Week 2 Flashcards
What factors affect the movement of drugs across cell membranes?
- Lipophilicty
- Size
- Ionisation
- Transport mechanism
What are OAT/OCT transporters?
- Type of solute carrier transporters
- These are non-selective transporters that can concentrate drugs in cells
- Facilitative transporters
- Highly expressed in the liver, kidney and GIT (areas of body associated with drug elimination)
What are p-glycoproteins?
- Type of ATP-binding casette transporters
- These are active transporters
- They are transmbrane efflux pumps
- When a drug enters a cell it will either be metabolised by the cell or it will be removed from the cell by a p-glycoprotein
- Account for multidrug resistance in cancer cells
Locations:
- Renal tubular brush border membranes – increase movement of drugs into the tubules
- Bile canaliculi – increase the movement of drugs into the bile ducts
- Brain microvessels – reduce the movement of drugs into the CNS
- GIT – decrease the GIT absorption
What are the different ways that drugs are distributed?
What factors affect this?
Drugs can:
- Remain in the vascular compartment
- Be taken up into the interstitial fluid
- Be taken up into cells
- Be stored in fat compartments
It is affected by:
- How easily it moves out of vasculature (movement of drug across membrane and plasma binding protein)
- How well it is delivered to tissues
- How well it binds to tissue compartments
What is plasma protein binding?
- Most drugs have some capacity for plasma protein binding in which the drug binds to the plasma protein in a plasma protein-drug complex (DP)
- D + P = DP
- The binding of the drug to plasma protein influences the movement of that drug and its distribution
- The limiting factor for DP is the concentration of the drug
- For most drugs the proportion of drug that is free and the proportion that is bound is constant e.g. 70%
How is drug distribution measured?
- Quantifying distribution of drugs is done with the concept of volume of distribution (Vd)
- Vd = total amount of drug in body (dose)/concentration of drug in plasma
- If the drug is large/has a high plasma protein binding the volume of distribution would be the same as the volume of plasma, Vd=0.05L/kg
- If someone recieves a high dose of the drug but the plasma concentration is low, the Vd is high and the estimated distribution is high
e. g. Vd <0.05L/kg body weight, drug is restricted to plasma (high mw, high plasma protein binding)
e. g. Vd <0.2L/kg body weight, drug is restricted to extracellular fluid (low mw but hydrophilic)
e. g. Vd ~0.55L/kg body weight, drug distributed throughout total body
What are the 3 ways the body can excrete drugs?
- Excrete the unchanged active drug via kidneys
- Metabolically break down drug (usually b liver) and excrete inactive drug via kidneys
- Metabolically break down drug (usually b liver) and excrete inactive drug via liver bile duct into faeces
Describe Renal Active Drug Elimination:
- Not a saturable process
- Glomerular filtration:
- The filtration of the drug from the glomerulus into the Bowman’s capsule - Reabsorption:
- The drug that has been filtered into the tubules is reabsorbed into the peritubular capillaries - Active tubular secretion:
- Usually done by OATs or OCTs that line kidney tubules and actively move drug from peritubular capillaries into the renal tubules - Excretion:
- Via urine
*This process only really works well for highly ionised drugs that are filtered and actively secreted, lipophilic drugs are often reabsorbed and biological drugs are too big to be filtered
How does drug metabolism work?
- The main location for metabolism is the liver
- The enzymes that do this can be saturated (can lead to drug interactions)
- Metabolism aims to make the drug more water soluble so it can be excreted
- There are 2 phases:
- Phase 1 Reactions:
- Catabolic/functional reactions
i. e. oxidation, reduction or hydrolysis
- Increases polarity of drug and therefore makes it more water-soluble - Phase 2 Reactions:
- Anabolic/conjugation reactions
i. e. conjugation with an endogenous molecule such as acetyl, sulphate or methyl groups
- Makes drug more water-soluble
What are the cytochrome P450 enzymes?
- An important family of oxidative enzymes in the liver responsible for the stage 1 metabolism of many drugs
- Major families are CYP1, CYP2 and CYP3
- Require molecular oxygen, NADPH and NADPH-P450 reductase
- Cytochrome P450 enzymes often are genetically polymorphic
What is enterohepatic cycling?
- Drug is metabolised by the liver and then secreted into the bile duct and then into the GI tract (to be eliminated via the faeces)
- When the metabolite moves into the GI tract enzymes there can de-conjugate it and it can be reabsorbed and recycled back into the liver
What is steady state concentration?
- The point at which the amount of drug administered is equal to the amount of drug being eliminated
- Steady state is usually reached in 4 half lives of the drug
What are first order drug elimination kinetics?
- The most common drug elimination kinetics
- There is a constant plasma half life of the drug
- The rate of elimination is proportional to the plasma drug concentration
What are zero order drug elimination kinetics?
- Occurs with some drugs e.g. alcohol and aspirin
- There is a linear relationship between concentration of drug and time taken to eliminate it
- This generally occurs in drugs when the amount of drug needed to saturate their elimination process (usually a metabolic elimination process) is very close to the therapeutic dose
- For drugs with zero order kinetics the plasma half-life of the drug cannot be defined
- This means that relatively small changes in dose can lead to disproportionate changes in plasma drug concentration
Describe Dosing and Loading Doses:
- Maintenance dose rate (DR) must be equal to rate of elimination
i. e. DR= CL x target plasma concentration - It usually takes 4 half lives of a drug for it to reach steady state
- This time taken to reach steady state concentration can be an issue if drugs have long plasma half lives as it can delay treatment
- A loading dose = Vd x target plasma concentration
- This aims to get the plasma concentration of the drug within the therapeutic range (above minimum effective concentration and below minimum toxic concentration)
What factors affect drug clearance?
- Movement of drug across cell membranes
- GFR
- Free drug concentration in plasma
- Hepatic blood flow
- Activity of metabolising enzymes
What are the main pharmacokinetic factors of drugs?
- Absorption
- Distribution
- Metabolism
- Excretion
What are the main pharmacodynamic factors of drugs?
- Binding to a target tissue (usually receptor)
- Efficacy (how much of an effect a given concentration of the drug can produce an effect)
- Affinity (how tightly a drug binds its target)
What is pharmacogenetics?
- The study of inter-individual variation (due to SNPs and VNTRs) in DNA sequence related to pharmacokinetics or pharmacogenetics
Why are CYP450 enzyme polymorphisms clinically important?
- All genes encoding CYP 1/2/3 family of enzymes are highly polymorphic
- Some people have a defective allele of this gene (will be poor metabolisers) and some people may have duplications of the gene (ultrametabolisers)
- This will affect how much of a drug they should be administered with
e. g. Warfarin is metabolised by CYP2C9 making some people poor/ultrametabolisers of the drug, Warfarin acts on VKROC1 so polymorphisms in this gene can also affect response to the drug
What clinically significant polymorphisms are relevant to B2 adrenoreceptors?
- Salbutamol is a short acting B2 adrenoreceptor stimulant
- Patients with a arg/arg phenotype of their B2 receptor respond more acutely to a dose of salbutamol compared to patients with a gly/gly phenotype however patients with the arg/arg become resistant to the drug
What is pharmacogenomics?
- The use of genetic information to guide drug therapy
e. g. herceptin to treat cancers with an overexpressed HER2 gene
What is the most common target for drugs?
How do they bind?
- Receptors
- Drugs bind to their target reversibly with non-covalent bonds including ionic/hydrogen/van der waal’s interactions
Give an overview of Drug Discovery:
- Identify a target for the drug
- Validate the target
- Screen compounds to identify lead compounds that can bind to the target
- By discovering the lead potential characteristics of the lead compound that allow it to bind and new compounds are synthesised based on this
- The new group of lead compounds are then optimised
- The lead compounds will undergo efficacy testing
- This process produces a candidate drug that can enter the drug development process
What are the properties of an ideal drug?
- Good pharmacokinetics properties: absorbable, well distributed to target, can be metabolised and extractable
- Pharmacodynamic properties: selective, potent, binds to valid target with high affinity
- Toxicological properties (non-toxic/cancer causing)
- Clinically effective
What are sources of new drugs?
- Screening of natural products (50% of drugs in use are derived from traditional medicine)
- Serendipity
- Rational drug design (rationally modifying natural product, using pharmacophores, starting from receptor structure)
- Screening of chemical libraries
What is a “hit compound”
- A compound selected as part of an initial screening process from the chemicals generated from rational drug design, natural sources etc.
What is lead optimisation?
- Taking a lead compound and making it have higher efficacy, affinity and selectivity as well as potentially better pharmacokinetic and toxicological properties (though these are usually assessed later in discovery/development)
What is a lead compound?
- A compound that specifically binds a series of related targets and activates/inhibits them
- NOT a drug
- NOT completely optimised for selectivity
- NOT optimised for humans
What are the steps of drug disovery?
- Target selection
- Target validation
- Screen compounds
- Lead discovery
- Synthesise new compounds
- Lead optimisation
- Efficacy testing (animal/in vitro studies)