semi - altered natural cmpds

synthetic - entirely made by chemists

proprietary - trade name; original drug-->$$ to make and market; patent protection for 17 yrs

non-proprietary - generic name; less $$, must achieve 80-120% blood levels as original

1 - no acceptable medical use; but okay to use in research

2 - has acceptable medical use; abuse = severe dependency; oral ppx orders are not accaptable unless it's an emergency

3 - acceptable medical use; abuse = moderate dependency; <5 refills before 6 mo.

4 - acceptable med. use; abuse = limited dependency; <5 refills in 6 mo.

5 - acceptable med. use; may even be obtained at descretion of pharmacist w/o prescription; unlimited refills

burden of proof that herbal product is unsafe is upon FDA and composition is not standardized due to variability in botanical components

ppx drugs must be proven safe prior to marketing

forward: compound discovered--->usefu mechanism determined

reverse: molecular target ID'ed---> desired drug designed for target

median lethal dose: fatal to 50% of animals

Phase 1 CT - IND (investigational new drug) application filed with FDA; 20-100 healthy volunteers; to assess safety and pharmacodynamics

Phase 2 CT - 100-200 pts; assess efficacy and adverse drug reactions

Phase 3 CT - 1000-6000 pts; assess efficacy and adverse rxns against current standard; NDA (new drug applcation) filed upon completion

Phase 4 CT - post marketing surveillance

FDA Modernization Act '97 - patent extension incentive

Pediatric Rule '98 - demands studies be done

Describe the way in which the following factors determines the rate of passive diffusion across lipid membranes.

1. degree of ionization

2. lipid solubility

3. concentration gradient

1. less ionized---> more lipid soluble---> faster diffusion

2. more lipid soluble---> faster diffusion

3. greater concentration gradient of non-ionized form---> faster diffusion

(weak acids: when pH<pKa; weak bases: when pH>pKa)

can CONTROL rate of absorption by:

- altering blood flow (epinephrine; cold/heat)

- altering vehicle (oil vs. aqueous)

in SI:

- largest SA for absorption

- pH progressively more alkaline

- longer transit time

- blood flow---> reduction = slower absorption = longer duration of action (e.g. epinephrine-->vasocinstriction of local capillaries)

- pH---> causes non-ionized form to be prevalent---> poorly water soluble and percipitates out---> slower absorption

Define the following terms relating to solid dosage forms and describe their significance.

- disintegration

- dissolution (How can this be prolonged?)

- disintegration: break-down into smaller solid particles---> increase SA

- dissolution: entry into aqueous GI medium---> availability for absorption (rate limiting)

prolonged by coating with water-insoluble material (e.g. wax) or embeddin in matrix

total body water: 60%

ECF: 20% (4% plasma; 16% in ISF)

ICF: 40%

highly lipid soluble

exceptions:

- infant BBB - relatively permeable to water-soluble drugs;

- inflammation alters permeability

- active transport possible through choroid plexus

drugs usually redistribute according to blood flow---> more rapidly perfused organs are usually the first to recieve drug;

subsequent distribution to less rapidly perfused organs (muscle and adipose)---> drug storage and lower drug concentration available for rest of the organs (decreased duration of action!)

lipid-soluble drugs are passively reabsorbed---> slow excretion

lipid-insoluble---> not reabsorbed (cause of charge), rapidly excreted

sodium bicarb: increases pH---> favors ionized form of weak acids; non-ionized form of weak bases----> enhanced secretion of weak acids

ammonium chloride: decreases pH---> favores non-ionized form of weak acids; ionized form of weak bases---> enhanced secretion of weak bases

active - diseased tubules; competition for transport sites

passive - pH alterations

Cl_r = U x V/C_p x T

units: mg/ml and min

liver (SER)

biotransformation---> drug transformed to less pharmacologically active, more polar form----> more readily secreted via kidneys and bile---> less toxicity

newborn: drug metabolizing enzymes not yet fully developed---> very slow biotransformation

elderly: drug metabolzing enzymed decreased due to decreased liver function---> v. slow biotransformation

C_a-C_v/C_a

(fraction of arterial drug content that is extracted during single passage through liver)

substrate-limited drugs: high extraction ratio---> rate of metabolism is sensitive to hepatic blood flow

enzyme-limited drugs: low extraction ratio---> rate of metabolism is not sensitive to hepatic flow

high extraction ratio--->free drug efficiently taken up by liver---> shifts plasma equilibrium to unbound (so plasma protein binding has little effect on rate of metabolism.

low extraction ratio---> no shift in equilibrium because of amount of limited enzyme available to metabolize drug (so rate of metabolism is limited by plasma protein binding)

first-order:

rate of elimination is proportional to plasma concentration (Cp), which is proportional to the drug amount (A); i.e. constant fraction of drug is eliminated per unit time

assumption: drug has equilibriated into its volume of distribution

positive slope---> rate of absorption is relatively greater than rate of elimination

negative slope--> vice versa

Amount(A_ss) = rate of administration (K_ad)/(rate of elimination (K_e)

assume zero-order kinetics for K_ad

Cp_ss = A_ss/Vd = (K_ad/K_e)/Vd = K_ad/clearance

higher concentration or higher affinity---> less of the given drug bound at a given concentration

[image]

affinity of C > of B

ability of drug to bind and induce maximum response; can range through 0-100%

antagonists have pharm. efficacy = 0%

partial agonists = <100%

full agonists = 100%

Kd = [drug] required to bind 50% of receptors; measure of affinity

EC50 = [drug] required to produce 50% maximal response;
measure of potency

What is the relationship between affinity and potency?

Why is EC50 slightly < Kd?

potency reflects affinity; higher affinity ----> higher potency

EC50<Kd because drug binds "spare" receptors contribute amplification that allows 50% max response before binding 50% receptors

Are A and B equally efficacious? Equally potent?

[image]

equally efficacious because can obtain desired effect in 100% of patients at some concentration.

NOT equally potent. A is more potent than B cause of lower ED50.

decrease in response to drug over milliseconds due to presence of constant drug concentration at site of action.

produced by agonists

1. receptor internalization

2. receptor desensitization (effector uncoupling)--> binding occurs but response is diminished

Describe metabolic (dispositional) tolerance. Is this response produced by agonists, antagonists, modulators, or all 3?

What is the mechanism of metabolic tolerance?

tolerance to drug due to repeated dosing over several days

produced by all 3

mechanism: induction of metabolizing enzymes

As conc. increases with each repeated dose, response decreases due to induction of metabolic enzymes

but decrease in response is LIMITED by saturation of these enzymes

internalization causes response to decrease while drug concentration stays constant

decrease in response is LIMITED by limit to decrease in receptor internalization

measures safety

= LD50/ED50

higher number---> safer drug

= TD₁/ED₉₉

(dose that's toxic to 1% of patients/dose that's therapeutic to 99% of patients)