pk-pd synchronous

pharmacology week 3 lecture

weak acids

best absorbed in the stomach

what are weak acids best absorbed in the stomach?

bc in the highly acidic stomach, the acids are in their unionized form

what diffuses more readily through cell membranes?

non-ionized substances

weak bases

best absorbed in the intestines

why are weak bases best absorbed in the intestines?

weak bases have enough in the unionized form for absorption in the intestines

carboxylic acid groups on drugs and change with pH

acidic pH (stomach):

• when in an acidic state, driven to unionized form

alkaline pH (intestine):

• when in a basic state, driven to ionized form

  • less tendency to be absorbed

amino groups on drugs and change with pH

acidic pH (stomach):

• will go into ionized form

alkaline pH (intestines):

• will go into unionized form

what is the main form of absorption?

oral

other forms of absorption

intramuscular, subcutaneous, transdermal, inhalation, sublingual, rectal, inhalation, topical

when does absorption occur?

with any administration that leads to the drug getting into the systemic circulation

does absorption occur with IV admin?

NO

bc the medication is injected directly into the systemic circulation

bioavailability

fraction of drug that reaches the systemic circulation

absorption: passive diffusion

transport through a cell membrane

drug MUST be in aqueous solution at absorption site

drug dissolves into and out of the lipid material of the membrane

follow’s Fick’s first law of diffusion

Fick’s first law of diffusion

movement will occur from areas of high concentration to areas of low concentration

can ions permeate the lipid material of the membrane?

no, since they have no lipid solubility

can electrolytes permeate the lipid material of the membrane?

yes

can weak acids or bases permeate the lipid material of the membrane?

yes

what are most drugs?

electrolytes, weak acids or bases

why are most drugs electrolytes, weak acids or bases?

bc the ionized moiety is usually lipid soluble

absorption: active transport

involves energy

drug binding to a carrier

often does against concentration gradient OR electrochemical gradient

where can active transport of drugs in the body be found?

active transport mechanisms can be found in many barrier membranes and help modulate the concentration of drug in an organ

first pass metabolism

drug gets metabolized/inactivated prior to reaching the site of action for the drug

where does first pass metabolism occur?

in the liver

but it can occur in other organs too

when does first past metabolism occur?

during and after absorption

one-compartment model

used for drugs which rapidly equilibrate with the tissue compartment

two-compartment model

used for drugs which slowly equilibrate with the tissue compartment

systemic circulation volume

~4.5 L

body water volume

~ 40 L

what is volume of distribution related to?

systemic circulation volume and body water volume

what affects volume of distribution?

physiology

drug characteristics

physiologic changes that affect Vd?

cardiac output, proteins binding

drug characteristics that affect Vd?

lipophilic, intracellular, low molecular weight

high molecular weight, high protein binding

for high Vd

higher concentration in tissue than in plasma

• relatively lipophilic, intracellular, low molecular weight

for low Vd

confined to plasma and interstitial fluids (not tissues)

• high molecular weight (mAb drugs), high protein binding

what is the main organ for metabolism?

the liver

what does most metabolism take place with?

CYP450 isoenzymes

what is metabolism?

the conversion of the administered drug into another substance by chemical reaction

what are the outcomes of metabolism?

active drug to inactive metabolite

active drug to active metabolite

inactive drug to active metabolite

prodrug

the metabolism of an inactive drug to active metabolite

how many phases does hepatic metabolism have?

2 phases

phase I of hepatic metabolism

biotransformation

• drugs undergo oxidation, reduction or hydrolysis to become more hydrophilic

phase II of hepatic metabolism

conjugation

• drugs receive a molecular attachment that facilitates transport within the body

can drugs be subjected to either or both phases of hepatic metabolism?

yes!

but often undergo phase I followed by phase II

CYP450 drug interactions

substrate

inhibitor

inducer

substrate

drug is metabolized by that CYP isoenzyme

inhibitor

drug decreases the activity of that CYP isoenzyme

inducer

drug increases the activity of that CYP isoenzyme

what happens if you inhibit metabolism?

increase concentration of drug in plasma

what is the main organ for elimination?

kidney

elimination: renal

the net of three mechanisms within the kidneys:

• glomerular filtration

• tubular secretion

• tubular reabsorption

what is used as a marker of renal function?

CrCl

glomerular filtration

passive diffusion; impacted by:

• molecular size

• protein binding

• glomerular integrity and total number of functioning nephrons

tubular secretion

transports drugs from the blood to the lumen of the nephron

active transport

tubular reabsorption

either via passive diffusion or by active transport systems

clearance

getting drug out of the body

expressed as volume/time

NOT the amount of drug removed, but the volume of plasma (or blood) from which drug is removed in a given time

total body clearance

the sum of all clearances by various mechanisms

Cl total= Cl renal excretion + Cl hepatic metabolism + Cl biliary excretion + Cl other

what affects plasma drug concentrations?

rate of drug administered

volume of distribution

clearance

conversion of plasma concentration v. time curve to straight line (first-order elimination)

allows for extrapolation of drug concentrations at various times for a drug

half-life

t1/2

time necessary for the concentration of drug in the plasma to decrease by one-half (50%)

area under the curve

indicator of overall drug exposure

the greater the area → the more drug absorbed

transmembrane signaling

cascade of steps

most drugs act on receptors on the extracellular face of the cell membrane and modify the intracellular function of those receptors by transmembrane signaling

agonist drugs

full activation/full drug effect

partial agonist drugs

partial activation/partial drug effect

antagonist drugs

no activation/drug effect

can also block the effect of agonist drugs

example of an antagonist

antihistamines

graded dose-response curves (individuals)

response of a particular receptor-effector system is measured against increasing concentrations of a drug, the graph response versus the drug concentration or dose

Emax

maximum efficacy

EC50 (ED50)

concentration (dose) needed to achieve 50% of the maximal drug effect

the small the EC50

the greater the potency of the drug (potency on the ceiling effect of the drug)

what does the slope of the line in a graded dose response curve represent

the change in response per unit dose

therapeutic window

range of concentration between minimum effective and toxic concentrations

therapeutic drug monitoring

monitoring drug concentration levels in the plasma/blood to reach therapeutic dosing goals while avoiding toxicity

subtherapeutic

plasma concentrations too low

NOT effective

supratherapeutic

plasma concentrations too high

TOXICITY

plasma drug concentration

he measurement of the drug's concentration in the blood over time, which is represented by a plot known as the plasma concentration–time profile

peak concentration

highest concentration that will occur in the plasma

typically drawn 30 minutes after IV admin to allow for distribution

trough concentration

lowest concentration in the plasma between doses

typically immediately before the next dose is to be administered

random concentration

drawn at any point during the dosing interval

concentration/time curves for oral administration

time for medication to transit to gut and be liberated from tablet

gradual rise in concentration over time due to needing to be absorbed into the plasma

Cpk

peak concentration

amount of drug being absorbed is equal to amount being eliminated

oral administration

concentration/time curves

intravenous bolus dose

concentration/time curves

intermittent infusion

concentration/time curves

continuous infusion

concentration/time curves

concentration/time curves for IV bolus dose

C0=Cpk

Cpk occurs instantaneously

IV bolus dose

medication is administrated directly into the bloodstream

• no need for absorption

IV bolus dose (IV push)

typically administered over 10-30 seconds

C0

concentration at time0

concentration/time curves for intermittent infusion

Cpk does NOT occur instantaneously

Cpk occurs at the end of the infusion

intermittent infusion

medication administered directly into the bloodstream

• no need for absoprtion

intermittent infusion administered over

10, 30, or 60 minutes

concentration/time curves continuous infusion

usually for drugs with a short half-life

continuous infusion

small amount of drug is administered to patient every second/minute

steady state

when accumulation rate=elimination rate

what is steady state?

a function of the drug’s half-life

how many half-lives does it take to reach steady state?

5

principle of superposition

continuous to build until reaches steady state→ will still have ups and downs

when a pt receives a subsequent dose of a medication and there is still drug present in the plasma, there is an additive effect on the plasma concentrations

Css ave

average concentration at steady state

IR v ER medications

extended release medications are formulated to release drug over a longer period of time

• results in less variability in Cmax and Cmin

physiologic factors affecting pharmacokinetics

elderly

kidney failure/dysfunction

hepatic dysfunction

obesity

pediatrics

pregnancy