Pharmacology - Melega Flashcards
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medical model of disease
diseases are related to underlying derangement of normal function
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Quantal dose-response curves (d-r)
- plots the fraction of population that responds to a given dose: response is recorded as either ‘present’ or ‘not present’ (it either occurs or does not occur). Log dose (x) vs %maximal response (or individuals responding)
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ED50
amount of drug that produces a therapeutic response in 50% of the people taking it
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TD50
amount of drug that produces a toxic response in 50% of the people taking it
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LD50
amount of drug that produces a lethal response in 50% of the people taking it
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TI
Therapeutic Index: TD50/ED50
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Pharmacodynamics
what the drug does to the body
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pharmacokinetics
what the body does to the drug ADME
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efficacy (drug)
refers to magnitude of response on d-r curve
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potency (drug)
Refers to effective concentration that produces 50% of its maximal response (EC50) when comparing two drugs with the same efficacy.
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full vs partial agonist
full: maximal efficacy, partial: partial efficacy
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spare receptors
even after brief introduction of irreversible antagonist, maximal efficacy still reached (bc cell had spare receptors that became activated)
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constitutive activity of receptors
receptor isomerization between active and inactive forms. receptors have some activity even in absence of agonist
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Kd
Kd is a measure of drug affinity (tendency to bind) for the receptor. Lower Kd = higher affinity since Kd=Koff/Kon
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4 main targets of drugs
(1) ligand gated ion channels (2) G coupled proteins (3) enzymes (4) transporters
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How does Exposure to Drug-Agonists Affect Receptor Function and Receptor Number
Short term: reduction in response tachyphylaxis. Long term response: decrease in receptor #. “receptor down regulation” less synthesis
Therapuetic window
the range of doses that produce a therapeutic response, without unacceptable side effects; - an index of drug safety. Seen on a plasma drug vs time graph
Bioavailability
the fraction of administered drug that reaches the systemic circulation. AUCoral/AUCiv x100 = % bioavailability
Factors affecting drug absorption
(1) route of administration (2) membrane diffusion (3) metabolism (first pass effect)
enteral vs parental
via GI tract (oral and rectal); easy, but first pass effect reduces bioavailability. Not GI tract (IV, sub-cutaneous etc), for drugs not easily absorbed. good for drugs that are poorly absorbed in GI
4 ways drugs cross membrane
(1) diffusion (gradient) (2) facilitated diffusion (3) active transport (4) pinocytosis
First Pass Effect
The intestinal & hepatic degradation or alteration of a drug taken by mouth, after absorption, removing some of the active substance from the blood before it enters the general circulation.
Ion trapping (drug distribution)
only neutral molecule can diffuse across the membrane. Once inside the weak base dissociates and is “trapped” inside. Thus ions can enter but not exit. How much diffuses depends on pH of solution and pka
metabolism
Need for Drug metabolism
Drugs are usually lipophilic (important for absorption). This makes them hard to excrete. Metabolism makes them more hydrophilic
metabolism
Main Categories of drug metabolism (2)
(1) Phase 1 functionalization reactions: polar substrate is introduced via oxidation, reduction, hydrolysis. GOAL: make metabolites more H2O soluble.
(2) Phase II reactions: Conjugate reactions. GOAL: make metabolites even more H2O soluble.A substrate (parent drug or phase I metabolite) is coupled to an endogenous compound such as glucuronic acid, glycine, or sulfate
metabolism
CYP P450 Enzymes
Most important enzyme system for Phase I. Catalyze oxidation of organic substances (monooxygenase rxn). p450 embedded in ER of cells. Highest concentration found in Liver (GI, skin, lung etc also). Metabolism and detoxification of compounds enterring the body p.o
metabolism
Phase I: Alcohol metabolism
alcohol dehydrogenase: alcohol to aldehyde (oxidation). Then oxidized again to carboxylic A. Side effect of excessive alcohol: decreased NAD+ levels and increased NADH. Increase in NADH pathways and decrease in NAD+ pathways (extremely dangerous if taking acetaminophen like tylenol which will then overwhelm liver)
metabolism
Phase I: monoamine oxidase
MAO: non p450 phase I oxidation. Amines–>aldehydes
metabolism
Phase I: hydrolysis
Esterases are present in plasma and other tissues; they rapidly metabolize esters and amides to carboxylic acids. Ex:For short term anesthesia, succinylcholine is administered by infusion; its neuromuscular blocking effect is terminated rapidly by hydrolysis by plasma cholinesterase
metabolism
prodrug
Drug is inactive before metabolism and is activated by metabolism. Designed to overcome delivery problems. 30% or all prescription drugs are prodrugs. Some metabolites of active drugs also are active (longer pharmacological action)
metabolism
CYP p450: induction and inhibition
Induction: increase in p450 synthesis. protein synthesized so delayed effect–> higher metabolism and decreased drug effect. Inhibition: competition with other drugs for active site of p450. reduces metabolism and increases drug action
metabolism
Factors affecting individual differences in drug metabolism
Age: less p450 in older people (lower the dose for elder;y). Genetic differences (EM and PM extensive and poor metabolizers). Environment (other drugs health etc)
metabolism
alcohol metabolisma and polymorphism
Asians often have a atypical type two ALDH (aldehyde dehydrogenase- second enzyme in pathway) leading to build up in acetaldehyde (nausea, tachycardia, and flushing)
B1W4Melega4-Pharmacokinetics
bioequivalence
two drugs are bioequivalent if bioavailabilities are similar after administration (same dose)
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Volume of distribution: Vd
Vd(L/Kg) = D(mg/kg)/C(mg/L)
D=dose,C=plasma concentration. Def. Theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Therefore the dose required to give a certain plasma concentration can be determined if the VD for that drug is known.
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Clearance
Cl= rate of elimination/plasma concentration. Clearance as a ratio is a constant. Most commonly measured as renal clearance but can also be liver clearance or total clearance when everything is summed
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relation of 1/2life, clearance, and Vd
T1/2 = .693 Vd/Cl, since Cl = K x Vd and .693/K = T1/2
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steady state concentration (Css)
input=output, no net change in concentration
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loading dose
an initial higher dose given to push blood concentration into therapuetic range early on and after which a maintenance dose can be prescribed. loading dose = Vd x C(desired)
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capacity limited elimination
saturation of enzyme or transporter
B1W4Melega4-Pharmacokinetics
zero order kinetics
drug eliminated at a constant rate
