart and asthma Propranolol--blocks receptors (antagonist) |
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Name the two nonreceptor-mediated actions of drugs.
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1. interaction with small molecules--chelating agents (EDTA) and antacids.
2. non specific physichemical interactions--general anesthetics and alcohol--produce effect via stabilizing lipid membrane |
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Is there one response/effect with each drug?
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No.
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What are three factors that effect the curve of dose or [c] verses % maximal effect?
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-slope
-potency -maximal effect |
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What is response dependent on?
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dosage
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At what point is the drug at 50% maximal effect? What kind of plot? How does that relate to potency?
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-ED50 or EC50--on graded dose-response curve. x= agonist; y -= % max. effect.
-often ploted log [agonist] for straight line effect. -potency is inversely proportional to ED50 |
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In the body, what is potency influenced by?
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-pharmacokinetics
-affinity of drug to produce response |
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What useful factors are more evident in a log dose-effect relationship?
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potency--x under curve
slope--method of action maximal effect = efficacy |
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What is the difference between a GRADED and LOG dose effect curve?
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graded--hyperbolic
log--sigmoidal |
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Is potency medical important? When does potency cause a disadvantage?
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potency is relatively unimportant. Only problem is when administered in large amt.
HIGH potency might cause increased risk of toxicity |
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What is efficacy limited by? Is it an important characteristic? Is it related to potency?
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-limited to its propensity to produce toxic effect--IN VIVO--toxic and reflex mechanisms.
-important characteristic of a drug -efficacy and potency are not necessarily related |
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What does the slope of a log dose-response effect curve refer to?
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refers to mechanism of action of drug and its binding to receptors. AND steeper curve means more dangerous
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List the steps of sedation.
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-sedative to hypnosis to anesthesia to respiratory to depression
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Is competitive antagonism reversible or irreversible? What about non competitive?
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Competitive antagonism is reversible, non-competitive is not; covalently bonded
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What is a competitive antagonist effectiveness dependent on?
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proportional to dosage and affinity
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What affect does the competitive antagonist have on the dose-response curve?
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right shift, Potency is DECREASED, max efficacy same
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What is inhibition of a competitive antagonist proportional to?
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To the concentration of the agonist and the competitive antagonist. Increase the agonist, reverse effect of antagonist!!
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Does increased dosage of agonist reverse non- competitive antagonists?
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No, because the non- competitive antagonist binds IRreversibly.
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How does the irreversible (non- competitive antagonist) alter the dose-response curve?
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shifted downward, decreased efficacy at full blocking dose of irreversible antagonist. no change in potency!!!
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Define physiological antagonism and chemical antagonism.
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-Physiological: two drugs act on different receptors to cause opposite effects on the same physiologic function (AKA--functional antagonism)
-chemical: one drug antagonizes actions of second drug by binding to and inactivating the second drug |
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What is an example of physiologic antagonism?
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epinephrine (dilate)in anaphylaxis and histamine (contract)
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What is an example of chemical antagonism?
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EDTA vs lead and Hg-- antacids vs tetracyclines
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When does biologic variation or quantal doese effect curve represent? What about dose-response?
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A group of patients.
dose response is individual |
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What types of biological variances exist?
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1. drug effects never identical from patient to patient.
2. magnitude of response differ among individuals w/ same dosage 3. range of effects produced by fixed dose 4. range of doses needed to produce specific intensity for people. |
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What is the difference between the freaquency distribution and the cumulative frequency distribution?
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frequency distribution is gauss distribution. normal dist. curve.
cumulative frequency distribution is the summation of the gauss. curve. AKA. quantal dose-effect curve. |
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What must be determined to do a Quantal dose curve?
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specify effect and determine # individuals at each dose who show specified effect. (all or none response)
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What is the median effective dose?
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ED50, 50% of individuals with specified intensity
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What is the median lethal dose?
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LD50, dose required to produce death in 50% individuals
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How is the therapeutic index determined? Should the # be high or low?
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LD50/ED50 = TD50/ED50
# should be large b/c want to be able to have large doses that don't kill people |
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Is a large or small therapeutic range desirable?
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larger is better. Want a large range of effectiveness, that is not toxic.
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What is considered a bad TI? good?
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bad less than 1, good greater than 100 (otc's)
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What is the difference between TD50 and Ld50?
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TD50 is median toxic dose, LD 50 is median lethal dose. They're the same damn thing
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How is the certain safety factor determined?
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certain safety factor: CSF= LD1/ED99
ld1=lethal dose in 1% ed99= effective dose in 99% |
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What does the CSF account for? Which is better csf or ti?
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csf accounts for slope. Ex. might have same ti, but sloope is different meaning that one drug is more lethal. CSF is better for determining drug safety.
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What is a safe value for a CSF?
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above 1! Below 1 is unsafe
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How are drug receptors regulated?
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1. by # or effectiveness of sites
2. desensitization of receptors |
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How do chronic agonists alter a receptor? What about a chronic antagonist? Give examples of each. What are synonyms for each?
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chronic agonist--downregulate, decrease # receptors. Ex. morphine.
DRUG TOLERANCE, DESENSITIZATION Chronic antagonist--up regulate, increase # receptors Ex. propranolol. Have to ween off drug due to SUPER SENSITIVITY |
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What is a hyperreactive drug?
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one that produces usual effect at LOW dosage
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What is supersensitivity due to?
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increased sensitivity due to surgical or pharmocological denervation
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What can a hyporeactive drug cause?
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Requires unusually LARGE doses of a drug for effect. Promotes tolerance and tachyphylaxis (acute tolerance)
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What is tachyphylaxis?
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ACUTE TOLERANCE --hyporeactivity that develops RAPIDLY after administration of a few doses of drug. ACUTE TOLERANCE
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What is pharmacokinetic tolerance? What is this an example of ?
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drug disposal tolerance, induction of liver microsomal enzymes and increased drug biotransformation. Have to increase dosage for effect. Ex. of hyporeactivity
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What is pharmacoDYNAMIC tolerance? How does this differ from pharmacokinetic tolerance?
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desensitation, adaptation, down regulation of receptors--cell response to repeated exposure of drug by decreasing the # of receptors on its surface.
Differs from pharmKINETIC because kinetic deals with biotransformation of drug, while DYNAMIC deals with # of receptors on cell surface |
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Does a drug produces only a single, specific effect?
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no way. produces side effects. We're happy with a prominent effect
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are drugs selective or specific?
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SELECTIVE drugs--bind to some receptors more so than others! Not so specific.
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What is selectivity?
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relationship betw doses required to produce undesired and desired effects
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What would the curve of a high risk drug look like? Give an ex.
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steep slope and low TI, digoxin, warafin must monitor plasma levels
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Define pharmacokinetics.
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-quantitative, mathematical descriptions of time course of absorption, distribution, biotransformation, and excretion of drugs in organism
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Give the fundamental hypothesis of pharmacokinetics.
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-relationship exists b/t pharmacological effect and [c] of drug in the blood
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Explain the one-compartment model of kinetics. Explain the two/multi compartment model.
Which is more accurate? which is used more often? |
-body as a single compartment with one process of absorption and elimination
-consist of central and peripheral compartments where a drug may either be eliminated or distributed into the peripheral compartment 2 compartment model more accurate b/c we have at least 2 compartments going on (excretion, metabolism, etc). One compartment model is often used b/c it is more basic |
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Describe the first order kinetics. What does the cartesian curve look like? What does the semi log plot look like?
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-elimination/absorption of most drugs leads to constant fraction of drug present is eliminated per unit time
-rate of process α [drug] -exponential caresian is concave up. semi log is straight line |
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What is the eq for half life?
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0.693/Ke (or elimination constant)
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In first order kinetics what is the t1/2 dependent on?
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Nada--it is a constant. It is the slope
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When has a 1st order rxn completed the elimination process. Absorption?
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at 4-5 t1/2
About 90% eliminated Absorption is the same, but must be continuously added |
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Give examples of zero-order kinetics in the body.
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1.IV infusion
2. saturation of elimination/enzymatic processes |
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Which is more common zero order or first rate kinetics?
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first rate kinetics
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What is the independent factor in zero order rxns? What is dependent?
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independent is the rate of drug elimination is constant
dependent--half life. t1/2 increases with dosage. |
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What does the zero order elimination curve look like?
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concave downward.
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What is a mixed order system and what is an example of one?
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exhibits saturation and follows the michaelis-menton eq V = Vmax [D]/ [D]+Km. The rate is a function of [drug],[enzyme] and affinity. Ex. is renal tubular secretion for durgs w/ max. tubular transport capacity.
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What is the relatinship between drug concentration and Km in 1st order and zero order rxns?
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1st order: Km>[D]
2nd order: [D]>>Km use this in michaelis-menton eq to determine constant or dependency. |
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what does the semi log plot for mixed order or saturation kinetics look like?
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cartesian is concave up, semi log is concave down
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What are the two plases in a single dose IV bolus?
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bolus= at one time.
1. distribution 2. elimination or equilibrium phase |
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What are the modes of administering a single doses?
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IV bolus, Oral, extravascular administration.
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Rate the following in terms of onset and length of time in the blood:1. IV, IM
2. SC, oral 3. P-IM |
IV, IM--rapid onset and elimination
SC, oral--shorter onset and longer in blood drug in oil (p-IM)prolonged duration >24 hrs. also increased onset |
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When is a plateau achieved in an IV infustion?
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when the amoutn of drug in equals amt drug out
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IV infusion is __ order?
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zero
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How many half lives does it take to reach the plateau? What is the rate of drug elimination equal to?
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4-5 t1/2's
rate of drug elimination is equal to rate drug infusion (but independent of drug conc!!). |
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What are flucutations between dosages proportional to? Inversely proportional to?
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proportional to dose and dose interval
inversely proportional to half time--less time it takes to eliminate greater fluctuation; longer time to eliminate less fluctuation. |
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What reduces fluctuation? How should drugs be administered in order to cause less fluctuation (or if there is a low TI)?
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slow absorption.
Drugs with a low TI--use smaller dose more frequently to minimize fluctuation. Keep drug in system at lower doses; monitor better |
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When is the initial loading dose given?
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to rapidly achieve optimal plasma concentration and therapeutic effect, then followed by maintenance doses to sustain the effect, e.g. drugs with long half-lives.
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What is the maintenence dose equal to?
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Maintenance dose is one-half the loading dose when the dosage interval is equal to the elimination half time.
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After 4-5 half lifes is the plateau concentration dependent on the loading dose?
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No only dependent on maitenance dose after 4-5 half lives.
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When is it beneficial to give a maitenance dose instead of a loading dose?
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maitenance dose is good for limiting risk of toxic effects and permits accurate adjustment of dosage during drug accumulation.
preferred in Diabetes and hyptertension. Lng term drugs |
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When should loading doses be given? What are the side effects?
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In cases of needing immediate therapy--MI.
Might cause initial drug toxicity. Lidocain |
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What is the bioavailability of an IV drug?
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100%
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How can bioavailabilty of a drug be determined in a time vs. plasma drug concentration curve?
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area under curve of oral drug/ area under curve of IV drug
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What factors affect bioavailabilty?
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solubility, stability in gastic pH, first pass (propranolol), naure of formulation
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What is the difference between bioequivalence and therapeutic equivalence?
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bio--comparable bioavailability and similar time to achieve peak plasma conc.
Therapeutic--have comparable efficacy and safety. Ex. generic drugs |
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What is the apparent volume of distribution? (Vd)
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hypothetical volume of fluid required to dissolve the drug in order to give the same conc. as in plasma.
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What does the volume of distribution determine?
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Determines the extent of the drug binding to tissues vs binding to plasma protein.
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What is the equation for volume of distribution?
What is the practical approximation? |
Vd = amount of drug administered/ conc. of drug in plasma
Vd= dose/Cpo (at time zero plasma concentration) |
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What does it mean if you have a high Vd value?
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high Vd means lots of drug in tissue, not a lot in plasma.
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What is clearance?
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volume of blood or plasma effectively cleared of durg by elimination (metabolism and excretion)
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What must be considered when calculating clearance?
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Cl = Cl renal + Cl liver
So when calculating elemination take into account all organs of elimination for that drug |
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What is the equation for clearance by an organ?
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Cl organ = Q (blood flow to organ) * ER (Where ER is the arteriole conc - venus conc. / art. conc.)
ER = extraction ratio |
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What is the ER for a drug that is virtually cleared by the liver?
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unity = 1
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How can renal clearance be detected? What is the normal GFR?
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Creatine clearance. Can determine GFR (glomerular filtration rate)
125ml/min |
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What is the eq. relating distribution volume and clearance?
What about relating them to half life? |
for 1st order
Cl=VdKe AND half life = 0.693/Ke; so also = 0.693Vd/Cl |
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What does rate of elimination equal?
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For first-order kinetics:
Rate of elimination = Clearance X Cp |
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How can half life be shortened?
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when another drug acts to Clear the initial drug faster (phenobarb)OR
when Vd is reduced. Ex. Cardiac failure |
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What is the equation for infusion rate at steady state?
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Infusion rate= plasma conc. * Cl
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How do you determine the dose of a multiple dose drug?
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Dose = avg. plasma conc * Cl * dosage interval
note avg. plasma conc @ the plateau |
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When giving intermittent injections what are you trying to achieve?
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An avg. rate of drug administration taht equals the rate of elimination at steady state
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What additional factor must be considered when determining dose for oral drugs?
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F= absorbed fraction. So
Oral dose= avg. plasma conc. * dosage interval / F |
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How is the loading dose calculated?
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plasma conc. at steady state * volume distribution.
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What is the result of renal disease in relation to pharmacokinetics?
How does this change the maitenance dose? |
decreased clearance and increased half time. Greater likelihood of toxicity.
Maitenance dose must be reduced |
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How should drug metabolism be dealt with in liver disease?
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Should monitor plasma drug concentration.
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In circulatory insufficiency, i.e., cardiac failure and shock how should drug dosage be handled?
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Vd and drug elimination are decreased= higher plasma concentration. Might need to lower dosage.
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