Lecture 5 - Pharmacokinetics Flashcards
What does pharmacokinetics provide?
an understanding of the FATE of the dose of a drug administered, the time course and levels of the unbound drug in the body
What does drug effects depend on?
- Pharmacodynamics: mechanism of action and effects on cellular functions (receptors, ion channels, enzymes, transporters)
- Physicochemical properties of the drug (affinity, efficacy and potency)
What does the physicochemical properties of the drug affect in pharmacokinetics?
ADME (concentration):
- Absorption
- Distribution
- Metabolism
- Excretion
Describe the process of drug distribution and absorption through the body
- Bulk flow transfer through the blood stream (CV system)
- Diffusion
Movement of drugs between compartments usually involves penetration of lipid diffusion barriers (i.e. cell membranes) which determines where and for how ling a drug will be present in the body after administration
The drug is required to cross the plasma membrane. Many small molecules can travel across via diffusion or by dissolving. The speed of this is based on the molecular weight - e.g. larger = slower.
Pinocytosis (fluid endocytosis)
Once across the membrane and in bulk flow, the physical/chemical properties are less important
What are factors affecting absorption - diffusion through lipids?
Physiochemical properties of drug
- Lipid solubility partition coefficent ((high partition coefficient = easily enters plasma membrane)
- Diffusivity
Non-polar (uncharged) molecules dissolve freely in lipids and penetrate cell membranes freely
- higher rate of absorption from gut
- higher penetration into brain and other tissues
- higher renal elimination
What is one of the most important determinants of the pharmacokinetics characteristics of a drug?
Lipid solubility - polar molecules are less effective at crossing membranes
What are other factors affecting absorption?
- pH and ionization
- Many drugs are weak acids or bases
e.g. weak acid HA <–> H+ + A- - leaving a charged acid, which means it won’t cross membranes easily
- putting the drug in an acidic environment leads to the acid being more likely to be non-dissociated (uncharged) - cross membranes more easily
- weak acid donates protons
What is the Henderson-Hasselbach equation?
pKa = pH + log10(HA/A-)
At low pH weak acids will be un-ionized.
Only uncharged species can cross lipid.
Describe how pH affects steady-state distribution of drugs between aqueous compartments
Basic environment (i.e. pH > 7) favours dissociation of acids. Weak acids become ‘trapped’ in basic compartment e.g. renal tubules. Urinary acidification retards excretion of weak acids. Increasing plasma pH (e.g. sodium bicarbonate) causes weakly acidic drugs to be extracted from CNS into plasma where they get ‘trapped’. Reduction in neurotoxicity - e.g. following poisoning with aspirin.
What are factors involved in the route of administration influencing drug absorption?
- Orally
- Pre/cutaneous absorption
- Intravenous delivery
- Intramuscular delivery
- Intrathecal (cerebrospinal fluid- e.g. epidural)
- Inhalation
What is bioavailability?
The fraction of ingested dose that gains access to circulation
What are factors affecting absorption? (transport)
- Carrier mediated transport - passive or active solute carrier (SLC) transports.
- ATP-binding cassette (ABC) transporters - e.g. sugars, amino acids, metal ions, neurotransmitters.
- Drugs compete with normal substrate
- over 300 human genes are believed to code these transporters, most of which act mainly on endogenous substrates, but some also transport foreign chemicals including drugs.
- Absorption (and elimination) of such drugs will be affected by saturation and competitive inhibition at the transporter
- Drug transporters usually have extensive binding affinity toward a broad spectrum of small molecule substrates and inhibitors - implication for drug-drug interactions and pharmacokinetics
How are genetic variants of organic cation transporter 1 (OCT1) associated with different responses to metformin in healthy humans?
In the presence of Metformin (diabetes drug), glucose regulation was less effective in patients carrying a polymorphism that impaired OCT1 function.
Type 2 diabetes - high levels of glucose due to non-functional insulin receptors
Metformin works at the liver in glucose handling. The Metformin doesn’t work in people with this gene, which codes for a transporter.
What are the 4 main fluid compartments of the body in which a drug distributes?
- Plasma
- Intracellular water
- Interstitial water
- Transcellular water
(non-water compartment - fat)
What compartment will a non-polar drug want to travel?
Fat - if not it will be distributed between the 4 compartments
What determines what concentration of the drug goes into each compartment?
the pH on the compartment - only ‘free’, unionized drug can cross between compartments
At equilibrium, what determines the concentration in each compartment?
- Permeability across tissue barriers
- Protein binding within compartments
- pH partition
- Fat:Water partition
What is pH partition?
how the pH of an area affects whether a substance is charged or not, influencing whether it can pass through membranes easily
How might drug distribution to the CNS may be limited?
By the Blood-Brain-Barrier
- endothelial cells lining blood vessels in CNS form TIGHT JUNCTIONS - impermeable to water soluble molecules
- lipid soluble molecules (e.g. Ethanol & caffeine) cross BBB easily
- Tight junctions can become leaky during inflammation - e.g. treat Meningitis with iv penicillin
What are other factors influencing drug distribution (and elimination)?
Binding to plasma proteins - albumin binds mainly acidic drugs
- high protein binding can lead to unexpected large increases in concentration of drug as protein binding sites become saturated.
- increase in conc. of dose, the amount of bound drug increases at a near-linear rate.
- at lower doses, the concentration are low for free drug. Once become saturated (of those sites), increases quickly.
What are other factors influencing drug distribution (elimination)?
Partition into specific tissues e.g. Body Fat. When putting someone to sleep, lots of fat absorb drug and also slow release
What is volume of distribution?
Volume of distribution of a drug (Vd) is a measure of the apparent volume of fluid that would be required to hold the total amount of drug ‘Q’ (related to dose) in the body AS measured in the plasma ‘Cp’
A small volume of distribution is a drug that is held in the plasma, shows little binding and distribution
A large volume of distribution is indicative of a drug that shows a lot of binding so concentrations appear low
LARGE VOLUME = HIGH LEVELS OF BINDING = LOW CONCENTRATION
SMALL VOLUME = LOW LEVELS OF BINDING = HIGH CONCENTRATION
What volume of distribution do drugs that preferentially reside in the blood have?
Low volume of distribution - low level of binding - high concentration
What volume of distribution do drugs that preferentially distribute to tissues have?
High volume of distribution - high level of binding - low concentration
