MLSCI 466 - Pharmacokinetics and Pharmacodynamics (Lec 1-3)

pharmacology definition

studies interactions b/w live organisms and chemicals that influence functions

toxicology definition

looks at undesirable effects of chemicals on living systems

3 categories of pharmacology

1. pharmacodynamics

2. pharmacokinetics

3. pharmacogenetics/pharmacogenomics

pharmacodynamics definition

looks at therapeutic and/or toxicity of drugs, receptor interactions (agonist/antagonist) concentration-effect component

pharmacokinetics definition

• effect of the body on the drug

  • mathematically describes fate of a drug w/ a specific dosing schedule, dosage form and route of administration

why are pharmacokinetics useful

1. makes predictions about drug effectiveness or toxicity

2. calc blood concentration in an individual under specific conditions

**helps us understand how a drug will act in a body —> optimize efficacy and safety

pharmacogenetics definition

effect of genetics on drug metabolism and effect on bodyPH

pharmacogenomics definition

related to pharmacogenetics but encompasses mutations in relation to drugs and how sequencing DNA can predict individual response to drugs

what does LADME stand for

L = liberation

A = absorption

D = distribution

M = metabolism

E = excretionwh

what does LADME describe

pharmacokinetic processes — determines how fast, in what [ ], and how long the drug takes to reach its target organ

pharmacodynamics vs pharmacokinetics

-dynamics = effect of DRUG on the BODY

-kinetics = effects of BODY on the DRUG

what does AUC stand for

area under the curve

availability definition

a function of liberation and absorption

what does rate of liberation depend on

1. formulation (polymer layers, distribution in formulation, liquid solutions)

2. amount (large bolus takes longer to dissolve)

3. drug solubility

4. environment pH

what are the two conditions that helps drugs dissolve

drug solubility + environment pH

what are the factors influencing absorption

1. gastrointestinal factors

2. physicochemical drug properties

3. transporters

4. rate of administration

name examples of GI factors

• food

• pH

• perfusion, motility, SA

• enzymes, microflora, permeability

name examples of physicochemical drug properties

solubility, charge, size, and structure

passive transport methods

paracellular transport, dilution, and facilitated diffusion

what type of transporter moves drugs into circulation

active transporters that aid large, charge molecules like drugs to get across lipid bilayer

what is the Henderson Hassel-Balch equation

pH = pKa + log([A-]/[HA])

why do we use the H-HB equation

to predict the charge status of a drug at a specific pH

Aspirin is a weak acid, with a carboxylic functional group (pKa of 3.5). In a stomach pH of 2.0, what is the ratio of charged to uncharged aspirin?

pH < pKa, therefore ratio is mostly uncharged

The intestines have a pH of 7.4. What is the ratio of charged to uncharged aspirin in the intestines?

pH > pKA therefore drug is mostly ionized and ratio is more charged

Is aspirin mostly absorbed in the stomach or the intestines?

stomachwha

what does AUC indicate

total exposure to a dose of a pharmacological compound (we look at this after absorption of drug)

bioavailability definition

amount of drug dose that reaches the circulation how

how do we estimate bioavailability

by calc the drug dose and AUC from the plasma concentration vs time plot

bioavailability equation

AUC administration route / AUC intravenous route

first pass metabolism definition

intestinal and liver metabolism reduce bioavailability of an orally administered drug before it reaches the systemic circulation

what is the bioavailability (F) factor

• the fraction of active dose that makes it to circulation

• intravenous/complete absorption is denoted as F=1

• extravascular/incomplete absorption is denoted as F<1

what is the chemical form (S) factor

• the fraction of formulation that is the active form of the drug

• considers form of drug (salt or ester) and active ingredient

effective dose equation

effective dose = F x dose admin (mg) or S x F x dose admin (mg) depending on chemical form

does bioavailability estimate rate of absorption

NO… it only estimates extent of absorption. It is availability that includes rate of absorption

factors influencing drug distribution

organ size, tissue perfusion, drug binding to plasma proteins/tissues and solubility

where do drugs circulate to

• plasma

• muscle

• bone

• fat

• connective tissues

volume of distribution units

L/kg

what can the volume of distribution tell us about pharmacokinetics

• tells us how extensively a drug can partition into different body compartments

volume of distribution definition

size of compartment required to contain total amount of drug in the body if it were present throughout the body in the same concentrations found in the plasma

volume of distribution equation

Vd = total dose (A) / [drug concentration (C) x weight (kg)]

how do we calculate total body water

TBW = plasma + interstitial + intercellular

would a smaller or larger Vd indicate more drug trapped in plasma?

a smaller Vd would indicate a higher blood concentration of the drug

what can a large Vd tell us about distribution

extensive distribution to peripheral tissues

[tissue] > [plasma]

what can a small Vd tell us about distribution

confined to vasculature, little uptake by tissues

[plasma] > [tissue]

factors influencing Vd

• drug solubility

• plasma protein binding

how would Vd change if it was more water soluble

increase plasma conc in turn decrease Vd

for a patient with liver cirrhosis, how would Vd change for an albumin bound drug

decrease albumin (PPB) in turn decrease plasma concentration → increases Vd

albumin

acidic drugs, bilirubin, LCFA

alpha-1 acid glycoprotein

basic drugs

lipoproteins

cyclosporine, cholesterol, vitamins, steroid hormones

which form of drug interacts with receptors

free (unbound) drug = active form

conditions that change the concentration of plasma proteins

• APR

• hypoalbuminemia

• uremia

• polypharmacy (i.e. phenytoin and valproic acid)

• overdose (protein binding saturation)

how to estimate body burden (amount of drug)

amount = Vd x patient’s weight x Cp

what does loading dose of a drug tell us

tells us how much of the first dose is required to reach a therapeutic range

loading dose equation

loading dose = [Vd x weight x Cp] / [S x F]

what is clearance

ability to get rid of drug from body; part of drug metabolism + excretion

how do we calculate total body clearance

CL = Vd x Kel; we are looking for the volume of plasma cleared of drug per unit time by processes of metabolism and excretion

what is total body clearance

metabolic clearance + non-metabolic clearance

physiological influences on drug clearance

blood flow and organ function

true or face: total body clearance does not tell us how much drug is removed, only the volume of plasma that drug is being displaced

true

how is Kel determined

by looking at clearance part of AUC, plotting the log concentration vs time of elimination, then the slope is the negative elimination constant

what must occur for Kel determination

reaction must be 1st order

drug elimination half-life (t1/2)

time required for the amount/concentration of drug in the body to decrease by 50%

drug elimination half-life (t1/2) equation

t1/2 = (0.693 x Vd) / CL

elimination half-life predictions

1. time to steady state

2. rate at which blood concentration falls after drug admin stops (important to consider how long until drug is undetectable in the patient)

3. estimate appropriate dosing interval (consider drugs with a really fast or long half-life)

what is the problem with doing TDM before patient is at steady-state

rate will be lower than actual value

steady state equation

S = salt form factor

F = bioavailability

Dose = dosing rate

what is the assumed steady state

5 half lives

unit for steady state

mg/min

what determines the time it takes to achieve steady state

drug half-life

what is steady state concentration determined by

dose and frequency of dose

maintenance dose

amount of drug administered to maintain a desired steady state drug concentration in the body

maintenance dose equation

derived from rate in = rate out

proper TDM

• drug is at steady state

• drug collected at trough or peak

• dose is adjusted as necessary

TDM candidates

• narrow therapeutic range

• clinically dangerous or difficult to interpret for over- or underdosing

• high biological variation

• concentration proportional to clinical effect

• availability of a standardized, reliable assay

• concentration changes with polypharmacy, inhibition, induction, diet

first-order elimination

rate of drug clearance is proportional to drug concentration therefore % of total drug removed is constant at any time

zero-order elimination

rate of drug clearance is constant regardless of drug concentration so a constant amount of drug gets eliminated

what types of drugs exhibit zero-order elimination

drugs that saturate excretion mechanism i.e. alcohol, phenytoin, and aspirin (at high dose)

organs that excrete drugs

mainly liver and kidneys, but also skin, lungs, and GI

route of enterohepatic recirculation

drug → small intestine → large intestine → rectum → anus → feces (non-absorbed drug)

path of drug in SI

drug absorbed → portal vein → liver → bile → gall bladder → bile → small intestine

excretory processes in kidneys

1. passive glomerular filtration

2. active proximal tubular secretion

3. passive distal tubular reabsorption (non-ionized)

what does OAT shuttle

weak acids

what does OCT shuttle

weak bases

factors affecting renal excretion

• drug properties

• plasma protein binding

• fluid intake (flow)

• urine pH

• other drugs

• kidney function

what can alter pharmacokinetics

biological variation i.e. age, gender, pregnancy, disease, etc…

how does bioavailability change in neonates and infants

• decreased gastric acidity

• prolonged gastric residence time

• slower intestinal motility

• transporter function varies with matural

• increased intestinal permeability

• increased skin permeability

• decreased bile salts

• absorbs pen G, ampicillin, and digoxin well

• poor absorption with phenobarb, phenytoin, and gabapentin

how does bioavailability change in geriatrics

• delayed gastric emptying

• decreased absorption surface

• decreased GI motility

how does distribution change in neonates and infants

• increased total body water to body fat ratio → increased Vd for hydrophilic drugs

• decreased binding capacity of albumin

• decreased concentrations of albumin and alpha-1-acid glycoprotein

• high bilirubin displaces drugs

how does distribution change in geriatrics

• decreased total body water to body fat ratio decreases Vd for hydrophilic drugs

• decreased plasma protein binding increases the free drug concentration in plasma

how does clearance change in neonates

• they have immature renal function

• unique metabolic pathways

• immature liver function (CYP p450 and UGT activity)

how does clearance change in geriatrics

• slight decline in renal function when clearing aminoglycosides, vancomycin, and digoxin

• slight decline in hepatic function when clearing propanolol or verapamil

• phase 1 metabolism either reduced or no change

why is pharmacokinetics important in TDM

makes sure dosage regimen is effective and safe for interpreting therapeutic drug monitoring resultd

is the parent drug or drug metabolite the active form?

metabolites—may contribute significantly to therapeutic effects and/or adverse side effects

xenobiotics

organic compounds not made by our bodies; usually lipophilic

features of most pharmacologically active molecules

lipophilic + remain non-ionized or only partially ionized at physiological pH

why can most drug metabolites be passively reabsorbed in the body after filtration in the kidney

because they remain non-ionized (or partially ionized) at physiological pH

drug metabolism

converting drug molecules into substances that are excreted easier. or to render metabolites less active or inactive in comparison to the parent drug

what is biotransformation

the enzymatic transformation of molecules by functionalization (P1) and/or conjugation (P2) into molecules that are polar and water soluble

what is a phase 1 reaction

introduction, exposure or modification of specific chemical (functional) group e.g. REDOX rxns