CPT PK AND PD Flashcards
Part 1 Know how key pharmacokinetic factors influence how medications are
administered and their importance in the consideration of approving therapeutic treatments
Absorption:
Bioavailability - affected by:
- Formulation
- Age (luminal changes)
- Food (chelation, gastric emptying)
- Vomiting/malabsorption (Crohn’s)
- Previous surgery (bariatric)
• First pass metabolism - metabolism before reaching systemic circulation (gut lumen, gut wall, liver and lungs)
Distribution:
Blood flow, capillary structure (poorly vs. well- perfused tissues)
Lipophilicity and hydrophilicity
Protein binding - only free drugs have response - Displacement of a drug from binding site can result in protein binding drug interaction - important if highly protein bound, narrow therapeutic index, Low V d.
Albumin – acidic drugs, Globulins – hormones, Lipoproteins + Glycoproteins – basic drugs
Second drug can be given and displaces first drug from binding
More free first drug to elicit a response - can cause harm e.g.– Pregnancy (fluid balance), renal failure,
hypoalbuminemia
Apparent Volume of distribution
Vd= Dose/[Drug]plasma
a smaller Vd = drug confined to plasma and extracellular fluid
larger = drug is distributed throughout tissues
Part 2 Know how key pharmacokinetic factors influence how medications are
administered and their importance in the consideration of approving therapeutic treatments
Metabolism:
Drug -> phase 1 enzymes - (Cytochrome P450 produced in smooth ER of hepatocytes - oxidation, reduction and hydrolysis) -> phase 2 enzymes -> conjugation by glucuronide, sulphate, glutathione, N-acetyl -> kidney/gall bladder -> urine/bile
CYP1A - induced by smoking
CYP2E - alcohol metabolise
CYP3A - metabolise 50% of drugs
CYP 2D6 -Hyperactive in ~ 30% of N/E Africans - Substrates include β-blockers, many SSRIs some opioids
active → inactive - most drugs
inactive → active - perindopril → perindoprilat
active → active – codeine → morphine, diazepam → oxazepam
• CYPs induced or inhibited by:
• Age ~↓
hepatic disease ↓
blood flow ↑↓
chronic alcohol ↑
cigarette smoking ↑
Excretion
Renal
Typically low molecular weight polar metabolites
Affected by:
1 GFR and protein binding (gentamicin)
2 Competition for transporters such as OATs (penicillin)
3 lipid solubility, pH, flow rate (aspirin)
• Manipulation of pH(↑) in poisoning/gout
alkalinisation - previously for salicylate poisoning
Hepatic:
Typically high molecular weight metabolites - conjugated with glucuronic acid
Bile for conjugates
Excreted in faces or reabsorbed
Enterohepatic circulation – environment for recycling of drugs eg bilirubin and steroid hormones
• Antibiotic drug interactions
-e.g. with warfarin, morphine
Other factors
Key factors:
Half-life
Inter-subject variability
Drug-drug interactions
Describe how inter-person variation in lifestyle, health, diet and pathology
affect PK providing examples
Know the factors affecting drug absorption and distribution and understand
that in reality it is a multi-compartment model
Know the association between volume of distribution, clearance and half-life,
their units and be able to calculate them
clearance = rate of elimination/ plasma concentration of a drug
Higher the elimination rate, the lower the Vd
Elimination rate proportional to 1/Vd
Half-life = 0.693 x Vd / Cl
So Vd and Cl dictate half-life
Elimination determines how much drug needs to be put back in so useful for chronic treatment dosing.
Demonstrate the difference between first order and zero order kinetics and
the clinical implications of dosing zero order drugs
First order - constant half-life
V. high doses of drugs eg alcohol, salicylic acid and phenytoin - zero order - half-life not easily calculated - dose change can cause unpredictable change in plasma.
Appreciate how steady state therapeutic levels in plasma are reached and
how loading doses are employed to expedite reaching desired plasma
concentrations
Be able to calculate a maintenance dose (= [CL x Css/F] x t) and loading dose
(= Vd x Css)
• Be able to calculate an infusion rate and volume needed to achieve a required
dose
Steady state plasma conc (Css) reached after 4-5 half-lives
Css = rate of infusion / clearance
In the case of oral medication:
Css = maintenance dose x oral bioavailability
/
Dose interval x clearance
Therefore
Maintenance dose = plasma conc we want x clearance
/
Bioavailability
And then multiply by dose interval
Loading doses:
relevant when rapid onset required or when giving drug with a long half-life.
It is the single dose to achieve desired concentration taking into account apparent Vd.
Loading dose = Css x Vd
Relate pharmacokinetic principles to dosing schedules, routes of
administration and how therapeutic indices inform dose, route and schedule
Dosing schedule - Maintain a dose within the therapeutic range
• To be safe
• Achieve adherence
• Initiating and terminating treatment – titrating up and down (increasing or decreasing dose)
Know that pharmaceutical preparations can me modified to manipulate
pharmacokinetic handling of a drug and when this can be advantageous to
patients including addressing adverse drug reactions and adherence
Know that drugs work as agonists, partial agonists, inverse agonists,
competitive, non-competitive and functional antagonists and provide
examples
Agonist - same action - adrenaline (L-DOPA?j
Partial agonist - same action but not as strong - formoterol
Inverse agonist - propranolol
Competitive antagonist - prevents from binding so cannot carry out function. Overcome by inc conc
Naloxone
Non-comp - bind to Allosteric site on target which prevents substrate from binding and cannot carry out function. Permanent.
Alpha blockers
Functional - bind to target and inhibit instead of just blocking - dopamine to prolactin?
Explain the importance of titrating some drugs both when initiating and
terminating therapy
