Pharmacokinetics and drug discovery (L9-11) Flashcards
What does concentration of drug in the body depend on?
ADME - absorption, distribution, metabolism, excretion
How are drugs usually absorbed and distributed throughout the body?
The bulk flow transfer of a drug is mainly through the blood stream and the cardiovascular system. Therefore, the drug has to diffuse to get to other parts of the body. SO, to get into cells it either needs to be lipid soluble, have the ability to move through an aqueous channel/carrier, or to be brought in by pinocytosis (ingestion of liquid into cell by budding of membrane). The movement of drugs between compartments usually involves penetration of diffusion barriers (membranes) which determines where and for how long a drug will be present in the body after administration.
What governs how easily a drug diffuses?
Its physiochemical properties like lipid solubility (partition coefficient) (very important) and diffusivity (diffusion coefficient) Non polar (uncharged) molecules dissolve freely in lipids and penetrate cell membranes freely. SO, there is an increased rate of absorption in the gut, increased penetration into the brain and other tissues, as well as an increased renal elimination. Route of administration is also a factor because it effects access to the desired site.
What are the different administration routes?
Oral, rectal, percutaneous (skin), intravenous, intramuscular, intrathecal (spinal canal), inhilation
What factors effect absorption?
Site/method of administration
Molecular weight - affects rate of diffusion
Lipid solubility
pH and ionisation
Explain how a pH and ionisation effects drug absorption
Many drugs are weak acids or bases (weak acids dissociate) pKa (the strength of an acid) = pH + log10(HA/A-)
At a low pH, weak acids will be unionised, and only uncharged species can cross the lipid membranes - so the weaker the acid, the more easily it will cross a membrane.
pH effects steady-state distribution of drugs between aq. compartments. Basic environments are in favour of dissociating acids, making them less lipid soluble. therefore, wek acids become ‘trapped’ in basic compartments like renal tubules (so they’re excreted in the urine more).
Urinary acidification slows down the excretion of weak acids and increasing plasma pH causes weakly acidic drugs to be extracted from the CNS into the plasma where they become trapped.- this leads to a decrease in neurotoxiciy (useful for overdoses)
Explain why it is hard to get drugs into the brain
Drugs entering the CNS are regulated by the blood brain barrier. Endothelial cells lining the blood vessels in the CNS form tight junctions impermeable to water soluble molecules
lipid soluble molecules e.g. ethanol and caffeine cross the BBB easily. Tight junctions can become leaky during inflammation so you can treat things like meningitis with IV penicillin.
How does albumin effect the distribution of drugs?
It is made by the liver and secreted into the blood stream - it binds to plasma proteins (and acidic drugs) and leads to partition (lipid solubility) into specific tissues e.g. body fat.
What are the general steps of drug metabolism?
Phase 1- catabolic reactions - can produce a more reactive compound
Phase 2 - synthetic (anabolic) reactions - Involves conjugation to produce the inactive product
How are drugs metabolised in the liver? give an example
Using microsomal enzymes (intracellular) e.g. cytochrome P450, alcohol dehydrogenase, MAO
Drugs must cross the plasma membrane (so must be lipid soluble or bind to transporters) to be metabolised. Some drugs (pro-drugs), only become active after being metabolised. Metabolism can alter or prolong the pharmacological actions of a drug. E.g. aspirin - broken down in salicylic acid, then in the liver its metabolised to glucuronide and excreted by the kidneys.
57 genes coding for P450 enzymes have been identified. P450s are enzymes that metabolise potentially toxic compounds or products of endogenous metabolism e.g. bilirubin (from breakdown of RBCs). Different isoforms of P450 enzymes react with different drugs.
What are the different routes of drug excretion?
Drugs can be eliminated from the body via urine, faeces, milk and sweat, or expired air. Renal excretion e.g. penicillin is cleared from the blood on a single transit, Vs diazepam which is cleared very slowly
Renal disease can effect drug clearance and therefore increase their toxicity.
What is meant by the term saturation kinetics?
When there is a disproportionate increase in the steady-state plasma conc - this can lead to clinical toxicity. (In the simplest cases, the time course of clearance follows a mono-exponential decay, the time course of which is determined by rate of metabolism and excretion.)
What are the typical stages of drug development? How long do they take?
- Basic research and target selection
- preclinical research
- clinical development (split into 3 phases)
- Regulatory review
Stage 1 and take take about 3-6 years, stage 3 takes 6-7 years and stage 4 takes about 1-2 years - about 15 yrs altogether. The different stages of phase 3 require more and more money and volunteers. Ends up costing about 1 bill dollars.
What are contract research organisation?
Companies that provide support to pharmaceuticals, biotech and medical device companies in the form of contracted medical research. They’re designed to reduce the cost of companies developing drugs in niche markets
How are targets for potential drugs identified?
Drug targets are usually enzymes, receptors or transport proteins. They’re usually identified by suing already known biological information e.g. how certain proteins interact, and then building on that to work out what is the best hing for your drug to target.
Genomic data and information about the structures of different targets can also be used.
