Basic pharmicokinetics/dynamics

Lecture 1

What are two types of drugs that have little overlap with human drugs

antiparasitic and anticancer

The US adopted names council (USAN) of the american medical assn. will negotiate on

generic name and brand name

What are the goals of drugs:

1. avoid medication errors

2. use of drug in unsafe ways

3. misbranding of the drug

What are the general characteristics of most drugs

• small, organic molecules

• “balanced solubility” in oil and water

• optimized to reduce off-target effects

what is the average M.W. of most drugs

400 daltons

why is balanced solubility important

to penetrate cellular lipid bilayers

What is the difference between pharmacodynamics vs pharmacokinetics?

dynamics: how does the drug act (potency, efficiency)

kinetic: how is the drug processed (ADME)

what is ADME

absorption, distribution, metabolism, elimination

What are the different types of drug targets

• receptors

• enzymes

• DNA

• Ligand-gated ion channels

• nuclear receptors

What do nuclear receptors target

hormone receptors (ex. cortisone, glucocorticoid, vitamin D)

what drugs target DNA

Cancer agents/chemotherapeutic agents

What is the case for bacterial pathogens, what are drugs targeting

target enzymes as it’ll disrupt the membrane and ribosomal protein synthesis

What is the traditional PK model

Drug → central compartment (blood circulation generally) → peripheral compartment (tissues with lower blood flow) → total drug elimination

what are some tissues with lower blood flow)

kidneys, liver + (lungs if dealing with vapor)

k; rate constant is dependent upon

barriers to PK pathway and time-dependent movement

What is the traditional PBPK approach

• tracks drug levels only in the blood

• empirical; uses simplified, abstract compartments

• fitted to data from one species/population

• hard to adapt to other species

• requires clinical data first

what is the modern PBPK approach

• tracks drug levels across many organs

• mechanistic

• adaptable across species

• useful when clinical data is limited

• can make predictions for complex scenarios

drug dose is always in consideration of

mass; not volume (even if the drug was given in fluid form)

elimination of the drug can be ___________ depending on drug or chemistry of the species

whole or metabolized

Advantages of orally-administered antimicrobial drugs

most common

can be administered at home

advantages of injectable antimicrobial drugs

good for patients with GI or neuro issues

usually administered in clinic

extravascular - enteral routes of drug admin

oral (PO) and rectal

extravascular - parenteral routes of drug admin

subcutaneous and intramuscular

why would we choose to give a medication rectally

to prevent the drug from getting concentrated in the liver/portal vein

what are other extravascular routes of admin besides enteral and parenteral

topical (skin, eye) and regional (nerve tracts, airways)

What is a consideration for some extravascular routes of admin

they are released outside of central circulation

types of intravascular drug admin

intravenous/arterial

What is Area Under the Curve (AUC)

measure of “internal” drug exposure.

the AUC is what relationship for a drug in serum or plasma

concentration x time relationship

What does AUC calculate

• bioavailability (PK term, F)

• clearance (PK term, CLt)

what can AUC be used for besides calculation

can be used in therapeutic drug monitoring (TDM) or PKPD modeling to optimize drug dosing

Explain the three windows of AUC

therapeutic is optimal

above the peak is the side-effect/adverse response

anything lower than therapeutic is sub-therapeutic

Why is sub-therapeutic concerning

bacteria can survive and reproduce at this point

What is Cmax

peak drug concentration achieved in the serum or plasma

Cmax relates to the

intensity of the side effects produced by a drug if its Cmax exceeds the therapeutic range

what is Tmax

time at which the peak drug concentration (Cmax) is reached

Tmax predicts

when drug side effects could occurand helps in determining dosing intervals.

Tmax also serves as the best time to

collect a blood sample for monitoring Cmax

T1/2 (elimination of half time) is the

time at which the drug concentration in plasma is at half of its peak value (C1/2)

T1/2 relates to the

elimination or total body clearance (PK term, CLt) of the drug from the blood

Why is half time important to consider

• determines whether it’s single or multiple treatments

• withdrawal time for food products

what drugs target ion channels

interact with enxymes and NSAIDs to modulate cyclooxygenase → prostaglandins

AUC unit

ug x hr/ml

Any route beyond the itssue barrier establishes a _______ _______ quickly

concentration rate

What is absolute bioavailability (F)

fraction of administered drug dose that reaches the blood circulation(F) after administration

How is absolute bioavailability calculated

AUC extravascular / AUC intravascular

What characterizes absolute bioavailability?

a drug encounters no barriers when given into a vein and can appear immediately in the bloodstream

how is absolute bioavailability expressed

as a fraction or percentage

what is relative bioavailablity?

comparing the different formulations (brand name or oral pill vs liquid) given by the same route of administration (often extravascular)

what is bioavailability

measurement of the extent of a therapeutically active drug that reaches the systemic circulation and is therefore available at the site of action

what does it mean to be bioequivalent?

there is no clinically significant difference in two drugs’ RELATIVE bioavailability

what would a graph of a non-bioequavalent material look like?

Cmax or Tmax would not be overlapping post-dose, they cannot different significantly in plasma concentrations

What are some variables of the DRUG that affects bioavailibility

physicochemical properties (dissocation constant or water vs lipid solubility)

pharmaceutical formulation of the drug (dosage form design or particle size)

what are some variables of the ANIMAL that affect bioavailability

• age (pre-ruminant vs ruminant, young vs old)

• ingested foods, fluids, and other incompatible drugs

• GI function (transporters, enzymes, gut motility, pH)

• liver function (enzymes, bile, porto-systemic hunts)

• blood flow

Why does age matter when it comes to bioavailability

younger animals may not have the appropriate enzymes to be able to process the drugs

What body part is highly vascularized, making it ideal for picking up and distributing drugs

muscle

Why is it important to know about the binding of antibiotics

some antibiotics bind to metal ions, so if there’s a potent amount of calcium in the gut that it binds to, it affects the bioavailibility (and also dictates if medication is given with food or not)

pre-systemic elimination or first pass elimination

fraction of the drug dose that reaches the bloodsteam is decreased because it either becomes metabolized in early compartments or is eliminated in feces

what factors contribute to pre-systemic drug elimination

• biotransformation of drug by gut bacterial enzymes or intestinal epithelial cell enzymes

• hepatic portal circulation (first pass)

• elimination via feces

what dictates if cerenia is given orally or subcu

cerenia is an entiemetic, so subcu may be used because the animal needs relief quickly and because they are vomiting (preoccupied). orally can be used pre-op

how do portosystemic shunts affect bioavailibility

they INCREASE drug concentration because they bypass liver enzymes.

is poor bioavailibility ever a good thing?

• can be for ingested toxins

• antibiotics that need to be used for gut relief/infection but cannot stay in the bloodstream for excessive periods of time (ie neomycin)

  • aren’t absorbed but remain in gut lumen and attain high GI concentrations

  • outcome: more drug exposure, less risk of systemic toxicity

where do drugs distribute first

tissues with high blood flow, then greatest body mass

Drug absorption across cell membranes may include

passive diffusion

carrier-mediated transport

active transport

The two types of passive diffusion

paracellular and transcellular (through epithelial cells vs between adjacent cells)

what are common issues we may run into with carrier-mediated transport (facilitated diffusion)

The proteins involved may have a limited amount, which results in saturation

the other issue is competition to use that protein

active transport (transcellular influx/efflux) is an ______ mechanism. Many drugs move this way

ATP-powered (energy requiring)

transport mode across the membrane depends on the drug’s

physicochemical properties

• size

• lipid solubility

• ionization

• formulation

lipophilicity - the balance between lipid and water solubility in drugs determines the

penetration of lipid bilayers by passive diffusion

Ionization of a drug molecules will increase its _______ and affect its ______

polarity; permeability

For large molecules and nanodrugs, what method do they have to use instead

endocytosis

what are some examples of drugs that need to be transported by endocytosis?

monoclonal antibody (ex: Librela)

polypeptide hormone (ie: insulin)

highly lipophilic drugs can be transferred via lipid absorption pathways into

intestinal lymphatic vessels

Highly lipophilic drugs OR large drug formulations stick for a much longer time in the body because

they go into the lymphatics rather than bloodstream

(ie Librela lasts 3-4 weeks)

Because lipophilic drugs don’t go into the bloodstream, they also bypass

first-pass metabolism (just end up hanging out in hepatocytes before moving into lymphatics)

Large drug formulations will enter and circulate in lymphatic vessels if

they can’t penetrate blood capillariars after EV injection

What is the significance of -vetmab

vet - relating to veterinary

-mab - monoclonal antibody

(ex: bedinvetmab, lokivetmab, frunevetmab)

passive diffusion Transport is ________ and not ________

non-selective; not saturable

What is the driving force of passive diffusion

concentration gradient

in passive transport, what is the ideal drug?

• small

• “unattached” to bigger molecules

• lipid-soluble

• uncharged

What are the two key drivers of passive drug diffusion

chemical polarity (water solubility) and lipophilicity (requires a balance between the two)

In passive transport, how does proton availability affect the drug?

it affects the fraction of the drug that is in a charged (ionized) form.

an acidic drug losing its H+ atom is ________ charged and a basic drug acquiring an H+ gains a ______ charge

negatively, positive

what will slow down the passive transport of a drug in its ionized state between body fluid compartments

pH differences

what kind of transport is represented by B

Passive transport

What kind of transport is represented by A

Active transport

What is the Henderson-Hasselbalch Equation?

log [protonated drug] / [unprotonated drug] = Pka-pH

The dissociation constant (pKa) is the pH at which

50% of a drug dose is ionized and 50% is un-ionized

For acidic drugs, over time they become _______ ionized

more

for basic drugs, they become ______ ionized over time

less

Why does the progression of ionization in acidic and basic drugs matter?

because they are unable to cross the permeable membrane, so they end up sitting, and slowly permeating as it becomes more and more ionized/un-ionized.

A drug entering a new fluid compartment with a different pH can become “trapped” if it becomes too _______. this can lead to _______ _________ in that compartment

ionized; drug accumulation

what are some examples of drugs that get trapped due to becoming too ionized

alkaloid drug entering stomach with acidic gastric contents, such as morphine or atropine, can become ionized and therefore trapped, leading to reduced absorption.

What is the issue with maternal blood mixing with fetal blood

fetal blood is more acidic than the maternal, causing the issues with pH imbalance.

what happens to patients with an acid/base disorders (like respiratory alkalosis)

It will determine if the medication utilized needs to be acidic (ionized) or basic (un-ionized) to maintain pH appropriately and to prevent trapping of the drug in a compartment

How might drugs affect milk?

antibiotics to treat mastitis can cause the milk to change pH and affect the milk:plasma concentration ratio

weak acids (like sulfa or penicillin) don’t change the ratio, so the drug is hanging out in the plasma rather than the milk

on the other hand, weak bases (like erythromycin) heavily affect the milk:plasma concentration ratio, making the milk more basic, and causing food regulatory issues. (erythromycin was almost 9x of the usual ratio)

think-pair-share: a sulfonamide antibacterial drug is a weak acid with a pKa=6. At pH=8, what is the difference in the amount of the charged from of this drug (A-) relative to uncharged (AH)?

100; more

10 pka-pH = [HA] / [A-]

10^6-8 = 10^-2 = 0.01

0.01 = [HA] / [A-] = 1/100

For every 1 uncharged HA, there are 100 charged A-

In facilitated diffusion, passive xeniobiotic transport, and active transport involves _______ and _____carrier proteins

selective; saturbal

In facilitated diffusion, the driving force is also the concentration gradient, but it is usually _________ than passive diffusion. it also is moving “downhill”

faster

What characterizes drugs that use facilitated diffusion?

• polar molecules with low lipophiliciyt and are ionized at plasma pH

  • Examples: organic cations, organic anions, nucleosides