Drug absorption, distribution, metabolism and excretion

Hannah Tribe
Flashcards by , created over 4 years ago

Degree Pharm Flashcards on Drug absorption, distribution, metabolism and excretion, created by Hannah Tribe on 10/23/2014.

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Hannah Tribe
Created by Hannah Tribe over 4 years ago
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Question Answer
Why is it important to know about ADME of a drug? It will determine the speed of onset of the drug, its duration of action and any potential problems, so is important for doctors to know how to design dosing regimens, monitoring compliance and substance abuse and allowing general safe use of medications
How can knowing the distribution of a drug in the body be useful? In multiple-dose therapy, understanding the distribution of a drug can help make sure the levels of that drug remain constant between each dose
Once an IV bolus dose is given, where does it go? Moves quickly to well-perfused areas, moving slower to less perfused areas, and leaving vessels (e.g. entering muscles cells)
Most drugs obey first-order kinetics. What does this mean? This means that the drug has a constant half life in the circulation, so despite the concentration of the drug given, the same fraction of it will always be removed after a period of time.
What is zero-order kinetics? If a drug obeys zero-order kinetics, then the drug is removed at a fixed rate, due to the limitations of enzyme complexes, for example.
What is an example of a drug following zero-order kinetics and why is this clinically undesirable? Alcohol. It is clinically undesirable because it becomes hard to predict the half life of the drug, and as the concentration of the drug increases, the longer time it will take to remove it.
How do you work out apparent volume of distribution (Vd)? Total amount of drug/[drug in plasma]
What does this tell you, and how is it limiting? Tells you the extent of distribution of a drug, but does not give any indication of which body compartment it is in.
What affects Vd and why is it clinically important? The biochemical properties of the drug affect its distribution (e.g. if it is lipophilic). This is important to help adjust the dosage of drugs.
What is plasma clearance of a drug? The volume of plasma cleared of the drug per unit of time
How can you calculate clearance? EITHER: Rate of elimination/[drug in plasma] OR: (Dose x Fraction of drug actually in cirulation)/Area under the curve of [drug] over time
What will the CL for drugs following 1st order kinetics be? Constant
What is F a measure of? Bioavailability (i.e. the extent to which absorption alters the amount of a drug that actually ends up in the circulation)
How is F calculated? Give the same doses of a drug both orally and IV, and plot a graph of [drug] over time. Work out the areas under each curve, and divide AUC oral dose by AUC IV dose
What is F for all IV doses and why? It is always 1, as the drug enters the circulation directly.
How is calculating F useful? Indicates how the dose needs to be adjusted to achieve maximum effect.
What causes low bioavailability? (3) 1. Poor absorption of the drug in the gut 2. Metabolism of the drug as it is absorbed (first-pass metabolism) 3. Chemical reactions at the site of delivery
Why are multiple doses of drugs given? To reach a steady state of [drug in plasma], avoiding large fluctuations or [drug] reaching zero.
What influences the [drug] over time? (2) 1. Half-life of the drug 2. Interval between doses of the drug
What is a steady state? Dosage rate = rate of elimination
What is Css? Steady state target concentration
How do you calculate dosing rate? CL x Css
How long does it take to reach a steady state? 4-5 times the half-life of the drug
What factors determine how much drug will be in the circulation? 1. Supply rate of the drug 2. It's distribution in the body 3. It's removal from the body
If the drug is not given IV what is the first step? Absorption into the bloodstream
How is the route of delivery of a drug chosen? (4) 1. Speed of onset 2. Bioavailability 3. Convenience for patient 4. Side effects
What does absorption require drugs to do and how does it mainly do it? Must cross biological barriers, transcellularly or paracellularly
How does absorption occur? (3) 1. Active transport 2. Facilitated diffusion 3. Passive diffusion (most drugs)
What determines the rate of diffusion? Ficks law
What are most drugs? Weak acids or bases, and are thus ionisable
What factors determine their extent of ionisation? (2) 1. pH of the environment 2. pKa value of the drug (dissociation constant)
What equation can be used to predict the extent of ionisation? Henderson-Hasselbach
In order for drugs to diffuse across membranes, what must they be? Uncharged
For acidic drugs, where are they best absorbed and why? They are best absorbed in the stomach, as this is an acidic environment and so will favour more of the drug being in its unionised form, allowing it to be absorbed into the circulation.
Where are basic drugs best absorbed and why? In the intestines, as this is a more basic environment so will favour more of the basic drug to exist in its unionised form, allowing it to be absorbed into the circulation across the mucosal cells.
What compensates for the fact that basic drugs are absorbed less efficiently? Large surface area of the intestines.
What set of rules is there for oral drugs? Lipinski Rules
How are drugs and their metabolites modified to ensure they are excreted? They are made water soluble so that they will be more readily excreted by the kidneys and not reabsorbed.
Why is it important to understand the metabolism and excretion pathways of drugs? (2) 1. To allow calculation of correct dosing regimens 2. Metabolites of drugs are often dangerous
What are 'prodrugs' and one example? Prodrugs are an inactive drug that is given, as the first stage of metabolism will yield the active drug. An example is enalapril, which in itself is inactive, but is metabolised into the active enalaprilat.
What is the first phase of drug metabolism? The addition of a chemically reactive group to the molecule in the liver (often oxygen) by CYP450 enzymes, so it becomes more prone to phase 2
What is phase 2 of drug metabolism? Formation of a water soluble compound by conjugating the drug/its metabolites with an endogenous molecule such as glucose or sulfate so that it is more likely to be excreted by the kidneys.
Why is paracetamol an exception to the drug metabolism rule? Paracetamol undergoes phase 2 metabolism before phase 1, as the result of phase 1 is a highly toxic compound (a quinone compound). Phase 1 will only take place when the enzymes for phase 2 are all saturated (e.g. on overdose)
Why is paracetamol more dangerous for alcoholics? In alcoholics, there is an upregulation of CYP450 enzymes, which perform phase 1 metabolism to the toxic quinone compound. This means when alcoholics take too much paracetamol, phase 1 will be favoured and there is a higher risk of hepatotoxicity.
Why is it important for drugs/their metabolites to be water soluble? When they are filtered through the glomerulus into the kidney tubule, a steep concentration gradient is created that favours reabsorption, so lipid soluble drugs would be reabsorbed by passive diffusion, whereas the water soluble ones cannot cross the tubular membrane so remain in the tubule for excretion.
How else can drugs/their metabolites be excreted through the kidney? Some drugs are actively secreted into the tubule by acid/base molecule carriers against the concentration gradient. This means there is a very low concentration of unbound drug in the plasma and therefore also favour unconjugation of drugs from plasma proteins, allowing more secretion.
How can net excretion be calculated? = filtration - reabsorption + secretion
What is 'renal clearance' of a drug? The volume of plasma cleared of the drug per unit time in one pass through the kidney
How can plasma CL be calculated from that? plasma CL = hepatic CL + renal CL
Why do neonates need to have lower doses of drugs? Their CYP450 system is not fully developed so cannot handle the metabolism of the high doses of drugs given to adults.
Why would a higher body fat % affect drug metabolism and excretion? Lipophilic drugs will accumulate in adipocytes, which takes longer to clear. In a person with a larger number of adipocytes, it will therefore take much longer for the drug to be cleared.
Why would liver or renal disease be a problem for people taking medicines? In liver disease, the patient may not have sufficient CYP450 enzymes to enable them to metabolise drugs properly. In renal diseases, the patients may have impaired filtration/reabsorption/secretion which wil affect the excretion of the drug.
Why might you monitor drug concentration in a patient as they are taking a course of a drug? (6) 1. To make sure the concentration remains in the therapeutic window (for drugs with a narrow therapeutic index) 2. To persoalise therapy 3. To confirm the patient is adhering to the treatment regimen 4. To diagnose toxicity if you suspect symptoms 5. To determine if patient is taking any other drugs (if they cannot tell you, for example) 6. To pick up drug interactions for post-marketing surveillance
What are type A adverse reactions? These are the majority of adverse reactions, and are related to the dose and its mechanism of action. You may get an excess of the pharmacological effect or effects at other tissues if a higher dose has been given. They are usually predictable.
What are some causes of type A reactions? (5) 1. If the drug has a steep response/concentration curve, a small change in concentration will result in a large change in the response 2. A narrow therpeutic index means only a small difference between therapeutic and toxic effects 3. Patient is given the wrong dose 4. Patient has renal failure causing impaired drug excretion 5. Interactions with other drugs (either by competing with it or causing an enhanced effect)
How can type A reactions be avoided? (2) 1. Consider the patient's factors - are they at risk of a type A reaction? 2. Monitor drug concentration over the course of the patient taking the drug
What are type B adverse reactions? These are idiosyncratic, and usually immune related. Usually unpredictable and often go unreported as patients do not notice them.
What causes type B reactions? 1. Interactions of drug/its metabolites with cell components, most commonly in the liver, skin or bone marrow, causing necrosis, carcinogenesis or mutagenesis. 2. Some drugs/their metabolites can interact with plasma proteins to form an immunogenic substance which triggers a hypersensitivity reaction.
Give 2 examples of hypersensitivity reactions 1. Type 1, in which IgE and mast cells are involved (classic 'drug allergy') 2. Pseudo-allergic reactions, in which IgE is not involved, by mast cells are activated directly.
What are 'yellow cards'? The Yellow Card system is a way of monitoring drugs throughout their product lifetime, reporting any adverse reactions. It is now online and so can be completed by anyone, but is not an obligation for doctors.
What is the 'Black Triangle' scheme? The European Medicines Agency places black triangles on new drugs which need extra monitoring for adverse reactions, as they want to collect more information about them.
What is the current 'Green Form' system? The Green Form system is a series of questionnaires customised for each drug to be monitored, that can be filled in online so that the Drug Safety Research Unit can look for patterns.
What is it important to remember when studying adverse reactions? That drugs are made up of multiple components, not just the active ingredient, so the adverse reaction may be to any of the components (Stabilizers, salt forms, devices for taking the drug etc.).
Considering aspirin specifically, where is the majority of aspirin going to be absorbed and why? Mostly absorbed in the stomach because this is an acidic environment, so most of the salicylic acid (active ingredient of aspirin) will be in its unionised form and can passively diffuse across the gastric mucosa.
Why does it not diffuse back into the stomach? Once the unionised salicylic acid reaches the plasma (pH approx 7.4), it becomes ionised and therefore cannot diffuse back across the mucosa and is thus 'trapped' in the plasma.
Through which 3 methods can the salicylate be excreted from the kidney? 1. Any aspirin not bound to plasma proteins can be filtered through the glomeruli 2. Unionised aspirin can travel by passive diffusion into the tubule 3. Ionised aspirin can be actively secreted into the tubule by anion transporters.
How does urinary pH affect the excretion of acid/basic drugs? If urinary pH is high, acidic drugs are excreted more readily, as they act as proton donors and thus levels of the ionised drug increase. If urinary pH is low, acidic drugs tend to exist in the unionised form, which makes them more likely to be reabsorbed by passive diffusion (and vice versa for basic drugs).
When can this be useful in clinical practice? In some drug overdoses, manipulating urine pH to deliberately make it more acidic or basic can encourage more of the drug to be excreted.