Week 2 Flashcards
1
Q
What factors affect the movement of drugs across cell membranes?
A
- Lipophilicty
- Size
- Ionisation
- Transport mechanism
2
Q
What are OAT/OCT transporters?
A
- 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)
3
Q
What are p-glycoproteins?
A
- 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
4
Q
What are the different ways that drugs are distributed?
What factors affect this?
A
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
5
Q
What is plasma protein binding?
A
- 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%
6
Q
How is drug distribution measured?
A
- 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
7
Q
What are the 3 ways the body can excrete drugs?
A
- 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
8
Q
Describe Renal Active Drug Elimination:
A
- 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
9
Q
How does drug metabolism work?
A
- 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
10
Q
What are the cytochrome P450 enzymes?
A
- 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
11
Q
What is enterohepatic cycling?
A
- 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
12
Q
What is steady state concentration?
A
- 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
13
Q
What are first order drug elimination kinetics?
A
- 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
14
Q
What are zero order drug elimination kinetics?
A
- 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
15
Q
Describe Dosing and Loading Doses:
A
- 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)
16
Q
What factors affect drug clearance?
A
- Movement of drug across cell membranes
- GFR
- Free drug concentration in plasma
- Hepatic blood flow
- Activity of metabolising enzymes
17
Q
What are the main pharmacokinetic factors of drugs?
A
- Absorption
- Distribution
- Metabolism
- Excretion
18
Q
What are the main pharmacodynamic factors of drugs?
A
- 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)
19
Q
What is pharmacogenetics?
A
- The study of inter-individual variation (due to SNPs and VNTRs) in DNA sequence related to pharmacokinetics or pharmacogenetics
20
Q
Why are CYP450 enzyme polymorphisms clinically important?
A
- 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
21
Q
What clinically significant polymorphisms are relevant to B2 adrenoreceptors?
A
- 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
22
Q
What is pharmacogenomics?
A
- The use of genetic information to guide drug therapy
e. g. herceptin to treat cancers with an overexpressed HER2 gene
23
Q
What is the most common target for drugs?
How do they bind?
A
- Receptors
- Drugs bind to their target reversibly with non-covalent bonds including ionic/hydrogen/van der waal’s interactions
24
Q
Give an overview of Drug Discovery:
A
- 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
25
Q
What are the properties of an ideal drug?
A
- 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
26
Q
What are sources of new drugs?
A
- 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
27
Q
What is a “hit compound”
A
- A compound selected as part of an initial screening process from the chemicals generated from rational drug design, natural sources etc.
28
Q
What is lead optimisation?
A
- 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)
29
Q
What is a lead compound?
A
- 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
30
Q
What are the steps of drug disovery?
A
- Target selection
- Target validation
- Screen compounds
- Lead discovery
- Synthesise new compounds
- Lead optimisation
- Efficacy testing (animal/in vitro studies)
