F - the amount of a dose that gets into the blood

Used to determine extent of drub absorption and in calculating dosing when drug is given orally

F=1 when drug is given by IV, therefore becomes negligable in any calculation

plasma decay curve shifts up or down with increased or decreased F; consider when avoiding toxic doses or attempting to acheive therapeutic doses

T1/2 - Time for blood concentration of drug to be reduced by 50%

Used to determine time for drug conc to read steady state/time it takes to be totally eliminated from the body

T1/2 = (0.693 x volume of Distribution)/ Clearance

 Since this is a hybrid term of two other PK parameters, it is NOT used to adjust dosing of drugs, but it is useful to det: 1) time to steady state, 2) time to elimination

Vd - theoretical volume into which drug goes

Used to determine LOADING dose

Vd = (Dose x F)/Initial Concentration

If Vd is greater than volume of patients blood, then drug went outside the blood compartment; if Vd is less than the adult blood compartment volume but there is evidence there is an effect of the drug in a tissue (i.e. brain) then the patient is likely a child or baby

C - volume of fluid from which all drug is removed/unit of time

eg: if the clearance of a drug is 100 ml/min then all drug is removed from 100 ml of blood in one minute

Removal (from blood/serum) occurs through distribution (into tissues), metabolism (espliver)  and exretion (esp kidneys)

C = Rate of elimination/Drug concentration

For first order kinetics drugs, as conc in bl. inc so does rate of elim, so clearance does not change; for zero order drugs, as conc in bl. inc rate of elim does not change, so clearance dec (drug hangs around longer: inc T1/2)

Used to determine MAINTENANCE dose

C peakes at teen years, then drops with inc age

-Drugs that are less lipid soluble (more polar/hydrophillic) and more ionized are better excreted

rate = k[D], where k=constant, [D]=drug concentration

Concentration dependent

Process: constant FRACTION per unit time

If a patient recieves 100 mg of drug and 10% eliminated than 10 mg lost /unit time

If a patient recieves 200 mg of drug and 10% eliminated than 20 mg lost/unit time

 If change the drug concentration, the curve shifts up or down (bc conc dependent!), but keeping the original curvature shape

rate = Vmax

Not concentration dependent: rate of reaction is constant

Process: Constant AMOUNT per unit time

If a patient recieves 100 mg of drug and 10 mg elimnated than 10 mg lost/unit time

If a patient recieves 200 mg of drug and 10 mg elimnated than 10 mg lost/unit time

The more drug a patient takes in, the longer the drug hangs around: eg. Etoh (drink more-->drunk longer); half life increases with an increase dose concentraiton - takes longer to eliminate

Plasma decay curve changes shape depending on drug concentration (bc rate does NOT depend on concentration)

Cannot really apply most PK principles to zero order reactions

serum drug concentration v. units of time

3 phases: absorption, plateau, elimination

plateau: amount in=amount out (instantaneous, transient steady-state)

Area under curve = Bioavailability (F)

If give drug IV, lose absorption phase; only have distribution and elimination phases

occurs when the amount od drug comin in (dosing) is at equilibrium with the amount going out (elimination)

This is the time when you can best eval the effect of a drug dosing regiment on the patient (unless the drub is causing toxicity)

Takes approx (4)-5 half lives to achieve steady state

Can exploit this with oral dosing to avoid extreme highs and lows in drug conc: give v tight dosing intervals (less drug more often) - or make drug thats slow-release

-As in all PK parameters, T1/2 is constant for a drug regardless of dose, but can change depending on individual pt: if drug is cleared via kidneys, if kidney function drops, clearance drops, T1/2 increases: now must wait 5x(new half life) to reach steady state to eval the effectiveness of the dosing regiment for this patient (unless becomes toxic in the meantime)

Calculated based on Vd

Relevant in a caase where a patient needs to acheive a certain drug concentration immediately and cannot wait 4-5 half lives: give a loading dose (mostly only applies to emergency situations)

aka Loading Dose

= (Dose x F)/Vd

aka Mainenance dose, Cpss

= (Dose x F)/(Dosing Interval x Clearance)

blood flow

nature of the drug

disease states

injury to absorption site

surface area

Most drugs abs this way; no plateau phase (unlike active transport); higher conc of drub gets absorbed

NON-ionized drubs more readily cross lipid membranes than ionized e.g. weak acid: less ionized in acid ph - more readily crosses membranes

Stomach=acidic; blood is slighly basic; urine=acidic

eg. when take cocaine (basic) take also with baking soda to make urine more basic so the drug is less ionized in urine, more likely to leave urine, less excreted, more stays around in blood

permeability constant x drug concentration difference x surface area

**explains why drugs are mainly abs in Small intestine: due to huge SA (even if drug is acidic and SI is basic - you'd think this would make the drug ionized and therefore less likely to cross lipid membranes and be absorbed, but actually the SI will still be the mn site of drug abs, even over the acidic stomach where the ph would leave the acid drug less ionized and therefore more readily crossing throug lipid membranes to be abs

product fomulation

intestinal trnasit time

drug interactions

magnitude of first pass effect (liver disease, liver blood flow, enzyme induction)

eg. if first pass effect is dec, then F inc and Cl dec: steady state bl conc will be MULTIPLIED: i.e. if the F inc 2-fold and the Cl dec 2-fold due to dec first pass effect, the serum con (SS conc) inc 4 fold

Therefore: patient can get a toxic effect from "normal" drug dose if drug usually gets a high first pass from liver but the patient's liver function is dec

transport processes (active v passive)

nature of drug (size, ionized): highly ionized, can't cross membs well

membrane integrity/specialization (i.e. morphine v codeine: codeine has memb more lipid soluble: enters brain more easily)

****PLASMA PROTEIN BINDING: amount unbound is critical conc bc this is the amt that can cross membranes to enter tissues from bl;

-Weak acids bind albumin;

Weak bases bind alpha one acid glycoproteins

via met (liver), excretion (kidney), dialysis (Artificial/iatrogenic)

usually drugs start Lipophillic (less polar) and changed to hydrophillic (more polar) to be excreted

meperidine (slows CNS) v. normeperidine (excites CNS)

Morphine v. morphine-6-Glucoronide

CYPs = cytochrome P450s

localized in ER in liver cells

sybstrates are lipid-soluble, esp foreign

cayalyze ox, red, hydrolysis rxns

**enzyme inductin occurs (more cyps activate if more substrate for those cyps are present: drug induces its own met and sometime the met of other drugs too)

much genetic variation in exp or CYP isozymes: eg. CYP2: met codeine: met into morphine - gives pain relief

Phase I met of tylenol: oxidized by CYPs

Phase II: met by glutathione enzyme; if lack this enzyme or overwhelm it, the tylenol metabolite becomes a free radical: damages hepatocytes

If drug has high extraction ratio (goes quickly from blood into hepatocytes): blood flow will affect clearance (i.e. inc flow: inc clearance)

If low extraction ratio, then blood flow does not affect clearance

1) glomerular filtration (depends on plasma protein binding: plasma protein bound drugs not get filtered, drug size/charge, diseases of glomerulus)

2) active tubular secretion: Proxmal tubule has nonspecific stransport system for organic acids eg penicillin and organic bases; Distal tubule has specific transport; can give other organic acid to compete with penecillin in kidney tubule so less pen excreted and more stays in system longer

3) passive reabsorption/passive ionic diffusion (depends on pH and lipid solubility): occurs at collecting duct; eg. if drug is naturally acidic, acidic drug will be less ionized in urine and more likely to pass thru membranes and less likely to be excreted.

Pharmacodynamics

plots the proportion of  a population that repsonds to a drug in an all or non fashion against the dose

Usually a bell curve; if use logarithmic scale, becomes sigmoidal

the dose of a drug that will produce a LETHAL effect in half the population

In clinical med, we can consider TOXIC DOSE as one which produces any adverse effect and thus TD50 rather than LD50

Homo Glu genotype at codon 27 is assoc with greater venodilatation after admin of isoproterenol

Homo Arg genotype at codon 16 is assoc with greater airway reponse to oral albuterol and greater desensitization to isoproterenol

receptor level; reduction in receptor responsiveness

short term exposure to agonist: loss of receptor responsiveness v. long term exp: loss of receptor number = desensitization and internalization

increased receptor responsiveness resulting from a)chronic reduction of receptor stimulation (eg beta adrenergic supersensitivity after prolonged treatment with bea blocker metoprolol), b)tissue response to pathological conditions (eg synthsis and surface recruitment of receptors during cardiac ischemia)

Can see "rebound effect" when withdraw from an antagonist due to receptor sensitization-->eg have seen an increased risk of MI afte clonidine withdrwal (clonidine stimulates alpha2 receptors in brain resulting in dec sns activity: used to dec BP in HTN) - had to treat with Labetalol to dec withdrawal symptoms: acts as competetive antagonist at alpha and beta adrenergic receptors: mediate effects of sns on heart and bl vessels)

Take home message: when withdrawing a patient from a drug (esp agonist/antagonist) TAPER THE DOSE

additive: 2 and 2 is 4

antagonisitc: 2 and 2 is 3

synergistic: 2 and 2 is 5

potentiated 0 and 2 is 3

a ligand which produces an effect when it binds to a receptor

HAS EFFICACY

a ligand which binds to a receptor and produces no effect on its own but will reduce the effect of an agonist

HAS NO EFFICACY

drug that has affinity for the receptor but less than full activity

Can act as antagonist: give increasing conc of agonist, eventually binds all the receptors instead of full agonist, therefore only get partial response rather than full reponse of the full agonist

aka positive allosteric modulator; has no effect by itself but enhances orthosteric ligand affinity or efficacy

eg. barbiturates, benzos, alcohol: act at/affect the GABA receptor but not the GABA binding site itself: increase GABA Receptor affinity/efficacy

binds allsoteric site without affecting orthosteric site but blocks action of other allosteric modulators (can thereby act as antagonist to allosteric enhancer or allosteric agonist?)

eg. flumazenil: can block effects of benzo (an allosteric enhancer)

ligand that reduces the action of another ligand by blocking access to its binding site; binds at same site/overlapping site as endogenous ligand; antagonism IS SURMOUNTABLE; shifts agonist log concentration/effect curve to RIGHT without change of slope/max effect (takes more and more agonist to have same effect as inc conc of antagonist) ED50 rises with each increase in antagonist concentration (takes more agonist for 50% response)

potency is reduced (rightward shift); efficacy is unchanged (can still reach max effect with enough conc of agonist)

a ligand which binds to agonist binding site and dissociates very slowly or not at all thus decreasing the action of the agonist; agonist is UNABLE t overcome antagonist occupancy

Shifts agonist log concentration-effect curve DOWNWARD

In a system with SPARE RECEPTORS: as long as the percentage of the receptors needed for full effect were eventually bound by agonist, the curve merely shifted right (looks like reversible antagonist is acting), but then when less than that percentage of receptors is bound by agonist, the curve shifts downward as you expect with a non-competetive antagonist

potency is reduced/unchanged; efficacy is reduced (curves shifted DOWN)