Term
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Definition
the study of substances that interact w/ living system through chemical process
-ficks law |
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Term
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Definition
| the undisirable effect of chemicals on the body. |
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Term
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Definition
-the biological effects of the drugs and their mechanism of action.
-drugs on the body
-effects vs. concentration
-theraputic toxin effect of drugs on the body. |
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Term
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Definition
- the action of the body on the drug
-involves ADME (absorption,distribution,metabolism,elimination)
- concentration vs. time
• Considerations of drugs
• Dose
• Regimen
• Form
• A=Absorption, D=Distribution, M=Metabolism, E=Excretion PKPD,
• The study of the concentration of a drug and its metabolites in the body over time
• A drug that remains in the body for a longer time period will require lower subsequent doses to maintain a specific concentration
• Concentration versus time |
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Term
pharmacogenomics
pharmacogenetics |
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Definition
| the study of genetic variation that causes different responses amond individuals or populations |
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Term
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Definition
| inserting a healthy gene into a somatic cell |
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Term
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Definition
-the parts of the cell that interact with the drug.
-initiates the change of events leading to the drugs effects.
- plays the regulatory role in drug interaction w/ spefici molecules in the body
-determines the relationship between dose and concentration.
-responsible for selectivity of drug action.
- mediates the action of agonist and atagonist. |
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Term
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Definition
-molecules that bind to receptor sites.
-involve chemical signaling, NT, hormones, drugs & messenger molecules |
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Definition
| drugs that are synthesised /in the body |
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Term
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Definition
| drug or chemicals that are made outside the body |
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Term
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Definition
| poision & harmfull effect |
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Term
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Definition
drugs activate and bind to receptor sites. (direct or indirect effects)
-has affinity & intrinsic activity |
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Term
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Definition
-prevents and binds to receptor sites prventing othe molecules from binding.
-has only affinity |
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Term
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Definition
| - penetration of liquid, gas, or vapor thourgh a solid. |
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Term
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Definition
-aqueous diffussion
-lipid diffusion
-transport carrier
- endocytosis & pinocytosis |
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Term
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Definition
- w/in lg. queous compartments
-arcoss membrane junctions
-betw blood & extravascular space
-FICKs law |
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Term
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Definition
-MOST important limiing factor
-aq to lipid & lipid to aq
-varies on pH of membrane |
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Term
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Definition
-MDR1 transport
-P-glycoprotein
cancer resistant
cancer resistant
-found in brain, testes, neoplastic cells & other tissues |
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Term
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Definition
-ivolves passive diffussion down a concentration gradient.
-connon sense relationship.
-drug absorption occurs faster in organs w/ a lg. surface area & thin membranes.
- |
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Term
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Definition
-excertion
-weak acids exceretedfaster in alkaline urine
-most drugs freely fitered in the glomerulus
-lipid soluble drug can rapidly reabsorb
-OD on weak acid drugs give bicarb to speed up excretion. |
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Term
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Definition
- weak acid faster in alkaline urine
-weak base in acidic urine
- pH can cause trapping, stomach, sm.intestines, breast milk, aqueous humor, vaginal & prostatic secretions |
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Term
| what is responsible for seletivity of the drug action |
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Definition
-size
-shape
-electrical charge
-mediate the action of the agonists and antagonist.
- regulatory protein
-mediates actions of endogenous chemical signals
-mediates the effects of many of the most useful therapeutic agent |
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Term
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Definition
dru binding was used to identify receptors from tissue
- unknown as ligands |
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Term
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Definition
| -can inhibit or activate by binding to a drug |
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Term
| dru concentration response |
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Definition
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Term
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Definition
-binds to receptor
- but does not activate it
-inhibits the agonsit response
-as it is eliminated it's concentration falls & there is less to compete w/ the agonist w/ = low potency |
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Term
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Definition
dose not let a reaction to happen and never leaves the binding site.
- |
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Term
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Definition
-produces a lower response at full receptor occupancy
-response is simalar to irreversibile antagonist
-prevents binding & activation of agonist
-duration of depends on the bodies ability to generate new receptor
-effects are seen long after the final dose has been administrated |
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Term
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Definition
| - produces a full response at full occupancy |
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Term
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Definition
| ionically binds to drug make it unavailable for interaction w/ receptor or other substances |
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Term
traget drug action
specific |
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Definition
receptors = hormones , NT
enzymes = insulin
transport system = ion channels |
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Term
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Definition
cardiac muscle
SA nodes of the heart |
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Term
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Definition
bronchial smooth muscle
GI smooth muscle
liver pancreas
uterus bladder |
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Term
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Definition
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Term
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Definition
a drug that binds to a receptor and stimulates its functional activity
-adrenaline = epiephrine
-dopamine agonist (used in parkinsons) |
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Term
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Definition
-drugs that can influence a receptor & produce no response. (block agonist from binding sites)
blocking agents:
beta blocker (carvedilol)
angiotensin receptor blocker (candesartan)
alpha blocker (terazosin, doxazosin)
(a key that fits a lock that but doesn't unlock the door) |
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Term
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Definition
| natural or synthetic antimuscarinic agents inhibit acetycholine NT action at muscarinic receptors. |
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Term
| what drugs inhibits enzymes |
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Definition
-Angiotensin converting enzyme inhibitor
-cyclooxygenae inhibitors for pain relief
- HMG- CoA inhibitors |
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Term
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Definition
| membrane spanning protein w/ binding sites for ligand in extracellular domain. |
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Term
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Definition
| causes rapid activation of 2nd messenagers in a cascade that eventully affect cells (stimulates, inhibits) |
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Term
agonist are ligands
endrophines |
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Definition
| are the body's natural agonist at the opiate receptors |
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Term
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Definition
ACh causes Nicotinic AChR (receptor) to open
AChR opened allows Na+ to flow
ACh causes Nicotinic AChR to open which allows Na+ to flow
4 polypeptide subunits
a chain, b chain, g chain, d chain. |
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Term
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Definition
Ach
-serotonin
-GABA
-glutamate |
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Term
ACH, GABA, & glutamate are ionotropic
they have direct actions on ino channnels |
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Definition
NE is metabotropic
has indirect action on ino channels via G proteins & sometimes 2nd messengers |
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Term
ion channel blockers
calcium blockers =
amiodipine & diltiazem |
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Definition
sodium channel blockers =
amiodarone & lidocain |
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Term
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Definition
| excittory NT used by the spinal cord to control muscle & by the brain to control memory |
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Term
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Definition
usually inhibitory NT that produces feeling of pleasure
multiple function |
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Term
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Definition
| major inhibitory brain NT |
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Term
| Nicotine binds to the presynaptic receptors exciting the neuron to fire more action potentials causing an increase in dopamine release |
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Definition
| Alcohol binds directly to receptors for acetylcholine, serotonin, and gamma aminobutyric acid (GABA), and glutamate |
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Term
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Definition
| common brain excitatory NT |
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Term
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Definition
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Term
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Definition
| a hormone & a NT in the PNS it's part of the "fight & flight" response. Usually excitatory but inhibitory in the brain causes VC |
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Term
| intracellular receptors for lipid-soluble agents |
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Definition
lipid soluble drugs across the cell membrane barrier & interact w/ intracellular receptors
nitric oxide stimulates guanyl cyclase which increases cGMP levels
-ligands include= coeticosteroids,minerialocorticoirds, sex steriods, vitamin D |
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Term
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Definition
small secreted proteins that control many aspects of growth & differentiation of specific types of cells, prolactin, IL, IFN,Granulocyte colony stimulating factors ERYTHROPOEITIN,
sinal interleukins, G_CSF, interferons
- respond to a group of peptide ligands |
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Term
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Definition
-generated from ATP by adenyl cyclase
-target protein kinases |
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Term
| hormones that act through cAMP mediated mechanism |
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Definition
ACTH
glucagon
TSH
vasopressin |
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Term
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Definition
reflects the limit of the dose-response relation on the response axis.
-efficacy of the drug in the maxium effect of a drug
-determined by drug's mode of interactions w/ receptors (as a partial agonist |
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Term
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Definition
concentration or dose of the drug to produce 50% of the drugs maxium effects.
- refers to the amt of drug needed to produce an effect, such as relief of pain or to reduce BP
drug strength=potency
efficacy = effectiveness |
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Term
| quantal dose relationship |
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Definition
-measured by therapeutic index
-measure a drug's safety |
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Term
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Definition
is the ratio of the drug that produces toxicity to the dose that produces the desired clinical effect
narrow TI = tocicty
large TI safer |
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Term
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Definition
potential maximal therapeutic response a drug can produce
-determine the by the route of administration. |
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Term
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Definition
| is a measure of the tightness that a drug binds to the receptor. |
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Term
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Definition
=is affected by the quantity of the drug that reaches the receptor & the degree of attraction (affinity) between it & its receptor on the cell's surface
Once bound to their receptor, drugs vary in their ability to produce an effect (intrinsic activity). Drugs vary in their affinity and intrinsic activity |
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Term
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Definition
is a measure of the ability of a drug once bound to the receptor to generate an effect activating stimulus and producing a change in cellular activity
• Intrinsic ability of the body or its organs of elimination to remove drug from the blood or plasma
• CL = rate of elimination
drug concentration |
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Term
| Factors Influencing Concentration of Drug |
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Definition
• Age (infant, elderly)
• Weight (infant, obese adult)
• Gender
• Disease state
• G6PD deficiency (avoid Nitrofurantoin, Dapsone, Bactrim, Naldixic acid, Primaquine, Phenazo’s) |
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Term
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Definition
• Gastritis, Enteritis
• Liver function (Cirrhosis, Hepatitis)
• Renal function (BUN, Creatinine, Stenosis)
• Cardiac function (HTN, Cardiac failure) |
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Term
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Definition
• No drug causes only a single specific effect
• Beneficial or Therapeutic effects
• Toxic effects
• Side effects |
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Term
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Definition
• Fraction of unchanged drug reaching systemic circulation after any route of administration
• When a drug is administered orally, subcutaneously, intramuscularly, rectally, sublingually, or directly into desired sites of action, the amount of drug actually entering the systemic circulation may be less than with the intravenous route-ex only 70% of a Digoxin dose reaches the systemic circulation (mostly due to lack of absorption from the gut)
• A drug must be absorbed and achieve adequate concentration at its site of action in order to produce its biological effects. Thus, when a drug is applied to a body surface (e.g., gastro intestinal tract, skin, etc.), its rate of absorption will determine the time for its maximal concentration in plasma and at the receptor to produce its peak effect
• Bioavailability refers to the extent to and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action |
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Term
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Definition
• When a drug is administered orally, it must transverse the intestinal epithelium, the portal venous system, and the liver prior to entering the systemic circulation
• A drug can be metabolized in the gut wall (eg, by the CYP3A4 enzyme system) or even in the portal blood, but most commonly, the liver is responsible for metabolism before the drug reaches systemic circulation
• A drug must be absorbed and achieve adequate concentration at its site of action in order to produce its biological effects. Thus, when a drug is applied to a body surface (e.g., gastro intestinal tract, skin, etc.), its rate of absorption will determine the time for its maximal concentration in plasma and at the receptor to produce its peak effect |
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Term
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Definition
• This is how the body in preparation for their elimination handles certain drugs and includes the fate of drugs biotransformation (e.g., hydrolysis, conjugation, oxidation reduction)
• Drug metabolites may be inactive or active
• Active metabolites -eg. N-acetyl-procainamide (NAPA) is an active metabolite of procainamide the antiarrythmic and accumulation may cause marked Qt prolongation or torsades de pointes ventricular tachycardia
• Metabolism is the major mechanism for elimination of drugs from the body |
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Term
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Definition
• The kidney is the most important organ for drug excretion but the liver, lung and skin are also involved in drug elimination. Drugs excreted in feces are mostly derived from unabsorbed, orally ingested drugs or from metabolites excreted in the bile and not reabsorbed by the intestine. The physical and chemical properties, especially the degree of ionization of the drug, are important in the rate of excretion
• Elimination occurs by excretion and metabolism
• 50% of drug elimination is accomplished after one drug-elimination half-life, 75% after two, 87.5% after three, etc
• First-order processes such as elimination are near-complete after four-five half-lives |
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Term
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Definition
• Rate and extent of absorption determines bioavailability
• Elderly patients have ↓GI motility, blood flow and ↑pH which results in longer time for drug absorption
• Intramuscular is more rapidly absorbed than subcutaneous injection
• decreased intestinal motility results in a longer time for drug absorption, which explains why drug absorption is quantitatively affected by aging |
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Term
• clearance of a drug
• Liver Metabolism
• Renal clearance
• Biliary excretion
• The sum of these=Total Body clearance of a drug
• Clearance=quantifies Elimination
• CrtCl=ml/min or volume of fluid over time
• Clearance is compromised in the presence of renal failure (affects the dosing of many drugs) |
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Definition
| • When drug is eliminated from the body, the amount of drug in the body declines over time. An important approach to quantifying this reduction is to consider that drug concentration at the beginning and end of a time period are unchanged, and that a specific volume of the body has been “cleared” of the drug during that time period. This defines clearance as volume/time. Clearance includes both drug metabolism and excretion |
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Term
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Definition
• When renal function ↓ = ↑plasma levels of free drug (a concern in patients w/CHF)
• When renal function ↓ = ↑plasma levels of free drug (a concern in patients w/CHF)
• Genetic variants, drug interactions, or diseases that reduce the activity of drug-metabolizing enzymes or excretory mechanisms may lead to decreased clearance and hence a requirement for dose reduction to avoid toxicity
• Vancomycin
• Aminoglycosides (Gantamicin, Tobramycin) |
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Term
| • drug distribution in elderly |
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Definition
• ↑ Age = ↓muscle mass, ↓body water
• Water soluble drugs are therefore distributed less effectively in such patients
• CV disease further compromises flow to organs
• ↑ Age = ↑Adipose tissue = ↑Vd of lipophilic drug (fat causes a depot) |
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Term
| factors affecting drug distribution |
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Definition
• Solubility
• Permeability
• pH and pKa
• Lipophilicity |
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Term
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Definition
| most drugs ionize in solution which sets the preface for absorption |
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Term
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Definition
rate at which a compound will pass through a membrane
• In vitro permeability may indicate whether a drug will be absorbed into a human body |
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Term
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Definition
• Tendency to accumulate in the hydrophobic core of the membranes (concept of partition coefficient)
• Important because of CNS penetration
• Grades of lipophilicity in drug development
• 3-5 Solubility is lower
• <0 Intestinal & CNS permeability problems
• >5 Low solubility, poor oral bioavailability |
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Term
| what organ/organ systems are involved in drug elimination |
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Definition
• kidney filtration secretion Liver metabolism secretion
• GFR
• Skin sweating saliva breast milk lungs expiration |
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Term
| • half life & concentration |
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Definition
• Time it takes to eliminate 50% of the original concentration
• Time it takes for a concentration to fall to half it’s previous value
• Half life as seen by the previous slide formula is influenced by clearance and volume of distribution
• Half life of Diazepam increases with age so the duration of its effect is prolonged in the elderly hence not the optimal benzodiazepine in the elderly- a better choice would be Lorazepam
• The elimination half-life not only determines the time required for drug concentrations to fall to near-immeasurable levels after a single bolus; it is also the key determinant of the time required for steady-state plasma concentrations to be achieved after any change in drug dosing
• Time required to change the amount of drug in the body by one-half during elimination or during constant infusion
• Indicates time required to attain 50% steady state or to decay 50% from steady state conditions |
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Term
| • rate elimination and AUC |
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Definition
• The higher the volume of distribution of the drug, the more rapid is its clearance.
• The higher the elimination constant, the more rapid is its clearance |
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Term
| what is zero order kinetics |
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Definition
• The rate of excretion of a drug is independent of its concentration
• A plot of the drug concentration vs time is linear
• Zero order not directional |
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Term
| what is first order kinetics |
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Definition
• Rate of drug excretion ∞ its concentration
• IV Bolus injection, collect blood samples at various times and measure the plasma concentrations of the drug
• We might see a steady decrease in concentration as the drug is eliminated |
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Term
| what is volume distribution? |
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Definition
• Vd- the measure of the apparent space in the body to contain the drug
• Dose in mm / conc
• Vd is important for drugs such as Digoxin, Amiodarone (drugs that require loading doses)
• If a patient is obese, drugs that do not readily penetrate fat (Gentamicin, digoxin) should have Vd calculated from ideal body weight
• Drugs with very high volumes of distribution have much higher concentrations in extravascular tissue than the vascular compartment
• Size of the compartment necessary to account for the total amount of drug in the body if it were present throughout the body at the same concentration found in the plasma
• Vd = amount of drug in body
concentration in plasma
Function of
• Lipid vs water solubility
• Plasma and tissue protein binding properties of the drug
• High volume of distribution have higher concentrations in the extravascular tissue
• Low volume of distribution higher concentration in vascular compartment |
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Term
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Definition
• LD(mg/kg) = Desired [Blood]* (mg/L) X Vd (L/kg)
• With age, lean body mass and lean body water ↓ resulting in ↓Vd
• Drugs that distribute into muscle (digoxin) or into body water (aminoglycosides) will attain a higher initial plasma concentration after administration as a result of ↓ Vd
• For some drugs, the indication may be so urgent that the time required to achieve steady-state concentrations may be too long. Under these conditions, administration of “loading” dosages may result in more rapid elevations of drug concentration to achieve therapeutic effects earlier than with chronic maintenance therapy |
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Term
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Definition
• Two major sites of drug elimination are the kidneys and liver
• Renal clearance
• unchanged drug
• Hepatic clearance
• Biotransformation into parent compound and metabolites
• Unchanged excretion into bile
• Other organs that participate in clearance include the lung, blood or muscle |
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Term
| what is capacity-limited elimination |
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Definition
Capacity-Limited Elimination (saturation kinetics)
o Clearance is saturable usually at or near therapeutic concentration of drug
o Once saturation occurs clearance rate fails to increase with increasing plasma drug concentrations
Clearance rate remains constant (zero-order kinetics)
o Clearance is non-linear
o AUC cannot be used to describe elimination
o Can result in dangerous concentrations of drug
Toxic or lethal effects
Examples include ethanol, phenytoin, and aspirin
• Extent of an organ’s contribution to drug clearance is quantified by extraction ratio
o Compares drug concentration in plasma immediately before entering and just after exiting organ
• Organ that contributes significantly to drug clearance has a high extraction ratio (closer to 1)
o ie: liver extraction ratio high for drugs that have significant first pass metabolism
• Organ that does not participate would have an extraction ratio closer to 0 |
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Term
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Definition
• Plasma concentration during constant rate of administration
• Provided that the dosing interval is shorter than 4 half-lives, accumulation will occur
• Inversely proportional to fraction of drug lost in each dosing interval |
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Term
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Definition
• After absorption across gut wall drug is delivered to liver via the portal system
• Metabolism by liver enzymes (most common) but can also occur in gut wall or portal circulation
• Elimination substantially decreases the amount of active drug reaching systemic circulation
• Effect of first pass hepatic elimination on bioavailability is expressed as extraction ratio (ER) |
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Term
| BENEFITS ASS. W/ ROUTES OF ADMINISTRATION |
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Definition
• Convenience (oral)
• Maximize concentration at site of action and minimize it elsewhere (topical)
• Prolong duration of drug exposure (transdermal)
• Avoid first pass effect
o Sublingual
o Transdermal
o Rectal |
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Term
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Definition
| – dosage regimen that will produce the desired therapeutic effect |
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Term
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Definition
| administrating a drug in such a way to maintain a steady state of drug in the body |
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Term
dosing rate/interval
• Dosing rate = CL X TC
– TC=target concentration
• Dosing rate must be modified for bioavailabilities less than 100%
– Dosing rateoral = dosing rate
Foral |
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Definition
• If intermittent doses are given
– Maintenance dose = dosing rate X dosing interval |
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Term
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Definition
a. All pharmacologic responses have a maximum effect (Emax)
b. Point at which no further increment in drug will produce an incremental response
c. Important to recognize maximum effect in order to avoid risk of toxicity |
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Term
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Definition
• Single most important factor determining drug concentrations
• Three factors influence clearance
– Dose
– Organ blood flow
– Intrinsic function of liver or kidneys
– Single most important factor determining drug concentrations
– Three factors influence clearance
– Dose
– Organ blood flow
– Intrinsic function of liver or kidneys |
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Term
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Definition
• Drugs cleared by the kidneys require adjustment proportional to renal function
o Renal function estimated using creatinine clearance
• Predicted creatinine production rate in women is 85% of calculated value
o Smaller muscle mass
o Muscle mass determines creatinine production
• Muscle mass decreases with age
o Age can affect creatinine production
• IBW should be used in creatinine clearance estimates
• Correction should be made for muscle wasting in severely ill patients |
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Term
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Definition
• DRUGS MADE OF CHEMICALS OUTSIDE THE BODY
• Substances absorbed across the lungs or skin or ingested in food, drink or drugs
• Environmental exposure may be inadvertent, accidental, or inescapable
• Many are innocuous but some may provoke biologic responses
o Many times relying on conversion to active metabolite |
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Term
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Definition
• Occurs between absorption and renal elimination
• Some occur in intestinal lumen or intestinal wall
• All reactions assigned to two major categories |
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Term
o Phase I reaction
Usually convert parent drug to more polar metabolite
Introducing or unmasking functional group
-OH, -NH2, -SH
Often inactive but can be modified or enhanced
If sufficiently polar then readily eliminated
Many times undergo subsequent |
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Definition
o Phase II reaction
Often endogenous substrate combine with newly incorporated phase I functional group to form highly polar conjugate
Glucuronic acid
Sulfuric acid
Acetic acid
Amino acid
• Usually occurs in liver
• Other sites include
o Gastrointestinal tract
o Lungs
o Skin
o Kidneys |
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Term
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Definition
• Oral medication absorbed small intestine
• Transported to the liver via portal system
• Extensive metabolism in the liver
• Reduces amount of drug delivered to systemic circulation
• Some drugs are extensively metabolized in the intestine which also contributes to first pass effect (ie: clonazepam, chlorpromazine, cyclosporine, midazolam) |
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Term
CYP3A4 metabolizes more than 50% of clinically prescribed drugs
• Enzyme induction |
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Definition
– Enhance the rate of synthesis or reducing its rate of degradation
– Accelerate substrate metabolism
– Decrease in pharmacologic action of the inducer and coadministered drugs
– May exacerbate metabolite-mediated toxicity |
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Term
| VARIATIONS IN DRUG METABOLISM |
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Definition
Individual differences in drug metabolism determined by
a. Age
b. Sex
c. Liver size
d. Liver function
e. Circadian rhythm
f. Body temperature
g. Nutritional and environmental factors |
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Term
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Definition
• Increased susceptibility to pharmacologic or toxic activity of drugs
o Very young
o Very old
o Differences in absorption, distribution, elimination and metabolism
o Slower metabolism due to reduced activity of enzymes or reduced availability of essential endogenous cofactors |
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Term
| LIVER DYSFUNCTION AND DRUG METABOLISM |
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Definition
• Hepatic conditions that can affect drug metabolism
o Alcoholic hepatitis
o Active or inactive alcoholic cirrhosis
o Hemochromatosis
o Chronic active hepatitis
o Biliary cirrhosis
o Acute viral or drug induced hepatitis
o Acute or Chronic diseases that affect liver function can also significantly affect hepatic metabolism of many drugs
o These conditions include:
o Alcoholic hepatitis---inflammation of the liver
o Active or inactive alcoholic cirrhosis---liver produces interlacing strands of fibrous tissue, between which are nodules (liver becomes tawny and characteristically knobby)
o Hemochromatosis---hereditary disorder in which there is excessive absorption and storage of iron…leads to damage and functional impairment
o Chronic active hepatitis----inflammation of the liver caused by virus, toxic substances, or immunological abnormalities..Hep A…Hep B…Hep C
o Biliary cirrhosis---chronic obstruction of the bile duct or autoimmune disease can cause it
o Acute viral or drug induced hepatitis |
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Term
| PULMONARY DISEASE & DRUG METABOLISM |
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Definition
• Pulmonary disease may also affect drug metabolism
• Examples
o Chronic respiratory insufficiency
Results in impaired hydrolysis of procainamide and procaine
o Lung cancer
Results in increased half-life of antipyrine |
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Term
| RENAL DISEASE AND DRUG METABOLISM |
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Definition
• Metabolism of drugs that are primarily renally eliminated can be greatly affected in the following renal patients
o Acute Renal Failure
o Acute Renal Insufficiency
o Renal Artery Stenosis
o Diabetic Nephropathy |
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Term
Durham-Humphrey Act of 1952
• Vested in the FDA the power to determine which products could be sold without prescription.
Kefauver-Harris Amendments (1962) to the Food, Drug, and Cosmetic Act
• Required proof of efficacy as well as safety for new drugs and for drugs released since 1938; established guidelines for reporting of information about ADRs, clinical testing and advertising of new drugs; thalidomide |
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Definition
Comprehensive Drug Abuse prevention and Control Act (1970)
• Outlined strict controls in the manufacture, distribution, and prescribing of habit-forming drugs; established programs to prevent and treat drug addiction.
Orphan Drug Amendments of 1983
• Amended Food, Drug, and Cosmetic Act of 1938; provided incentives for developing drugs that
• a) treat a disease with less than 200,000 patients in USA
• b) drug cost are not expected to be recouped by US sales |
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Term
| GENERAL.” PRECLINICAL TOXICITY TESTING |
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Definition
• Acute toxicity
• Subacute toxicity
• Chronic toxicity
• Effect on reproductive performance
• Carcinogenic potential
• Mutagenic potential
• Investigative toxicology |
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Term
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Definition
• No-effect” dose
• The maximum dose at which a specific toxic effect is not seen
• Minimum lethal dose
• The smallest dose that is observed to kill any experimental animal
• Median lethal dose (LD50)
• The dose that kills approximately 50% of the experimental animals |
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Term
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Definition
| • Patients tend to respond positively to any therapeutic intervention |
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Term
Open study
• Trials are nonblinded or “open”
Single-blind study
• Uses a placebo or dummy medication
Double-blind study
• Identity of medication is controlled by a third party (two identical bottles, different drugs) and not revealed until all clinical data is collected |
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Definition
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Term
Phase 1
• Effects of a drug as a function of dosage in a small number (25-50) healthy volunteers (Exception: cancer/AIDS trials often conducted in volunteers with the disease)
• Nonblinded, open trials
• Find maximal tolerated dose and to avoid severe toxicity
• Pharmacokinetic measurements |
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Definition
Phase 2
• To determine efficacy in modest number of patients (100-200) who have the target disease
• Single-blind design
• Detect a broader range of toxicities |
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Term
Phase 3
• To further establish safety and efficacy in large number of patients (100s-1000s) with target disease
• Double-blind, crossover technique
• Designed to minimize errors caused by placebo effects, variable course of disease, etc.
NDA
• New Drug Application
• If phase 3 results meet expectations an NDA is submitted to FDA to request permission to market new agent in US
• Contains full reports of all preclinical and clinical data pertaining to the drug (chemistry, pharmacology, medical, biopharmaceutics, and statistics)
• In addition to safety and efficacy data, proposed labeling and manufacturing also included |
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Definition
Phase 4
• Monitoring safety of a new drug under actual conditions of use in large number of patients
• Dependent on careful and complete reporting of events by physicians and patients
• Many important drug-induced events have an incidence of 1/10,000, so may not be detected until phase 4 trials |
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Term
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Definition
• Investigational Exemption for a New Drug
• Filed with FDA once a drug is ready to be studied in humans |
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Term
| What is drug distribution |
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Definition
| • The volume of distribution of drugs extensively bound to plasma proteins but not to tissue components approaches plasma volume; warfarin is an example. By contrast, for drugs highly bound to tissues, the volume of distribution can be far greater than any physiologic space. For example, the volume of distribution of digoxin and tricyclic antidepressants is hundreds of liters, obviously exceeding total-body volume. Such drugs are not readily removed by dialysis, an important consideration in overdose |
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Term
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Definition
• Drugs cleared by the kidneys require adjustment proportional to renal function
• Renal function estimated using creatinine clearance
• Predicted creatinine production rate in women is 85% of calculated value
• Smaller muscle mass
• Muscle mass determines creatinine production
• Muscle mass decreases with age
• Age can affect creatinine production
• IBW should be used in creatinine clearance estimates
• Correction should be made for muscle wasting in severely ill patients
• Clearance = Dose
• AUC
• Cockroft Gault Equation
• CrtCl(ml/min) = (140 – Age) IBW(kg) ♂
• SrCr(mg/dl)x72
• Multiply this by factor of 0.85 for females ♀ |
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Term
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Definition
• Harmful or unintended response
• Preventable ADRs occur in hospitals
• All ADRs must be reported to FDA before approval
• Surveillance, evaluation and reporting continue to be required post FDA approval
• Event that are both serious and unexpected are required to be submitted within 15 days to the FDA |
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