【Pharmacology】 Pharmacokinetics

Pharmacokinetics

1. Definition

Pharmacokinetics is currently defined as the study of the time course of drug absorption, distribution, metabolism, and excretion.

Clinical pharmacokinetics is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient.

2. Step

a. Absorption: Movement of a drug from its site of administration to the bloodstream

Happen in 4 different ways

Passive diffusion

most of drug
simply move from area of high concentration to area of lower concentration
water-soluble: move through a channel or pore
lipid-soluble: pass through membrane

Facilitated diffusion

large molecule
move from area of high concentration to area of lower concentration through a carrier protein

Active transport

require energy from hydrolysis of ATP to ADP (breaking of phosphate bond)

Endocytosis

large molecule
engulfment by cell membrane

*Absorption is a variable process depending on pH surface area and blood. 👉Bioavailability

When a drug is given intravenously, absorption is not required, and bioavailability is 100% because the active form of the medicine is delivered immediately to the systemic circulation.

However, orally administered medications have incomplete absorption and result in less drug delivery to the site of action. For example, many orally administered drugs are metabolized within the gut wall or the liver before reaching the systemic circulation. This is referred to as first-pass metabolism, which reduces drug absorption.

So, the bioavailability is 👇

b. Distribution: Journey of the drug through the bloodstream to various tissues of the body

Dependent on factors:

Lipophilicity

Lipophilic drug ↑ (easy to dissolve through some membrane)
Hydrophlic drug ↓

Blood flow

Brain ↑ (high blood flow, accumulate faster)
Skin ↓

Capillary permebility

Liver ↑ (lots of slit junctions through which large proteins can pass)
Brain ↓

Plasma & Tissue binding

Albumin ↓ (Binding with major drug binding protein, slow down the process)

Volume of distribution

Lower molecular weight drugs ↑
High molecular weight drugs ↓
Formula:

High molecular weight drugs tend to be extensively protein bound and don't pass through the capillaries as easy as smaller molecules thus they have higher concentration in blood plasma and lower volume of distribution.

Lower molecular weight drugs especially the lipophilic ones which will distribute extensively into tissues and will result in larger volume of distribution.

This helps predict estimating drug dosing.

c. Metabolism: process that breaks down the drug.

mainly through hepatic renal and biliary route
total body clearance is simply the sum of individual clearance processes
First order kinetics & Zero order kinetics & Steady state

First order kinetics

Most of drug
the amount of drug eliminated over time is directly proportional to the concentration of drug in the body.
eg. starting with 1000 milligrams of a drug the amount eliminated per each time period will be different but the fraction will be constant, which is 16%

Zero order kinetics

Few drugs such as Aspirin
the amount of drug eliminated is independent of drug concentration in the body, so the rate of elimination is constant
eg. starting with 1000 milligrams of a drug the amount eliminated per each time period will be same, which is 200 milligrams, but the fraction will be different
easy to determine half-life of a drug

the time that is required to reduce drug concentration in plasma by a half
helps to predict steady state concentrations

Steady state

when doses of a drug are repeatedly administered, a drug will accumulate in the body until the rate of administration equals the rate of elimination

Graph it when after each additional dose the peak and trough concentrations stay the same

typically attained in about 4 to 5 half-lives

concentration of a drug high enough to be effective but not too high to be toxic so the goal is to maintain steady state concentration within therapeutic range
Large loading dose: when life-threatening infections

to reach desired concentration more rapidly

d. Excretion: the removal of the drug from the body

through kidney which excrete drugs into the urine
however a kidney can't efficiently get rid of lipid soluble drugs as there a passively reabsorbed
Liver comes to the rescue by transforming lipophilic drugs into water soluble substances that are then easily removed by kidneys
mainly through two metabolic reactions: phase 1 and phase 2

Phase 1--Oxidation, Hydrolysis, Reduction

making a drug more hydrophilic
these reactions involve introduction or unmasking of a polar functional group
catalyzed by cytochrome p450 enzymes

Still too lipophilic👇

Phase 2--Glutathione conjugation, Acetylation, Sulfation and Glucuronidation

conjugation reaction which involves addition of a polar group
these reactions produce polar conjugates which cannot diffuse across membranes, therefore they're easily eliminated from the body

two metabolic reactions: phase 1 and phase 2

Cytochrome p450: Large family of enzymes is essential for the metabolism of drugs

Catalyze vast majority of phase 1 reactions:

CYP 3A4
CYP 3A5
CYP 2D6
CYP 2C8
CYP 2C9
CYP 1A2

Drug interactions arise from drug's ability to induce or inhibit,

Some of the important inducers (PCRABS)

Phenytoin
Carbamazepine
Rifampin
Alcohol (chronic)
Barbiturates
St. John's Wort

Some of the important inhibitors (GPACMAN)

Grapefruit
Protease inhibitors
Azole antifungals
Cimetidine
Macrolides (except Azithromycin)
Amiodarone
non-dihydropyridine calcium (Diltiazem + Verapamil)

3. Reference:

https://drawittoknowit.com/course/pharmacology/glossary/pharmacology/volume-of-distribution

https://www.youtube.com/watch?v=NKV5iaUVBUI

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