The Principles of Prescribing Flashcards
Cmax
Peak Plasma Concentration
Tmax
Time to peak plasma concentration
Steady State Concentration
When the inflow of the drug into plasma is equal to the rate of removal
How many half-lives does it take to reach 95% clearance of a drug?
Approximately 5 half-lives
What ionisation state are drugs best absorbed in?
Unionised
Hence, acidic drugs best absorbed in stomach, while basic drugs best absorbed in small intestines.
Examples of pro-drugs
Codeine -> morphine
Azathioprine -> mercaptopurine
Enalapril -> enalaprilat
Cyclophosphamide -> phosphoramide mustard
How does phenytoin affect other medications?
It can affect the concentration of concomitant antiseizure medicines by inducing the metabolism of other drugs and reducing their serum/plasma concentration.
Volume of Distribution Definition
The theoretical volume of fluid that would be needed to achieve the actual plasma drug concentration.
Volume of Distribution Calculation
Vd = (total amount of drug in the body) / (plasma-drug concentration)
How does Vd affect plasma concentration?
High Vd will give a low plasma concentration
Low Vd
Highly water soluble drugs (e.g. gentamicin, atenolol, insulin)
Extensively protein-bound drugs (e.g. warfarin)
Due to drugs staying in the plasma
High Vd
Highly lipid soluble (e.g. digoxin, morphine, diazepam)
Due to drugs moving out of the plasma into the tissues and organs
How does pregnancy affect Vd?
Increase total body water therefore water soluble drugs have a higher Vd and lower plasma concentrations
How does dehydration affect Vd?
Water soluble drugs will have a lower Vd
Lipid soluble drugs will have a higher Vd
Why do fat-soluble drugs tend to have longer half-lives?
Some drug is taken up into fat and when the drug is stopped being given the plasma concentration lowers and the drug moves from the fat back into the plasma. The fat acts as a reservoir with ‘slow release’.
What plasma protein do acidic drugs bind to?
Albumin
What plasma protein do basic drugs bind to?
alpha-1-acid-glycoprotein
Total Clearance (CL)
CL = CLH + CLR
Hypothetical volume of blood from which the drug is completely removed per unit time.
Elimination rate constant (k)
k = CL / Vd
Half-life calculation
t1/2 = 0.693/k
t1/2 = ln(2) / k
Phase 1 Liver Metabolism
Renders the drug more polar by oxidation, reduction or methylation so it can combine with another molecule.
Cytochrome P450 group of enzymes are responsible for the majority of Phase 1 reactions.
Phase 2 Liver Metabolism
Conjugation - results in a water soluble compound which is usually inactive and more easily excreted in the urine or bile.
Some mechanisms of Phase 2 reactions (e.g. glucuronidation and sulphation) have been shown to be impaired in liver disease
P450 Inducers
E.g. phenytoin.
Accelerate the metabolism of concomitant drugs
P450 Inhibitor
E.g. erythromycin.
Slows down the metabolism of other drugs.
What drugs are routine TDM recommended?
Digoxin
Gentamicin
Lithium Salts
Vancomycin
What level of digoxin indicates toxicity?
> 3 micrograms/litre
How does muscle mass affect volume of distribution?
Lower muscle mass lowers distributable space for water soluble drugs within the body and therefore reduces the volume of distribution. This leads to higher serum levels with a smaller dose.
Affinity
Measure of how well a drug binds to a receptor.
Proportion of receptors occupied calculation
p = ([D]) / ([D]+Kd)
Where Kd is the ratio of k-/k+
How does a competitive antagonist affect the drug concentration curve?
Right shift
Agonist
A chemical that binds to its target to increase its activity
Antagonist
A chemical that opposes the action of another chemical therefore should have no action on their targets in the absence of an agonist
Competitive antagonist
Competes with an agonist for the same binding sites.
Causes right shift in the relationship between agonist conc and binding.
Reversed by increasing conc of agonist to ‘out-compete’ antagonist
Non-competitive antagonist
Prevents the agonist from producing a response at its receptor
Effects cannot be overcome by increasing the conc of the agonist
The maximum response of the agonist is reduced
Efficacy
How well an agonist achieves a response
Potency
Often described by the concentration or dose that is able to elicit 50% of the maximal response (ED50)
A drug with a higher potency will have a lower ED50
Partial Agonist
A drug that has a lower maximal response resulting from lower efficacy
Allosteric Modulators
Bind to proteins at sites other than the binding site for the principal agonist
What effects can allosteric modulators elicit?
Alter the affinity of the binding sites for its agonists OR change the efficacy of the response when the agonist binds
Their action can be either positive (increase potency of the agonists) or negative (decrease the potency of the agonists)
How many alpha subunits genes are there for calcium channels?
10
How many alpha subunits genes are there for potassium channels?
40 - very few examples of drugs targeting this channel type
How many alpha subunits genes are there for sodium channels?
9
When is the HMG-CoA reductase enzyme most active?
At night - therefore statins with short half-lives should be taken at bedtime for the most benefit
According to the GMC when is prescribing an unlicensed medicine potentially necessary?
1) There is not suitable licensed alternative that would meet the patients needs
2) There is a suitable licensed medicine that would meet the patients needs but it is not available
3) Prescribing is part of a properly approved research project
4) Serious risk to public health and the MHRA has temporarily authorised the sale or supply of an unlicensed medicine (e.g. vaccine or treatment) in response
5) A POM that is unlicensed in Northern Ireland has been supplied under the NIMHRA Authorised Route
AWaRe
Access
Watch
Reserve
Start SMART (AIPD)
Assess - for clear evidence of infection to establish if antimicrobial therapy is likely to be beneficial
Investigate - obtain appropriate cultures prior to starting treatment (where appropriate) and undertake other investigations as per local policy
Prescribe - start antimicrobials within ONE HOUR of recognition of red flag sepsis, septic shock or life-threatening infections
Document - document evidence of infection, indication for treatment, antimicrobial prescribed (dose, route and frequency) and state a review or stop date
Then Focus (CARES)
At 48-72 hours, review and revise the diagnose and need for continuing antimicrobials. Document a clear management plan including one of the following five review outcomes:
1) Cease treatment (i.e. if no evidence of infection)
2) Amend antimicrobials (i.e. based on sensitivities)
3) Refer for Complex Outpatient Parenteral Antibiotic Therapy (COPAT) or virtual ward
4) Extend current treatment and document next review or stop date
5) Switch antimicrobials from IV to oral route
Bacteriostatic Agents
Macrolides
Tetracyclines
Efflux Pumps
Pump any antibacterial which has passed through the outer membrane back out before they reach the target site (e.g. P. aeruginosa)
Antibacterial-modifying enzymes
Destroy the antibacterial before it reaches its target within the cell (e.g. beta-lactamase or aminoglycoside-modifying enzymes)
What information should you provide when calling for advice on infection management?
- Any known previous colonisation and/or infection with an organism with antibacterial susceptibilities
- Any known allergies - especially to antibacterials
- Any recent hospitalisation
- Any recent procedures or surgery
- Any recent travel or any relevant social history
- Any obvious source of current infection
What antibiotic is used for empirical treatment of suspected C. diff?
Metronidazole
What 4 acute infections do NICE recommend the majority of patients do not require antibacterials for?
Acute cough
Acute otitis media
Acute sinusitis
Acute sore throat
