End of semester test Flashcards
Target concentration
Target concentration approach links PK with PD to predict the right dose for a patient. A target effect might be pain relief. Ideal dose prediction requires individual estimates of Emax, C50, V and CL. To find the target you randomises concentration controlled trials. PK/PD varies because of systematic (body size, disease state and genotype) and Random (between/within-subject variability) variables.
= (Target effect x C50)/(Emax - target effect)
Theophylline is metabolised by
CYP1A2, which is induced by polycyclic hydrocarbons in cigarette smoke. Enzyme induction reduces variability because there is a max biological limit in the extent of enzyme induction.
Three ways to dose: population
Is commonly used, but patients all receive the same dose, meaning that some patients are over/under dosed.
Three ways to dose: Group
Is when the same dose for similar groups is given, e.g. the same weight, CLcr (CL creatine) and genotype (more so in kids)
Three ways to dose: Individual
Dose is determined by individual response e.g. by BP, international normalised ratio, blood concentration. Used when the within-subject variability is large and predictable individualisation is not really possible.
INR
measures the degree of change in coagulation properties of blood
Target clearance
- Uses responses such as BP as a substitute for being able to measure the clinical disease state that is being treated.
- When medicine is working well or not working at all the clinical disease state may appear to be the same.
- Is used when group based dosing is not enough to reduce the between-subject variability so that the drug can be used safely and effectively.
- Can only work however is the within-subject variability is small enough so that dose individualisation is really predictive for future use of the medicine in the same patient.
Measuring Concentrations
The least informative time to do this is just before the next dose (trough) unless this is paired with another peak. This is because CL determines the average concentration, so measuring concentration in the middle of the dosing interval will be closer to the average and therefore better at predicting CL. A concentration in the middle of the dosing interval (Ctmid) will be closer to the average steady state concentration (Css) then either a peak or a trough. CL= does rate/Css which is approximated by CL= Dose rate/ CTmid.
Gentamicin and dosing intervals
Concentrations vary widely in a dosing interval so two concentrations are needed to reliable estimate CL. The trough concentration at 24h is often unmeasurable because it is below the limit of quantitation. Concentrations are best measures 1h and 8h after the dose.
Therapeutic drug monitoring
Traditional concept, that if the dose is within the therapeutic range then it is not adjusted. A concentration at the bottom of the range (ineffective) is very different from one at the top (possibly toxic), but TDM usually ignores this and are happy to do nothing as long as it is within range.
Target concentration intervention:
Is a science-based method that uses PK and PC principals to identify who patients are different and uses PK-guided does individualisation to achieve a precise target. It has been shown to improve clinical outcome as well as being cost effective.
Three was to think about time course effects
- Drug effects are immediately related to observed drug concentration
- Drug effects are delayed in relation to observed drug concentration
- Drug effects are determined by the cumulative action of drug
Law of mass action
the binding of a drug to a receptor should follow a hyperbolic curve, it is assumed that effect is directly proportional to the binding then the C50 will be the same as Kd
Kd
is the equilibrium binding constant, and the concentration at which 50% of the binding sites are occupied
Emax model
E = (Emax x conc)/(C50 + conc).
- The model is the description of a concentration-effect relationship.
- An important prediction of the model is that all biological systems will reach a maximum.
- Many drugs will have a steeper concentration and effect relationship so that a smaller change is required to see the same change.
The sigmoid Emax model
E = (Emax x conc^hill)/(C50 + conc^hill).
This model is showing 4 different values for the hill coefficient.
When hill >10
The concentration effect relationship is like a switch, the effect turns on at a threshold concentration close to the C50.
When hill = 2
It only takes a 4 fold change in concentration to go from C20 to C80.
When hill <1
the curve is shallower than Emax
When hill >1
the curve is steeper than Emax
When hill = 1
the curve is the same as the Emax model
Conc peak = 10 x C50
This shows how the time course of immediate drug effect depends upon the initial concentration as well as the PK of the drug. Shows the time course concentration after a bolus dose at time zero. Initial conc is 10 x the C50 and produces and effect that is 90% of Emax. After one-half life, the concentration is halved but the effect has changed by less than 10%. As conc falls the effect disappears more quickly
Conc Peak = C50
Initial concentration is the same as the C50 then the initial effect will only be 50% of Emax. At these lower concentrations, the time course of effect is almost parallel to the time course of concentration.
Conc Peak = 100 x C50
When a very big dose is given, the initial effect is close to 100% of Emax. The effect changes very little despite the big changes in drug concentration. After more than 5 half lives when nearly all the initial does will have been eliminated the effect will still be 70% of Emax. This is common for receptor agonists.
Time Course
Time course of effect can be described the three regions by considering if the concentration is about C80 or below C20.
- When the concentration is above C80 the curve is almost flat.
- When the concentration is low, below C20 the curve is almost exponential. The time course of concentration and effect are almost parallel to one another. This is the only time where you can describe the effect as having a “half life.”
- In between C20 and C80 the time course of loos of drug effect is almost a straight line.
Doubling the dose
Prolongs the duration of effect to nearly one half-life, at this time the concentration is equal to 10 mg/L- with the same level of effect (50) that was used to mark the end of response for the lower dose. Doubling the dose does not lead to doubling of effect. Doubling the dose will increase the duration of effect by one-half-life. Concentration-effect curves are non-linear (Emax model) effect do not increase in direct proportion to the dose.
1942 - Goodman/Gilman
Chemo is shown to reduce lymph gland cancer (nitrogen mustard)
1958 - Hertz/Li
Methotrexate cures choriocarcinoma
1978 - Rosenberg
Anticancer platinum complex discovered and approved for medical use to cure testicular cancer. Has a broad range of solid tumour activity (testicular, ovarian, cervical, bladder, head and neck, lung, colorectal and other cancers)
Cancer 1998 (Trastuzumab)
targeted therapies involving specific molecules involved in cancer development and progression. Potential for more effective, less toxic and individualised cancer therapy. Trastuzumab (Herceptin) approved for Her-2 positive breast cancer.
Cancer 2001
Imatinib (Glivec) approved for chronic myelogenous Leukaemia
Cancer 2011
immune checkpoint modulation: Monoclonal antibodies binding Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) (eg. ipilimumab) or programmed death 1/programmed Death ligand 1 (PD1/PDL1) e.g. nivolumab. Results in durable responses in subgroups of patients with melanoma, non-small cell lung cancer and others. Immune-related side effects, colitis and dermatitis.
Chronic myelogenous Leukaemia:
Is the acquisition of the Philadelphia chromosome [t(9;22) translocation], abnormal fusion protein (bcr-abl) and self-sufficiency of growth signals. Survival of CML patients treated with Imatinib had a 95% survival rate over the first few years
5 levels of selection for animal tests - species/strain
May not have the relevant target, may be subject to diurnal variation, time of dosing might be important
5 levels of selection for animal tests - end-points
pharmacological, direct toxicity (skin irritancy), genotoxicity( bacterial mutagenicity tests) and immunotoxicity (immune suppression/allergic reactions)
5 levels of selection for animal tests - dose
response curves, toxicity can be represented on a log dose response curve. Populations, due to non-reversibility of many toxic end points it is not possible to look at the response of a tissue to increasing doses, instead, the dose required to produce a desired end point is studied in population. Acute toxicity taste, determine the effects that occurs within a short period after dosing, only a single dose given by different routes.
Testing involves 5 levels of selection for animal tests- what are they?
Species/strain End-points Dose Route Duration of tests.
C x T = K (Harber’s rule)
noted that exposure to a low concentration of a poisonous gas for a long time often had the same effect as exposure to a high concentration for a short period of time.
Sub Acute toxicity tests
Involve exposing animals to the compound for 28-90 days. Exposure is frequent and usually daily. The test provides information in the target organs and major toxic effects, that may have a slow onset can be detected. Clinical measurements may indicate the development of any pathological lesions.
Chronic toxicity tests
involves lifetime exposure of animals to the compound, changes in simple measurements (weight, food) can be recorded. The choice of dose, species, strain, route are influenced by the type of chemical. Often rats and dogs are used, and the drug is often administered in the food, or inhabited.
Limitations of animal testing
limited choice of species, species switching between taste, interspecies variability in metabolism and response, lack of subjective ADR, and lack of suitable human models.
ADR
leading cause of medical injury. Most reactions are definitely or possibly avoidable.
Type 1 ADR
predictable, dose-dependent based in the known pharmacology of the drug.
Type 2 ADR
not predictable, no clear dose dependency and not due to the known pharmacology of the drug.
Type A ADR - agumented.
predicted from known pharmacology of the drug, usually drug-dependent and reduced by dose reduction.
Type B ADR - bizarre
not predicted from basic pharmacology on simple dose-response relationship
Type C ADR - chemical
biological characteristics can be predicted or rationalised in terms of chemical structure of the drug
Type D ADR - delayed
Occur after many years of treatment
Type E ADR - end of treatment
due to withdraw of treatment, especially if done suddenly
NSAID induced gastro-duodenal ulceration
Ulceration/bleeding reported in 15-30% of chronic users. NSAID may induce lesions by interacting with phosphatidylcholine and reduce the ability of gastric mucosa to protect itself from e.g. HCL. Inhibition of COX important because some prostaglandins are cytoprotective and so initial lesion results in overt damage.
Renal toxicity (acute)
PGs are crucial for maintenance of renal perfusion through renal blood flow. PGI2 and PGE2 cause vasodilation ( inc bf, dec proximal reabsorption of na+). Renin release controlled by PIG1 so NSAIDs can influence RAAS (dec aldosterone recreation, so inc k+ - hyperkalemia). HETES inhibit Na+/K+atpase. NSAIDs may reduce the effectiveness of diuretics.
Acute ischemic renal insufficiency
May occur within hours of the initial dose of susceptible patients. Characterised by a marked decrease in urine, weight gain, increase BUN, increased serum creatine. Readily reversed when drugs were withdrawn.
Analgesic-Associated Nephropathy
may be secondary to acute interstitial nephritis, and requires continuous analgesic abuse over many years. Patients present with hypertension, GI ulceration, UTI, headaches, depression and CVD. 5-year survival (50%). Involves necrosis within the loop of hence and medullary capillaries spreading throughout the papilla.
Importance of Metabolism
metabolism may lead to the formation of a chemically-receive species that binds to and inhibits the biological function of a macromolecule. Formation of toxic metabolites may be influenced by dose, inter-individual variability in enzyme expression of PK interactions.
Inter-individual variation in drug metabolism
- Lack of metabolism: enhanced plasma concentrations and exaggerated pharmacological responses.
- Lack of a metabolite pathway in certain individuals: compound is bioactivated in a different enzyme
- Enhanced toxicity: due to the lack of a detoxification pathway
- Lack of bioactivation pathway: poor metabolisers are at less risk
- Increased protein expression or catalytic activity: with subsequent increase in the formation of toxic metabolites.
Paracetamol:
In an overdose, normal pathways of metabolism are saturated, so other routes of metabolism may take place. Metabolites can bind to and destroy key proteins, leading to cell death in the liver, potentially leading to liver failure and eventually death. Loss of intracellular calcium regulation disrupts mitochondrial function and leads to necrotic cell death. The toxic metabolite is a quinonimine that can react with sulfhydryl groups in critical cellular proteins.
Drug-drug interaction
is the effect of one drug in influenced by the co-administration of another drug, which may be desirable or not. Two or more compounds act at the same receptor or on the same pathway. You can get additive effects (increase the effect) or get an antagonistic effect (cancel each other out) if they work in the same pathway you may get the synergistic effect (more simple than additive).
Anna Nicole Smith
Toxic combination of lots of drugs many that acted on the GABAa receptors that were designed as anti-hallucination or sleep drugs, but dampened her response so much she sedated herself to death
DDI Absorption
Reduced uptake —> decreased effect. For example some antibiotics form insoluble complexes with metals which decrease the absorption of the drug.
DDI Metabolism
reduced clearance, increased plasma concentrations —> too much effect. Inhibition of one pathway, greater clearance through bioactivation pathway —> increase toxicity. Induction of enzymes, decreased plasma concentrations. EG. drug B or chemical can inhibit the enzyme that metabolises drug a. Not used as a strategy to increase drug concentrations unless drug a has a very short half life. Simply give more of drug a or more often. Or e.g. drug b/chemical can induce the enzyme responsible for the metabolism of drug A, therefor plasma concentration of drug a is less than expected (can lead to therapeutic failure). EG st johns wort - a potent inducer of enzymes involved in the metabolism of .70% of all drugs.
DDI distribution
competition fro uptake transporters or protein binding, increased plasma concentrations —> +/- effect depending on target
DDI Excretion
competition for efflux transporters, decreased elimination —> increased prolonged plasma concentrations
Antimalarial therapy DDI
combination kills parasites faster by synergistic action, and reduces the potential for the development of parasite drug resistance.
Paracetamol and Ibuprofen DDI
Combination gives faster and better pain relief, no PK interaction but mat increase chance of adverse effects.
Pharmacokinetics interactions: Mixing
Effects can be mixed, on a single dose there may be inhibition, on chronic therapy, there may be induction. Drug A may have one type of interaction with drug B and a different interaction with drug C.
Drug Food interactions
Food may alter absorption - solid foods ten to delay gastric emptying nut non-nutrient liquids may the the opposite effect. Dairy products containing Ca2+ may produce clinically significant reaction in Cmax of for example some antibiotics. Food may alter metabolism - caffeine metabolism by CYP1A2 inhibits clozapine metabolism, so caffeine consumption may influence effectiveness in schizophrenics. Grape fruit juice has a number of clinically relevant interactions with drugs metabolised by CYP3A4.
Alcohol interactions
Alcohol may alter absorptions - studies have reported gastric emptying may be increased, decrease or not effected, dependent on the dose/concentration of ethanol. Alcohol (acute, high dose) can inhibit drug metabolism - decreased warfarin metabolism, increased anti coagulation, decreases benzodiazepine metabolism. Alcohol (chronic) can induce drug metabolism - increased phenytoin elimination and benzodiazepine metabolism. Alcohol can reduce threshold of drug toxicity - through the depletion of chemical protection. Alcohol can enhance renal elimination - its a diuretic. Alcohol had a pharmacodynamic interaction - particularly through GABA receptors.
