Pharmacokinetics Flashcards
Describe how a drug works to have its desired effect safely
§ To achieve its effect a drug must first be presented in a suitable formulation at an appropriate site of ADMINISTRATION and then (usually) ABSORBED and DISTRIBUTED through the body to its site of action. For the effect to wear off the drug must almost always be METABOLISED and/or EXCRETED with these residues being VOIDED (REMOVED) from the body.
Ultimately, what is meant by pharmacokinetics
The journey of a drug through the body (ADME)
Administration
Distribution
Metabolism
Excretion
What does pharmacokinetics ultimately determine
Determines how much of the drug you need to put in so that it can get to the tissues to have its desired effect. Therefore it is important because it Determines ‘dose’ of drug available to tissues- therefore we need to understand how the body deals with the drug (pharmacokinetics) to ensure that we give the correct, safe dose
Summarise the drug administration routes
§ Drugs can be:
o Systemic – across the entire organism.
o Local – restricted to one area of the organism.
§ Sites used for administration are (examples left);
o Enteral – Gastro-intestinal administration.
o Parenteral – Outside the GI tract.
§ IV administration has a rapid onset of action but is invasive and requires training.
Why do we need to administer some drugs systemically
So that they can access tissues deeper in the body- hence we need to administer drugs to the bloodstream.
Why do we need to administer some drugs locally
Don’t need to access the bloodstream- they just need to act in a certain, readily accessible part of the body
List the drug administration routes
dermal intramuscular subcutaneous intraperitoneal intravenous inhalation ingestion
all are paraenteral EXCEPT for ingestion which is enteral
Give some examples of systemic drugs
Cannabis- want it to enter bloodstream once inhaled- to get to the brain
aspirin
nicotine- diffuse into the skin and enter the bloodstream
Give some examples of local drugs
Salbutamol (Ventolin)
Betnovate ((Betamethasone)- steroid cream to reduce inflammation- don’t want it in the bloodstream
Antacids- only want them to work in the stomach
What do we need to think about when administering drugs
Where exactly we want the drugs to have their effects
Describe the two ways in which drugs can move around the body
bulk flow (i.e in the bloodstream, lymphatics or CSF) diffusion (molecule by molecule- over short distances)
Describe bulk flow
Movement with the flow of fluid in that system
The chemical nature of the drug makes no difference to its transfer by bulk flow. The cardiovascular system provides a rapid long-distance distribution system for drugs
Why do we need drugs to be water and lipid soluble
Drugs have to traverse both aqueous and lipid environment
Compartments = Aqueous e.g. Blood, lymph, extra-cellular fluid, intra-cellular fluid
Barriers = Lipid i.e. cell membranes (epithelium/endothelium
How can drugs cross these lipid barriers
By diffusing directly through the lipid
By combination with a solute carrier (SLC) or other membrane transporter
By diffusing through aqueous pores formed by special membrane glycoproteins (aquaporins) that traverse the lipid
By pinocytosis- drug engulfed by membrane and flipped to the cytosolic side
Which of these methods of transport are most important for drugs
Diffusion through lipid and carrier-mediated transport.
Although diffusion through aquaporins is important in the transfer of gases, the pores are too small in diameter <0.5nm to allow most drug molecules (which usually exceed 1nm in diameter) to pass through. Consequently, drug distribution is not notably abnormal in patients with genetic diseases affecting aquaporins
Describe pinocytosis
Pinocytosis involves invagination of part of the cell membrane and the trapping within the cell of a small vesicle containing extracellular constituents. The vesicle contents can then be released from the cell, or extruded from its other side. This mechanism is important for the transport of some macromolecules (e.g insulin which crosses the BBB by this process), but not for small molecules.
Compare the rates of absorption for the different methods of administration
§ IP and IV are fast absorption while IM, dermal and subcutaneous are slower.
Describe the diffusional characteristics
Ability to cross hydrophobic diffusion barriers is strongly influenced by lipid solubility. Aqueous diffusion is part of the overall mechanism of drug transport, because it is the process that delivers drug molecules to and from the non-aqueous barriers.
The rate of diffusion of a substance depends mainly on its molecular size, the diffusion coefficient being inversely proportional to the square root of molecular weight.
What is the number of molecules crossing the membrane per unit time determined by
The permeability coefficient, P, and the concentration difference across the membrane. Permeant molecules must be present within the membrane in sufficient numbers and must be mobile if rapid permeation is to occur.
Thus, two physiochemical factors, contribute to P, namely solubility in the membrane (which can be expressed as a partition coefficient for the substance distributed between the membrane phase and the aqueous compartment). And diffusivity, which is a measure of the mobility of molecules within the lipid and is expressed as a diffusion coefficient.
Summarise the flow of drug through the body- using aspirin as the example
Aspirin- ingested- travels by bulk flow down to the stomach.
First barrier it encounters is the microvilli on the intestinal wall- needs to cross this (and then the capillary endothelium) to get into the blood (portal circulation)- goes to the liver to be metabolised- then goes to the systemic circulation
Encounters its third barrier (capillary wall) to get into the ECF
It may then need to cross the lipid bilayer to get into individual cells- however most drug targets are on the outside of the cell
What can non-polar substances dissolve in
Non-polar substances can freely dissolve in non-polar solvents i.e. can penetrate lipid membranes freely
What is important to remember about drugs
Most drugs are either weak acids or weak bases.
Therefore drugs exist in ionised (polar) and non-ionised (non-polar) forms – the ratio depends on the pH
What is important to remember when drugs cross epithelial barriers
An epithelial barrier, such as the G.I mucosa or renal tubule, consist of a layer of cells tightly connected t each other so that molecules must traverse at least two cell membranes (inner and outer) to pass from one side to the other.
What are the dissociation reaction for weak acids and weak bases
BH+ – B+ H+
pKa = pH +log10 BH+/B
AH – A- + H+
pKa= pH +log10 AH/A-
What is the dissociation constant pKa determined by
The dissociation constant (pKa) for the loss of protons are determined by the Henderson-Hasselbalch equation:
Show the ionisation of aspirin (weak acid) and morphine (weak base)
See diagram!
What are the effects of the ionisation states on the diffusional properties of the drug
The unionized forms of aspirin and morphine are going to be more lipid soluble than the ionized (charged) forms of the drugs. Charged molecules are more polar and thus less lipid soluble and will find it difficult to cross membranes.
