Pharmacokinetics Flashcards
How is pk translated to useful clinical practice
- Knowledge of bioavailability allows balanced or needed formulation to be selected for non iv. dosing
- Volume of distribution, clearance and half-life provide information for dosing regimens to be proposed
- Differences in intra-subject PK parameters allows tailored dosing regimens to be initiated
- Understanding patient specific PK is important to understand why a patient may fail to respond to therapeutic agent
- Probably more important why a drug has caused toxicity or predicted toxicity based on knowledge of drug-drug interactions
- PK of therapeutic agent affected by very many factors, some variable, some consistent and patient specific (we will consider many of them through CPT unit)
What are some things to consider when thinking about pk
Ss
Describe drug therapy
Ss
What is bioavailability
• Measure of drug absorption into body compartment where it can be
used – typically circulation – Bioavailability (F)
• Drug administered via intravenous bolus is said to have 100% bioavailability
• For other routes of administration referenced as a fraction of i.v.
What is bioavailability affected by
Bioavailability affected by • Absorption - Formulation - Age (luminal changes) - Food (chelation, gastric emptying) - Vomiting/malabsorption (Crohn’s) • First pass metabolism - metabolism before reaching systemic circulation (gut lumen, gut wall, liver)
What sis modified release preparation
Rm (dotted line) - single dose - conc in plasma takes longer to rise but its maintained in therapeutic window for longer - once.a day amybe - extended release - better for adherence
Eg GTN for angina, sublingual - poor bioavailability
Describe distribution
• Following absorption, drug needs to “dissolve” in the body, adequate plasma levels and reach the target organ
• How well a drug dissolves – is distributed through interstitium from circulation is governed by several factors:
Blood flow, capillary structure
Highly vascularised vs poorly vascularised tissues, endothelial structure and slit junctions
Lipophilicity and hydrophilicity
Liphophilic drugs will readily cross through cell membranes whereas hydrophobic drugs require junctions in the endothelium
Protein binding
Albumin – acidic drugs, Globulins - hormones, Lipoproteins
– basic drugs, glycoproteins – basic drugs
Volume of distribution (Vd) – see later
Descrbe drug protein binding an distribution
• Displacement of a drug from binding site can result in Protein Binding Drug Interaction
• Clinically important if:
- highly protein bound
- narrow therapeutic index - Low Vd
• Increased free drug - will be able to afford response and or be eliminated
BBB
Target receptor
BB
Target receptor
• Second drug displaced first drug from binding proteins
• More free first drug to elicit a response through receptor
• Potentially causing harm – entering toxic dose concentration
- Pregnancy (fluid balance), renal failure, hypoalbuminemia (malnutrition) among others
Protein bound - cannot elicit effect - highly protein bound _eed to pay attention to. Narrow therapeutic index - concerning bc narrow margin o where drug conc needs to be - problem. Low ve
What is volume of distribution
• Vd is typically hypothetical measure of how widely a drug is distributed in the body (apparent Vd)
• Vd ~ Dose/[Drug]plasma
• The amount of fluid required to contain the total amount (Dose) of drug in the body at the same concentration as in the plasma ([Drug]plasma)
• Useful for estimating dosing regimens if Vd is known
• In general
a smaller apparent Vd suggests drug confined to plasma and extracellular fluid
a larger apparent Vd suggests drug is distributed throughout tissues
• t1/2 is proportional to Vd
Describe the metabolic process
• Majority of phase I catalysed reactions utilise the P450 system –
equally important for endogenous substances
• Numerous genes that encode these enzymes, few CYP families deal with most reactions (see pharmacogenetics lecture)
• Many therapeutic formulations designed as pro-drugs or inadvertently have active metabolites
• active → inactive - most drugs
inactive → active - perindopril → perindoprilat, levodopa → dopamine active → active – codeine → morphine, diazepam → oxazepam
• CYPs can be induced or inhibited by endogenous/exogenous compounds affecting phase I metabolism
• Age, hepatic disease, blood flow, alcohol and cigarette smoking also
influence phase I
Give n example of enzymeinhibition and drug interactions
Ss • Absent in ~ 7% Caucasians
• Hyperactive/increased induction in ~ 30% East Africans
• Substrates include some antiarrhythmics, antidepressants and opioids
• Inhibited by some SSRIs, other antiarrhythmics and other antidepressants
What factors affect drug prescribing
• Important for drug prescribing (common esp. novel drug development)
• Consider OTC and food as drug-drug interactions (charcoal grill 1A+;
grapefruit juice 3A-)
• Other factors (generally):
– Race (see pharmacogenetics lecture)
– Age (reduced in aged patients & children)
– Sex (women slower ethanol metabolisers)
– Species (drug development, interpretation of evidence) – Clinical or physiological condition
What is elimination
- Finally drugs and or metabolites need to be removed from the body
- Primarily via the kidney (~25% of systemic blood flow)
- Other possible routes: pulmonary, biliary, faecal sweat, genital secretions, saliva, breast milk
- Typically if drug or metabolites are partially water soluble
What is elimination affected by
Affected by:
1 GFR and protein binding (gentamicin)
2 Competition for transporters (penicillin) 3 lipid solubility, pH, flow rate (aspirin)
What is clearance
- Clearance of drug from the body is the rate of clearance from all routes – both metabolism and excretion taken together by definition (mL/min)
- mostly GFR
