Pharmacokinetics Flashcards
How would you work out Molarity?
Molarity = grams per litre/molecular weight
Give some possible targets of drugs
Enzymes GPCRs Ion channels Transporters Nuclear hormone receptors Other receptors Integrins
What is affinity?
The likelyhood of a ligand binding to its target
What are Bmax and Kd?
Bmax= max binding capacity (gives info of number of receptors)
Kd= the dissociation constant, the concentration of drug needed for 50% receptor occupancy. The lower Kd the higher the affinity
What is efficacy?
The likelyhood of activation
What are Emax and EC50?
Emax= the maximum response EC50= the effective concentration, the concentration that gives 50% of the maximal response, a measure of potency
What type of ligands have affinity and efficacy?
Agonists
What type of ligands have affinity only? (No efficacy)
Antagonists
How would you obtain binding information for drug-receptor interaction?
Use radioligands
What’s the difference between concentration response curves and dose response curves?
Concentration response curves are used in measuring a response in cells/tissues.
Dose response curves are used in measuring a response in a whole animal.
What is the potency of a drug determined by?
Efficacy, affinity and number of receptors.
EC50 is a measure of potency, the lower EC50, the higher the potency.
How does salbutamol target B2-adrenoceptors to relax the airways in asthma, but avoid the other B-adrenoceptors (such as B1 in the heart that increase the rate and force of contraction)?
Salbutamol is a B2-adrenoagonist.
It has a slightly lower Kd for B2 receptors than B1, so has slightly higher affinity for B2.
A high B2 selective efficacy and route of administration (oral spray) limits B1 activation and side effects.
How does salmeterol target B2-adrenoceptors to relax the airways in asthma, but avoid the other B-adrenoceptors (such as B1 in the heart that increase the rate and force of contraction)?
Salmeterol is a longer activity B2-adrenoagonist.
It has no selective B2 efficacy but side effects are prevented through a large difference in affinity. Kd is much lower for B2 than B1 so affinity for B2 is much higher.
Why may less than 100% receptor occupancy give 100% response ie. EC50<Kd
Some tissues have spare receptors (receptor reserve)
Why do some tissues have spare receptors?
It increases sensitivity, which allow for bigger responses at smaller concentrations of agonists.
Explain what is meant by ‘partial agonist’
Agonists that cannot produce a maximal response, even with full receptor occupancy.
EC50 is equal to Kd, partial agonists can be more or less potent than full agonists (since potency depends on affinity and efficacy).
Is a particular agonist always a full/partial agonist? Explain
No, a partial agonist may not always be a partial agonist, depending on the tissue and the biological response.
Ie. In one tissue the activation of all receptors may not be enough to produce a full response, but another tissue may have more receptors so may produce sufficient signal for a full response.
Discuss the clinical use of partial agonists
Morphine is a full agonist of the u-opioid pain relief receptor but can cause respiratory depression.
Buprenorphine is a partial agonist with a higher affinity but lower efficacy than morphine. Can be advantageous as it may give adequate pain relief with less respiratory depression.
When can a partial agonist act as an antagonist of a full agonist?
If the partial agonist has higher affinity but lower efficacy than the full agonist it occupies receptors and limits the response.
What are the three different types of antagonist?
- Reversible competitive
- Irreversible competitive
- Non-competitive
Explain what IC50 is
The concentration of antagonist giving 50% inhibition
Describe the properties of Reversible Competitive antagonists
They are surmountable (can be overcome by increased agonist concentrations)
Cause a parallel shift to the right of an agonist concentration response curve.
Give an example of a reversible competitive antagonist
NALOXONE
Competitive antagonist at u-opioid receptors to reverse opioid mediated respiratory depression. High affinity means it competes effectively with other opioids eg heroin
Describe the properties of Irreversible Competitve antagonists
Occurs when the antagonist dissociates slowly/not at all.
Not surmountable (not overcome by increased agonist concentrations) so at higher concentrations the maximal response is suppressed.
Causes a parallel shift to the right of agonist concentration response curves.
Give an example of a irreversible competitive antagonist
PHENOXYBENZAMINE
Non-selective irreversible competitive antagonist a1-adrenoceptor antagonist used in hypertension in pheochromocytoma.
Describe the properties of Non-Competitive antagonists
Bind to allosteric site, not the orthosteric site on the receptor and reduce effects of agonist binding.
Has high receptor subtype selectivity.
Causes parallel shift to the right and decreased maximum response of agonist in concentration response curves.
Define pharmacokinetics
What the body does to the drug
List local sites of administration for drugs
Eye
Skin
Inhalation
List the systemic sites of administration for drugs
Enteral: oral, rectal, sublingual
Parental: subcutaneous, intramuscular, intravenous, inhalation, transdermal
Define oral bioavailability
The proportion of a dose given orally (or by any other route other than intravenous) that reaches the systemic circulation in an unchanged form.
How can bioavailability be expressed?
Bioavailability can be expressed as amount or rate.
Amount: depends on GI absorption and first pass metabolism, measured by area under curve of a blood drug level against time plot.
Rate: depends on pharmaceutical factors, measured by peak height and rate of rise of drug level in blood.
Explain the therapeutic ratio
The maximum tolerated dose/the minimum effective dose
= LD50/ED50
What is the relevance of the therapeutic window?
Drug levels must be kept within the therapeutic window.
Drugs with larger therapeutic windows (eg penicillin) are safer because they are less likely to reach toxic levels
How are drugs with smaller therapeutic windows kept within the window?
Use regular administration to keep drugs between ED50 and LD50, or use drug with slower release
Describe the first pass effect
Substances absorbed from the lumen of the ileum enter venous blood, drain into hepatic portal vein, transported directly to the liver which is the main site of drug metabolism.
Any drug absorbed from the ileum may be extensively metabolised during the first pass through the liver.
How can the way the patient receives the drug differ?
Formulation of the drug: solid/liquid
Site of administration: local/systemic-enteral/parenteral
Which methods of drug administration avoid the first pass effect?
All parental routes
Sublingual
Rectal
Define drug distribution and state how it is calculated
The theoretical volume into which a drug has distributed assuming that this occurs instantaneously
= amount given/plasma concentration at time 0
Do hydrophilic or hydrophobic drugs have smaller volume of distribution and why?
Hydrophilic drugs have a smaller volume of distribution because they remain in plasma and are not absorbed by fat.
Do hydrophilic or hydrophobic drugs have larger volume of distribution and why?
Hydrophobic drugs have a larger volume of distribution as they are continuously absorbed by fat, so are removed from the plasma.
Define an object (class 1) drug
The object drug is used at a dose much lower than the number of albumin binding sites, as an equilibrium is reached with some free drug
Define a precipitant (class 2) drug
The precipitant drug is used at a dose greater than the number of albumin binding sites as all binding sites must be filled before any free drug exists.
Explain protein binding interactions
Class 2 drugs (precipitant drug) can displace class 1 drugs (object drug), raising the free levels of the object levels which increases risk of toxicity.
When are protein binding interactions important?
When the object drug:
Is highly bound to albumin (>90%)
Has a low therapeutic index
Has a small volume of distribution
Why are protein binding interactions transient?
Although free drug levels rise, elimination rates will also rise (in 1st order kinetics) so a steady state can be restored in a few days
What precipitant drugs can displace warfarin?
Aspirin
Sulphonamides
Phenytoin
What precipitant drugs can displace tolbutamide?
Sulphonamides
Aspirin
What precipitant drugs can displace phenytoin?
Valproate
How can you calculate the rate of metabolism of a drug metabolised by enzymes that obey michaelis-menten kinetics?
Vmax [C] / Km+[C]
When do first order kinetics occur?
When the drug is used at a lower concentration that Km
When do zero order kinetics occur?
When the drug is used at concentrations much larger than Km
Define first order kinetics
The rate of decline of plasma drug level is proportional to the drug concentration.
Half life can be defined
Define zero order kinetics
The rate of decline of plasma drug level is constant regardless of concentration (as the enzyme is saturated)
What lines do first order and zero order kinetics give on a plasma concentration is plotted against time?
Zero order - straight line down
First order - decreases quickly then levels out
What lines do first order and zero order kinetics give when log plasma concentration is plotted against time?
Zero order - decreases slowly at start then more rapidly
First order - straight line down
During drug administration, how many half lives does it take to reach a steady state?
5
How can you produce an immediate effect when the drug has a long half life?
Use a loading dose
Do first or zero order kinetics give a predictable response? Explain
First order give a predictable therapeutic response as it is proportional to drug concentration.
Zero order gives a response that can suddenly escalate as elimination methods saturate.
What reactions occur in the 2 phases of liver metabolism?
Phase 1- oxidation/reduction/hydrolysis
Phase 2- conjugation
Why is phase 1 drug metabolism necessary?
Most drugs are stable and unreactive so a reactive group must be exposed/added to generate a reactive intermediate that can be conjugated with a water soluble molecule in phase 2.
What is required for phase 1 drug metabolism to occur?
Cytochrome P450 enzyme system
NADPH
What can effect cytochrome oxidase?
Enzyme inducers and inhibitors
Give an example of cytochrome oxidase inhibitor and its effects
Cimetidine
Affects warfarin, can raise free levels above LD50
Give an example of cytochrome oxidase inducer and its effects
Rifampicin
Affects oral contraceptive, can lower levels below ED50
What is enzyme induction/inhibition of cytochrome P450 more likely to matter clinically?
When the drug:
Has a small therapeutic window
Is used at minimum ED
Metabolism follows zero order kinetics
Why can some drugs bypass phase 1? Give an example of a drug that does this
They already have an exposed reactive group.
Morphine
What is drug conjugation?
The reactive intermediate from phase 1 is combined with a polar molecule (the conjugate) to form a water soluble complex
Give examples of conjugates
Glucoronic acid (most common)
Sulphate ions
Glutathione
What is required for phase 2 drug metabolism?
Specific enzymes
High-energy cofactor: uridine diphosphate Glucoronic acid (UDPGA)
For weak acidic drugs, how can you increase excretion? Explain
Make the urine alkaline.
Ionises the drug so there will be less tubular absorption because the charged drug stays in the tubule lumen, hence more is excreted
For weak basic drugs, how can you increase excretion? Explain
Make the urine acidic.
Ionises the drug so there will be less tubular absorption because the charged drug stays in the tubule lumen, hence more is excreted
In renal disease what happens to the loading dose and maintenance doses?
Loading dose remains the same as it still requires 5 half lives to reach a steady state.
Lower maintenance dose required as the half life of the drug is prolonged.
