Pharmacokinetics

What does the ADMA process apply to?

All drugs administered to the patient, regardless of the administration route

• Although, the absorption phase is bypassed with intravenous administration 

What does ADME stand for?

A - Absorption

D - Distribution 

M - Metabolism 

E - Excretion 

Absorption

Site of administration to systemic circulation (bloodstream)

The route of transmission will have an impact on the ..

Absorption - the path of where the medicine has been administered and when it is in the bloodstream

Absorption varies with ..

Different drugs

Paracellular barrier

• For very small drug particles

• Through the tight junctions between cells

Transcellular barrier 

Through the cellular membrane 

Crossing cell membranes 

• Direct/simple diffusion 

• Transmembrane carrier protein - Facilitated diffusion + Active transport 

• Other mechanisms - Pinocytosis, Phagocytosis, Aqueous pores 

What drugs use passive/direct diffusion in absorption?

Lipophilic drugs

What drugs use Transmembrane carrier proteins in absorption?

Hydrophilic drugs

Aqueous pores allow ..

Fluids to transfer to one side of the cell membrane to the other

To cross a cell membrane, a drug must be

Lipophilic

Lipophilic - ‘Fat loving’ 

• Fat soluble - dissolves readily in fat

• Non-polarised

• Non-ionised

Lipophilic drugs can pass through cell membranes due to ..

Their solubility in membrane bilayers

Hydrophilic - ‘Water loving’

• Water soluble - dissolves readily in water

• Polarised 

• Ionised 

What do hydrophilic drugs require in relation to absorption?

A carrier

Lipophilic or hydrophilic nature affects pharmacokinetic properties, such as ..

• Absorption

• Distribution 

• Excretion 

What is the concentration gradient for simple/direct diffusion? 

Gradient from High → Low 

The rate of diffusion depends on ..

• Concentration gradient 

• Drug molecule size 

• Lipophilicity 

• Temperature 

• Thickness of membranes 

The larger the concentration gradient ..

The quicker the drug molecule will diffuse through it

Small drug molecules will pass through the membrane .. than large drug molecules 

Quicker 

Drugs of a high lipophilic nature, will pass through the membrane (1), whereas hydrophilic drugs will (2)

1 - Quicker

2 - Not pass through

Absorption - If the temperature increased, this provides increased energy which means the drug molecules ..

The drug molecules will have quicker movement through the membrane

If the membrane is thin, the drug molecules will pass though .. than if it was thick

Quicker

Carrier proteins (transmembrane) - this mechanism is required for ..

Absorption of hydrophilic drugs

Active transport

Drug molecules move against a concentration gradient and energy is required (ATP). The drug molecule changes shapes, gets through the membrane by binding to the carrier protein then reverts to original shape once it has passed through

The rate of diffusion (for hydrophilic drugs) is affected by ..

The number of carrier proteins - If there are lots of drug molecules, but not many carrier proteins, diffusion will be slower (and vice versa) 

Factors which can affect absorption are .. 

• Administration route 

• Drug formulation

• Method of crossing membranes

• Lipophilic:Hydrophilic nature

• Environmental pH

• Tissue perfusion

Blood supply to the tissue can affect absorption. In a highly perfused area (e.g. a muscle) there is .. in contrast to a poorly perfused area (e.g. subcutaneous tissue) 

Less distance for the drug to diffuse through 

Bioavailability

The percentage (%) if administered drug which reaches the bloodstream after administration

Bioavailability - Indicated by a decimal and the letter ‘f’ or ‘F’ (fraction), for example .. 

• 1.0F = 100% bioavailability (100% of the drug successfully absorbed)

• 0.25f = 25% bioavailability

• 0.50f or 0.50F = 50% bioavailability (50% of the drug is successfully absorbed)

Drugs that are administered intravenously have a 100% bioavailability, why is this?

The drug has been administered directing into the bloodstream (100% of the drug is absorbed) 

The presence of food within the gastrointestinal tract when .. 

Administering oral drugs 

Drugs administered orally can be affect by .. 

First-pass metabolism 

Cmax

The highest (peak) plasma drug concentration that is reached after administration of a drug dose

Tmax 

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

Area Under Curve (AUC)

The area under the plasma drug concentration which reflects the actual exposure to a drug after administration - This is equal to the bioavailability 

After abruption, the drug needs to be ..

Distributed to the target site

Volume of distribution (Vd) - Tissue penetration of the drug, is dependent on ..

• Perfusion

• Capillary wall permeability - Paracellular, Transcellular 

• Protein binding 

Vd is a pharmacokinetic value that provides an ..

Approximation of the extent to which a drug is distributed throughout the body. It is determined by looking at the concentration of a drug in the blood shortly after drug administration. 

The larger the Vd, the more tissues and body compartments are penetrated, meaning the concentration of the drug in the blood is .. 

Lower 

The smaller the Vd, fewer tissues and body compartments are penetrated, meaning the concentration in the blood is .. 

Higher 

If an animal is overweight or obese, the Vd is not necessarily larger because .. 

Some drugs may not readily pass into the fat - this is why dosing on bodyweight is not always ideal and instead, dosing should be based on ‘normal/healthy/ weight 

Distribution is responsible for what in regards to IV injections? 

The rapid fall in drug concentration after IV injection. 

The half life of a drug will be .. if the drug has a small Vd

Short

The half life will be .. if the drug is widely distributed through-out the body (large Vd)

Long 

Distribution barriers 

• Blood brain barrier (BBB) 

• Placenta 

• Testicles

Protein binding

• A protein-bound drug will bind to albumin or globulin → holds drug in circulation

• Protein molecules are large - cannot easily pass into tissues 

• Bound drug is generally inactive (Just being carried around!) 

• Free drug is active - can move into tissues and have an effect 

• Bound drug is not metabolised/excreted 

• An equilibrium exists between bound and free drug 

Why might protein binding proportion be relevant if the animal is hypoproteinaemic or if the animals is on multiple medicines which are highly protein bound?

Binding sites could be overwhelmed leading to an overdose

What does metabolism aid?

Detoxification (proactive role) and elimination

What is metabolism?

Conversion from one chemical entity to another (changing the drug molecule)

Where does metabolism mostly occur?

In the liver

Apart from the liver, where can metabolism occur?

In the gastrointestinal tract and respiratory tract

Metabolism 

• Biotransformation 

• Conversion from one chemical entity to another (changing the drug molecule) 

• Aids in detoxification (proactive role) and elimination

• Does not always render the drug inactive 

• Mostly occurs in the liver 

Metabolism - Phase I

Original drug molecule chemically transformed by oxidation, reduction and/or hydrolysis → produces a metabolite (more hydrophilic) 

Metabolism - Phase II 

Metabolite combined with anther chemical (sulphate, glucuronic acid) → conjunction

During Phase II of metabolism, what does reduced bioactivity mean?

It cannot be reabsorbed

During Phase II of metabolism, what does easier to excrete mean?

More water soluble

What enzyme involved in phase II (of metabolism) reactions, do cats not have?

Glucuronyl transferase - linked to paracetamol toxicity 

What organs are involved in excretion of drugs?

• Kidneys 

• Liver

• Lungs

• Hair

• Milk

• Saliva

• Sweat 

Excretion

Getting the drug out of the body

Renal excretion

• Glomerular filtration

• Passive tubular resorption 

• Active tubular secretion

Some drugs can alter the pH of .. 

Urine 

Excretion - From the kidneys, then into the .. 

Into the urine

Excretion - From the liver into the bile, then bile into the ..

Faeces

Excretion - From the lungs, then out through ..

Expiration

Excretion - From the hair, in the ..

Keratin

What can influence the excretion rate?

Hydration status

Hepatic excretion

• Either metabolised by liver first or excreted straight into the bile

• Bile excreted via the intestines 

• Bile excreted out in the faeces 

• Potential enterohepatic recycling 

The liver can excrete drugs, how does this happen?

• Drug molecules will passively diffuse into the liver cells 

• Move into the bile unchanged or metabolised in the liver and then moved into the bile 

• Then excreted into the intestines and out in the faeces 

If enterohepatic recycling occurs this means that the drug is ..

Excreted via the bile into the intestines. Then it is reabsorbed from the intestines into the systemic circulation again - This can prolong the action of the medicine if the metabolites are active 

Pharmacokinetics - an overview

• ‘The path of medicine through the body’ or ‘what the body does to the medicine’ 

• Absorption, Distribution, Metabolism and Excretion 

• Drug specific features will be investigated during medicine development and licensing