Describe what you need to consider when prescribing dosage for Digoxin, consider its elimination
- Large apparent Volume of Distribution (Vd)
- Predominantly excreted by kidneys
- Relatively long half life (as proportional to Vd) = 40 hours
- Thus 5 half lives to steady state will be >1 week.
- Needs loading doses to achieve a rapid therapeutic effect – e.g. for patients who present with AF.
- Maintenance doses need reducing if renal failure leads to reduced clearance. Also need to consider age (older => smaller dose)
- Loading dose can remain much the same in renal failure unless renal failure is very severe
- The clinical effectiveness of the drug (after it is stopped) will depend on the therapeutic window and the minimal effective plasma drug concentration. It also depends on the half-life of the drug
If patient becomes digitoxic (bradycardia, xanthopsia- abnormal colour vision –yellow vision)….occurs mostly in older patients with AKI
If normal GFR: 40 hours to reduce the p[drug] to 50%
If renal failure present, then clearance is reduced – t1/2 will be increased and thus longer for [drug] to return to therapeutic levels. There is delayed elimination.
You can give an antidote e.g. DigiFab – decreases effect of drug, treats symptoms
Describe paracetamol metabolism and what happens in an overdose
The glucoronide and sulphate routes are easily saturated and the NAPQI route is the spillage route. In substantial OD, the conjugation of NAPQI is saturated leading to increasing toxic levels of NAPQI which is highly hepatotoxic.
Therefore treatment is to replace Glutathione i.e. N-acetylcysteine (Parvolex). Given in IV form early enough, it is highly effective at decreasing [NAPQI] but if a patient delays presentation, the damage may already be done and can’t be reversed.
Describe Loading Dose Calculations
- Vd ~ Dose / [Drug]t(0)
- Loading Dose = Vd x [Drug](target)
- If Vd = 1L and drug = 100mg, [Drug]t(0) = 100mg/L
- Example Phenytoin: Vd phenytoin = 0.7 L per kg body weight. If a patient is 100kg, Vd phenytoin = 70 L. Phenytoin has a long half life.
- Cpss phenytoin = 20 mg/L (steady state)
- Loading Dose = 70 x 20 = 1400 mg
- However Phenytoin is administered as a salt, comprises 92% of phenytoin.
- True drug loading dose = 1.4g/0.92 = 1.5g
- NB: if treating a chronic condition probably don’t need a loading dose – no need for a rapid therapeutic effect.
Describe half-life calculations
Slope of the curve = elimination rate constant (k)
k = Ratio of clearance (Cl) to volume of distribution (Vd)
t1/2 = loge 0.5 / k = 0.693/k
t1/2 = Vd / Cl
t1/2 is proportional to volume of distribution and inversely proportional to clearance
Vd = 1000ml
[Drug]t(0) = 100 mg / L
Clearance = 10 ml / minute
Clearance (total) = Clearance (kidney) + Clearance (liver) + Clearance (other organs)
k = clearance / Vd
k = (10 ml / min) / (1000 ml)
k = (1 mg / min) / (1000 ml)
k = 0.01.
t1/2 = 0.693/0.01 = 69 minutes.
t1/2 is proportional to Vd (per Kg)
Drug A Vd = 0.5L x kg
In children, Vd is higher and clearance is generally quicker. As renal function deteriorates with age, in older adults, half-lives are longer (longer to eliminate, longer effects).
How would you account for CKD?
Clearance (kidney) is proportional to renal function (GFR)
t1/2 is proportional to 1 / Clearance (GFR)
E.g. assuming t1/2 of 4 hours with a GFR of 90 for a drug exclusively eliminated via the kidneys. The half life of drug in a patient with CKD stage 3 and GFR of 45 = 8 hours. This can occur in patients with AKI who take digoxin.
What is meant by Multi-Compartment Modelling?
So far pharmacokinetics has been discussed in terms of a single compartment – using the single beaker analogy, this would only relate to plasma.
Most drugs do not remain in the plasma. Therefore distribution occurs in 2 or more ‘compartments’ e.g. plasma, fat, muscle, organs etc. The equilibrium between these compartments are not equal therefore the rate of elimination can be different – there are a number of different rate constants.
What is meant by Pharmacodynamics and how do most drugs work?
Awareness of drug-drug interactions is of growing importance as increasing numbers of patients receive drugs in the therapeutic combination. Whilst these interactions can be positive and maximise therapeutic benefit, they can also interact adversely.
Pharmacodynamics is concerned with describing how drug molecules bind to a range of biological receptor molecules. Once bound at their specific sites on the receptor molecule, they then exert a measurable effect on some aspect of cellular function. This usually has some systemic effects that reduce the severity of the disease or pathology the clinical is trying to treat.
Most drugs work by interacting with endogenous proteins
Some activate endogenous proteins (agonists)
Some antagonize, block or inhibit endogenous proteins (antagonists)
A few have unconventional mechanisms of action
Drugs work at cell surface receptors, nuclear receptors (steroids), enzyme inhibitors, ion channel blockers and transport inhibitors. The four principle classes of receptor sites are: Receptors; Enzymes; Carriers or Transporters; Ion channels. These are sensitive to endogenous biological molecules with a signalling role that regulate their activity.
What is meant by Unconventional Mechanisms of Action?
Disrupting of structural proteins e.g. vinca alkaloids for cancer, colchicine for gout
Being Enzymes e.g. streptokinase for thrombolysis
Covalently linking to macromolecules e.g. cyclophosphamide for cancer
Reacting chemically with small molecules e.g. antacids for increased acidity
Binding free molecules or atoms e.g. drugs for heavy metal poisoning, infliximab (anti-TNF)
What is meant by Specificity and Sensitivity?
The ideal drug would mimic the specificity of the endogenous controlling molecule, or if one actually existed, would act only at the one specific site required to produce the desired clinical effect.
This is rarely realised and drugs almost always bind at other sites, where they can affect signalling processes.
The more selective a drug is for its target, the less chance that it will interact with different targets and have less undesirable side effects. E.g. penicillin target – enzyme involved in bacterial cell wall biosynthesis. Mammalian cells does not have a cell wall so penicillin has few side effects.
Drug specificity: targeting drugs against specific receptor subtypes often allow drugs to be targeted against specific organ e.g. adrenergic receptors (heart B1 receptors, lungs B2 receptors). The more specific a drug acts the less action on other organ. What is meant
Describe the Dose Response Curve
Drug Concentration is a major determinant of magnitude of response
The response to a drug is generally proportional to the number of receptor sites bound by the drug. However, target receptors can exist at different tissues throughout the body. Actual expression levels in different tissue may also vary widely and the receptors in only one of these tissue types may actually serve as the desired therapeutic site of action (passive non-pharmacodynamic binding sites vary in their density throughout the designated kinetic compartments).
How can therapeutic response show linear and non-linear dynamics?
As drug concentration increases, the number of sites generating a therapeutic response become saturated and show a non-linear saturated response to further increases in drug concentration.
Additionally, as therapeutic responses themselves are instigated via a chain of post receptor messenger processes, these responses can show non-linear responses without saturation that are not easily modelled. This is in part genetically determined and can also account for idiosyncratic responses to otherwise moderate doses of a drug.
How does the type of drug - receptor interaction determine therapeutic effect
Currently, the modelling of the mechanism of the all important Drug Receptor Interaction proposes that the receptor exists in two molecular states or conformations – active and inactive.
In the active state, the receptor actively carries out its specific task e.g. signalling by permitting ion movements for ion channels, enzymatic transformation or transporting a particular molecule or ionic species.
In the inactive state, the receptor molecule is not carrying out this task.
This simple two state model has been expanded to include other intermediate activity states but using these two states, the specific action of many drugs has been classified into 3 main categories: agonist, antagonist and partial
What is meant by an agonist?
when an agonist binds to its receptor it stabilises it whilst bound, in the active conformation.
What is meant by an antagonist?
when antagonists bind to the receptor these stabilise it whilst bound, in the inactive conformation.
What is meant by a partial agonist / antagonist
some drugs can act as a mixture of the above. The overall action of this activity class of drugs is dependent on the proportion of which the drug stabilises the receptor in the active:inactive conformation.
E.g. if the proportion of active:inactive sites was 80%-20%, then this drug would be acting as a strong partial agonist and a weak partial antagonist. If this was reversed to Active:Inactive sites of 20%:80% then the drug would be acting as a weak partial agonist and a strong partial antagonist.
The therapeutic activity of these classes can be further defined by their affinity, efficacy and potency. These largely determine the therapeutic dosage of a drug as much to limit toxicity as maximise therapeutic effects. What is meant by affinity?
this defines the tendency of a drug to bind to a specific receptor type. The terms often used to define this are K(d) for agonists and K(i) for antagonists. These symbols are used to indicate the concentration at which half the available receptors are bound. The lower the Kd the higher the affinity.
What is meant by efficacy?
: this defines the maximal effect of a drug when bound to a receptor – the ability of a drug to produce a response as a result of the receptor or receptors being occupied. This is expressed in percentage terms of the response, when no increase in drug concentration brings about any further increase i.e. when the response is saturated and the response becomes non-linear.
NB: binding alone may not produce a therapeutically relevant effect or any response in differing tissue types. Even though the receptor type across tissues (e.g. GPCRs) may outwardly be the same, the pathways or systems the receptor feed into can be very different.
Agonists: agonist activity is referenced against itself as the activator of a given receptor. Within that system they will be modelled as having 100% activity at the concentration when the response becomes saturated.
Antagonists: because antagonists keep a bound receptor in the inactive state, they are said to possess zero efficacy. Their specific effect therefore is to reduce the number of receptors available for binding by agonists. Therefore antagonist activity is referenced against how it antagonises or competes against the activity of a specific agonist.
Partial agonists/antagonists: depending on their specific therapeutic use, they are referenced against the maximal efficacy of another named agonist acting at a specific receptor. They are then referenced against the maximal effect of that agonist given at a specified concentration.
What is meant by Potency?
Potency describes the different doses of two drugs required to exact the same effect (lower dose drug has greater potency).
Agonist Potency is defined by the drug concentration at which 50% of the maximal response is obtained. This is referred to by EC(5). Because the potential for non-linearity of response following binding at a receptor, the EC(50) is often not equal to the Kd. So in the example below, hydromorphine and morphine are equally efficacious (both give maximal responses) but hydromorphine is far more potent (smaller dose required). Aspirin has poor efficacy and poor potency in comparison.
Antagonist Potency is defined by the concentration of a drug that reduces maximal activation of a receptor by 50%. This can really only be done in vitro. The antagonist is compared against a specific agonist drug at a given concentration that induces 100% efficacy in that preparation. The antagonist drug can then be added in increasing concentrations till the maximal responses is reduced by 50%.
Describe Competitive Antagonism
In Competitive antagonism, agonist efficacy can be restored by simply increasing agonist concentration to increase the competition for receptor sites. The dose-response curve is shifted to the right. EC(50) changes but the maximal effect value for that agonist stays in the same.
Describe Non-Competitive Antagonism
In non-competitive antagonism, the antagonist can bind in 2 ways.
At the same site for the agonist binding irreversibly or unbinding very slowly.
At a separate site to the agonist either reversibly or irreversibly.
In this case, no matter how much the agonist is added, maximal effect will be depressed proportional to the degree of antagonist binding to the receptor. However, because the agonist does not have to compete to occupy its binding site, the EC(50) remains the same.
What is meant by the Therapeutic Index and Therapeutic Window?
The therapeutic index is the relationship between concentrations causing adverse effects and concentrations causing desirable effects. Therapeutic index = EC50(adverse effect) / EC50(desired effect).
Therapeutic window: drug concentration over which it exerts a clinically useful effect but without exerting significant toxic effects. It is the range between the lowest dose that has a positive effect and the highest dose before the negative effects outweigh the positive effects.
Ideally drugs would have a wide therapeutic window (wide margin of safety dose) to reduce the likelihood of serious toxicity. E.g. heparin has a relatively narrow therapeutic window and the plasma level that results in serious bleeding is less than twice that required for therapeutic effect.
In reality, the width of the clinically practical Therapeutic Window varies depending on its specific therapeutic use. The upper end of the window is also in practice set by the concentration of drug that results in the appearance of unacceptable side effects in a given percentage of patients.
Why is it important to consider Drug-Drug Interactions and what are the different types?
Important to consider drug-drug interactions due to increasing polypharmacy. This can lead to variability in control of therapeutic levels and increased risk of toxicity/ADRs due to increased systemic drug concentration. The negative side of polypharmacy is offset by combination therapies that achieve a better clinical outcome.
Interactions either enhance or reduce therapeutic outcome through actions on the receptors.
Drug interactions can occur via different receptors or different tissues.
Specific therapeutic drug-drug interactions can be broadly divided into 2 interaction groups:
- Pharmacokinetic interactions between one or more drugs given in combination
- Pharmacodynamic interactions between one or more drugs given in combination
Non-Selective Nature e.g. anti-depressants interact with many receptor subtypes: adrenergic, noradrenergic, serotoninergic, cholinergic and Na channels.
Enhanced effect by other means e.g. Digoxin toxicity enahcned by hypokalaemia caused by a loop diuretic e.g. Furosemide.
Describe possible Drug-Drug Interactions that would affect Absorption (Pharmacokinetics)
Drugs given via the oral route can be affected by co-administration of other agents affecting gut motility and passive or active absorption by the gut. E.g. metoclopramide acts primarily as a dopamine antagonist used as an anti-emetic and gastro-prokinetic. This will clearly increase the rate of gastric emptying and can therefore increase the rate of uptake via the small bowel.
Food reduces the rate of alcohol absorption. Codeine slows gastric emptying so less alcohol is absorbed (so lowers blood alcohol concentration) and it also interacts with alcohol, increasing CNS effects (CNS depression).
Reduced absorption of tetracycline caused by simultaneous ingestion of ferrous sulphate.
Describe possible Drug-Drug Interactions that would affect Distribution (Pharmacokinetics)
can be affected by competition between drugs at protein/lipid binding sites. For the most part, with drugs exhibiting linear kinetics and a reasonable therapeutic window, these effects are offset by an increased clearance. If the drug has non-linear pharmacokinetics and/or a narrow therapeutic window, such as that seen for phenytoin, then this can lead to serious toxicity.
Vd ~ Dose / [Drug]t0 – measure of how widely a drug is distributed in body tissues.
Low Vd – limited to plasma / fluid compartments
High Vd – limited to tissue compartments
Describe possible Drug-Drug Interactions that would affect Metabolism (Pharmacokinetics)
drugs can significantly affect metabolism of themselves or other drugs by either induction or inhibition of the CYP 450 enzymes.
CYP 2D6 19% (varies between race / person to person)
CYP 3A4 36% (most abundant)
Describe Enzyme Induction
can take place by increased transcription, translation or slower degradation. Over 200 drugs are known to act as inducers. Depending on the specific CYP 450 enzyme involved, induction leads to a more rapid elimination i.e. shorter half-life and increased clearance of the therapeutic substrate. Dosing of the affected drug may then have to be increased.
Induction typically occurs over 1-2 weeks and monitoring of drug levels/ therapeutic effect need to take this into account.
Usually Phase 1 processes
Rate depends on drug and enzyme
Importantly, withdrawal of the inducing agent without a change in the therapeutic agent can lead to toxicity if dosing is not re-adjusted.
Additionally, CYP 450 induction may lead to increased production of a toxic metabolite that results in an ADR.
Many drugs induce CYP 450 activity e.g. Carbamazepine induces CYP 3A4 faster metabolism (decreases the effect of warfarin). Slow onset-care is required when one drug stopped.
Describe Enzyme Inhibition
many drugs can act as inhibitors of P450 enzymes and this can also result in ADRs. The effects on metabolism may then be reversed i.e. increased half life and decreased clearance of affected non-metabolic drug. Inhibition of CYP450s can occur through both competitive and non-competitive inhibition. Onset of inhibition is relatively quick onset (several hours to days). E.g. Cimetidine is an inhibitor of warfarin.
Describe possible Drug-Drug Interactions that would affect Excretion (Pharmacokinetics). Also consider effect of urinary pH.
The primary mechanism affecting drug excretion involves changes in protein binding, inhibition of tubular secretion and changes in urine flow/pH. Decreased protein binding increases the amount of free unbound drug which accelerates its removal. Inhibition of tubular secretion will result in increased plasma levels of drug. This can also be used for improved therapeutic effect in some cases if tubular secretion is very rapid, e.g. penicillin.
Probenecid was specifically developed to enhance the therapeutic action of penicillin by reducing its renal excretion. Importantly, NSAIDs can also act to reduce tubular secretion.
Urine pH is a great influence on whether a drug is excreted quickly or slowly. Most drugs are either weak acids or weak bases. In alkaline urine, acidic drugs are more readily ionised. In acidic urine, alkaline drugs are more readily ionised. Ionised substances (also referred to as polar) are more soluble in water so dissolve in the body fluids more readily for excretion. In aspirin poisoning for example, making the urine more alkaline with sodium bicarbonate increases ionisation of the salicyclic acid (aspirin metabolite) and increases excretion from the body.
How can pharmacodynamic drug-drug interactions be categorised?
They can be categorised as those used to enhance therapeutic outcome and those that result in either a reduction in therapeutic outcome or an ADR.
The clinician can target a number of receptor types in different tissue types to contribute to changing the disease state – a ‘holistic’ approach. E.g. controlling hypertension can involve employing calcium channel blockers (antagonists) whose principle site is arteriolar smooth muscle, in combination with an ACE inhibitor (antagonists) that act primarily on Angiotensin Converting Enzymes located on pulmonary and coronary arterial endothelial surfaces.
Administration of agonists and antagonists with either primary or secondary actions at the same site will results in reduced therapeutic effects e.g. a B-adrenergic antagonist such as propranolol, would reduce the effectiveness of salbutamol a B-adrenergic agonist, for treating asthma.
A lack of consideration of the summation of pharmacodynamics effect can also result in serious and fatal effects. E.g. the use of aspirin, a non-competitive COX inhibitor would both pharmacodynamically augment the antithrombotic action of warfarin and pharmacokinetically increase its unbound concentration by displacing it from plasma proteins.
Which 5 major drug classes do Drug-Drug interactions commonly arise from?
Anticonvulsants: especially phenytoin and carbamazepine
Anticoagulants: especially warfarin
Antidepressants: especially mono-amine oxidases
Antibiotics: especially quinolones, macrolides and rifampicin
Antiarrhythmics: especially amiodarone.