lecture 5 and 6- pharmacokinetics

pharmacodynamics

what a drug does to the body

pharmacokinetics

what the body does to a drug

why is pharmacokinetics important in drug discovery

in the clinic you can see individual variations within populations and ethnic groups in how they respond to drugs, so the dose and frequency of administration needs to be adjusted to ensure control of the amount of drug in the body is within the ‘therapeutic window’

in pharmacodynamics, physiochemical properties of the drug affects…

affinity, efficacy and potency

in pharmacokinetics, the physiochemical properties of the drug affects…

absorption, distribution, metabolism and excretion

as the concentration of the drug increases…

the effect increases (for most drugs)

the time it takes for the drug to start working, reach its maximum effect and then wear off, directly mirrors…

how the amount of drug at the specific location where it acts changes over time (with the exception of irreversibly bound drugs)

distribution is from…

the bulk flow transfer through the bloodstream to take the drug to its target and to its sites of elimination

what is the diffusion coefficient (for the absorption of a drug) proportional to

1/sqrt(MW): the smaller the drug, the higher the diffusion coefficient so the faster the drug diffuses

what determines where and for how long a drug will be present in the body after it has been administered

the movement between compartments, generally involving penetration of non-aqueous diffusion barriers

what are some types of barriers a drug might diffuse through

• plasma membrane

• vascular endothelium

• the CNS and placenta

pinocytosis

a process where the cell takes in extracellular fluid and dissolved small moleceules by engulfing them with its membrane

process of pinocytosis

the cell membrane forms a small pouch around the fluid and solutes, which then pinches off to form a vesicle inside the cell (this is a form of endocytosis)

factors affecting absorption

• diffusion through lipids

• pH and ionisation

• route of administration

• transport

the diffusion of drugs through lipids depend on…

the concentration gradient and diffusion coefficient

the concentration gradient in cell membranes will depend on…

the lipid-water partition coefficient (lipid solubility)

what is the advantage of non-polar drugs

they are easy to eliminate

many drugs are weak acids or bases:

HA ⇌ H+ + A-

the Henderson-Hasselbalch equation:

pKa=pH + log10(HA/A-) or pKa=pH +log10(BH+/B)

at low pH, weak acids will be…

unionised

weak acid

a molecule that can give up a H+

pH affects steady-state distribution of drugs between…

aqueous apartments

weak acids become trapped in…

basic compartments

where is the main site of absorption in the body

the small intestine (not stomach) due to its enormous absorptive surface area (surface area overrides determinant of the site of the drug)

give an example of how pH affects drugs

• drugs like metoclopramide (speeds up gastric emptying) promote aspirin (weak acid) absorption

• drugs like propantheline slow down aspirin absorption

weak acids will accumulate in compartments with…

high pH

intravenous route

most direct, fast acting, used in emergencies

IV treatment, goes directly within the vein

intrathecal route

the substance is directly injected into the spinal canal which contains cerebrospinal fluid

used when a high/ rapid amount of a drug is required to reach the CNS, mainly used in childbirth

oral/ rectal route

most common, most drug absorption occurs in the gut by passive diffusion (rate of absorption will depend on gut motility, presence of food, particle size of the tablet, encasing of the tablet and physiochemical factors)

sublingual administration

when the drug is placed under the tongue to be absorbed

percutaneous route

includes skin patches, cornea eye drops, nasal mucosa cold remedies and some peptide hormones (injected under skin)

useful when you want a local affect but most drugs do not penetrate very well unless they are lipophilic

inhalation route

restricted to gases used for general anaesthetics and for local effects like administration of bronchodilators in asthma

intramuscular route

vaccinations, done deeper than percutaneous so it has better administration and distribution

soluble carrier transporters (SLC) are associated with…

passive or secondary transport

the main sites of solute carrier transporters are:

organic cation transporter (OCTs) and organic anion transporters (OATs) including:

• the blood brain barrier

• the gastrointestinal tract

• the renal tubule

• the bile tract

• the placenta

ATP-binding cassette transporters (ABC)

assoicated with primary active transport

OCTs-uniporters- OCT2

transporter of proximal tubular cells in kidneys and concentrates drug such as cisplatin (anticancer drug)

drug transporters usually have extensive binding affinity towards…

a broad spectrum of small molecule substrates and inhibitors

genetic variants of OCT1 (found in liver cells) are associated with…

different responses to metformin (lowers blood sugar) in healthy humans

OCT1-variant is __ effective at lowering blood sugar

less

most drugs do not spread rapidly throughout all body water compartments to acheieve a uniform concentration at equilibrium, the concentration in each compartment will depend on:

• permeability across tissue barriers

• protein binding within compartments

• pH partition

• fat: water partition

why may drug distribution in the CNS be limited by the blood brain barrier

the endothelial cells lining the blood vessels in the CNS form tight junctions impermeable to water soluble moloecules

what does inflammation in the blood brain barrier cause

• the blood brain barrier becomes leaky, so drugs like penicilin can reach the blood brain barrier CFS and treat things like meningitis

• chemoreceptor trigger zones also become leaky which is useful in counteracting nausea associated with some drugs

infections compromise the blood brain barrier so antibodies can…

easily pass through

body fat acts as a

drug reservoir

tetracyclines accumulate in bones and teeth because of…

high affinity for calcium (problem in children)

phase 1: catabolic reactions

changes the nature of the drug to make it more reactive

phase 2: synthetic (anabolic reactions)

changes the chemical nature of the drug to make it inactive and to facilitate its secretion

where and how are drugs mediated

mediated in the liver using microsomal enzymes- the drug must first cross the plasma membrane to be metabolised

elimination of aspirin

aspitin → salicylic acid → glucuronide

the salicylic acid is short lived because in phase 2 a sugar is added onto the hydroxyl group (it can no longer bind to its target and can now be excreted)

what type of processes happen in phase 1

oxidation, hydroxylation, dealkylation, deamination, hydrolysis

what type of process occurs in phase 2

conjugation

products of the phase 1 reactions may have increased…

toxicity and carcinogenicity

what enzymes carry out phase 1 reactions

the cytochrome p450 family

what kind of environmental factors influence the activity of cytochrome p450

• grapefruit juice inhibits p450 (cardiac dyrhythmias)

• brussel sprouts and tabacco can induce p450

what happens when you overdose on paracetamol

the phase 1 reaction produces NAPQI which is extremely toxic (in phase 2 it becomes inactive). overdosing on paracetamol can lead to a build up of this toxic intermediate and the body cannot keep up with the phase 2 reactions; it begins to kill liver cells

why is it okay to combine paracetamol with ibuprofen

they use different metabolism pathways

why is the inducer of p450, carbamazepine, a problem

the p450 cytochrome is also used to metabolise carbamazepine, which affects drug concentration

excretion of drugs via the kidneys happens by 1 of 3 main routes:

1. glomerular filtration (unless highly protein bound)

2. active tubular secretion (for weak acids/ bases, uses OAT and OCT transporters)

3. passive diffusion (for lipid-soluble drugs, inefficient excretion)

what other ways are drugs eliminated from the body

GI excretion and lung excretion

why is predicting time course of drug action very important clinically

it underpins the dosing regime time course of drug concentrations attained in the body during and after dosing

what does first order kinetics show in a graph

the body eliminates the drug at a proportional rate to the drug concentration. the time it takes to reach a steady state is the same for all doses

what does a zero order kinetics graph show

once the elimination pathways become saturated, the drug is eliminated at a constant, fixed rate, regardless of concentration. the drug accumulates much faster and the time to reach steady state is longer

steady state

when the overall rate of drug input into the body is equal to the overall rate of drug output

the maximum rate at which the drug can be administered should be limited by…

the maximum rate at which it can be eliminated