Pharm - Pharmacokinetics Flashcards
What is the difference between pharmacokinetics and
pharmacodynamics?
Pharmacokinetics describes the relationship between the dose administered and
the changes in drug concentration in the body over time, i.e. the effect that the
body has on the drug.
Pharmacodynamics describes the relationship between drug concentration and its
pharmacological effect at the target site, i.e. the effect the drug has on the body.
What are the broad processes that influence the concentration of
a drug within the body?
Absorption
Distribution
Metabolism
Excretion
Describe how Absorption effects drug concentration of the body?
The rate and extent of drug absorption after its administration via a particular route depends on:
i Patient factors
– Malabsorption, e.g. coeliac disease, ileus
ii Drug factors
– Pharmaceutical preparation: smaller particle size allows faster absorption of oral drugs
– Physicochemical interactions: the presence of other drugs/food may inactivate
or bind orally administered drug, e.g. milk and tetracyclines
– First-pass metabolism (FPM): this occurs within the gut wall or liver and reduces the bioavailability of orally administered drugs
– FPM depends on the metabolic capacity of particular enzyme pathways and protein binding, e.g. a highly bound drug with a low metabolic capacity, such as phenytoin, will have a narrow therapeutic window because small alterations in protein binding will not be accommodated by an increase in metabolism as the pathway is almost completely saturated
iii Route of administration
– Sublingual route avoids hepatic first pass metabolism
– Intramuscular administration avoids problems associated with oral route – onset is more rapid and bioavailability approaches 100%, but the rate of absorption depends on local blood flow
– Can therefore be unpredictable, with delayed absorption being a risk if the drug is administered when muscle perfusion is poor, e.g. shocked state
– Subcutaneous administration can be used for depot injections, but delayed absorption is a risk as with IM administration
– Inhalational administration may be used for local or systemic effect: droplets <1 μm diameter can reach the alveoli, and hence the systemic circulation
Describe how Distribution effects drug concentration of the body?
The volume of distribution (Vd) is the theoretical volume into which a drug is distributed, and relates the plasma concentration to the administered dose. It depends on regional blood flow and factors that influence the passage of drug across the cell membrane:
i Molecular size
Graham’s law states that the rate of diffusion is inversely proportional to the square root of molecular size
ii Concentration gradient
Fick’s law states that the rate of diffusion is directly proportional to the concentration gradient across the membrane
iii Ionisation
– The lipophilicity of the cell membrane only permits the passage of the unionised fraction of drug
– Degree of ionisation of a drug depends upon its dissociation constant (pKa) and the pH of the solution in which it is dissolved
iv Lipid solubility
This is independent of pKa and may affect absorption
– Highly lipid-soluble fentanylmay be used effectively as a transdermal patch
– Morphine is less lipid-soluble than diamorphine so is more likely to spread cranially when administered intrathecally and produce respiratory depression
v Protein binding
Only the unbound fraction of drug in the plasma is free to cross the cell membrane, so if a drug is highly protein-bound (i.e. >90%) small changes in the bound fraction will produces large changes in the amount of unbound
drug (may be compensated for by increased metabolism unless enzyme pathways are close to fully saturated)
vi Presence of facilitated diffusion or active transport mechanisms
Describe how Metabolism effects drug concentration of the body?
In general, the process of metabolism produces a more polar (water soluble) molecule that can be excreted in bile or urine. Active metabolites may result from this process, e.g. morphine-6-glucuronide (13 times more potent than morphine). There are two phases of drug metabolism:
i Phase I (non-synthetic) reactions:
– Oxidation
– Reduction
– Hydrolysis
Most occur in the liver (but also in the lung, GI mucosa, kidney and brain) and are carried out by the cytochrome P450 system (which is subject to genetic polymorphism). Phase I metabolism relates to mitochondrial monoamine oxidase (catecholamines), alcohol dehydrogenase (ethanol), plasma esterases (remifentanil, suxamethonium, atracurium), ACE.
ii Phase II reactions increase the water solubility of the drug and occur mainly in the liver
– Glucuronidation, e.g. propofol, morphine
– Sulphation, e.g. quinol metabolite of propofol
– Acetylation, e.g. isoniazid
– Methylation, e.g. catecholamines
Describe how Excretion effects drug concentration of the body?
This refers to the processes of removal of drug from the body and mainly occurs via the urine and bile, hence may be affected by renal or liver failure. The relative role of each route depends on molecular weight (molecules >30 kDa are not filtered by the kidney) and structure of the drug (highly charged molecules may be excreted unchanged in the urine).Elimination is the processes of removal of drug from the plasma and includes distribution, metabolism and excretion.
How might the absorption of drugs be altered in critically ill patients?
Delayed GI absorption
- Delayed gastric emptying
- Prolonged transit time, e.g. ileus
- Altered gastric pH, e.g. with PPi/H2RA therapy
- Reduced GI perfusion and venous drainage
Impaired GI absorption
- Fast transit time, e.g. diarrhoea, prokinetic use
- Vomiting
- Bacterial overgrowth
- Villous atrophy
- Interaction with enteral nutrition
How can drug distribution be affected in critical illness?
The Vd is commonly increased due to an increase in total body water, which can result in underdosing. Additionally, plasma proteins, particularly albumin, are reduced in stress states. This produces decreased protein binding and increased free drug fraction. In turn, this may result either in increased clearance, or toxicity (particularly if a drug’s metabolic pathway is close to saturation).
How may metabolism of drugs be altered in critically ill patients?
Reduced hepatic metabolism
- Reduced hepatic blood flow due to local hypoperfusion or systemic, e.g. shock / low-flow states, vasopressor use
- Direct hepatic injury due to mediators released in response to illness
- Ischaemia (affects cyP450 system)
- Hypothermia (affects cyP450 system)
- Drug-induced cyP450 inhibition (see Table 62.3) may reduce clearance of drug
Increased hepatic metabolism Increased basal metabolic rate, e.g. hyperthermia
Drug-induced cyP450 induction may increase clearance of drug
Reduced spontaneous degradation Hoffmann degradation of atracurium reduced by acidosis and hypothermia
Reduced tissue metabolism Reduced perfusion of kidneys, brain, lungs etc. due to shock / hypothermia
Reduced plasma metabolism E.g. plasma cholinesterase deficiency in acute/ chronic hepatic failure
Name some CyP450 inducers and inhibitors?
Inducers
- Phenytoin
- Carbemazepine
- Barbiturates
- Rifampicin
- Alcohol abuse
- Sulphonylureas
- Smoking
Inhibitors
- Amiodarone
- Omeprazole
- Erythromycin
- Valproate
How might drug excretion be affected in critical illness?
Reduced urinary clearance - Reduced renal blood flow due to local hypoperfusion or systemic, e.g. shock/low-flow states, vasopressor use
- Reduced glomerular flow rate (GFR) – in general, renal drug clearance is proportional to GFR
- Inhibition of tubular secretion
- Direct renal injury, e.g. acute tubular necrosis (ATN)
Increased urinary clearance
- High cardiac output states, e.g. sepsis, trauma, burns
Effect of RRT Variable
- Drugs with a high molecular weight, increased protein binding and large Vd are less likely to be removed by RRT
Reduced biliary clearance
- Biliary stasis
- Recirculation due to increased GI transit time
Describe the Pharmacokinetics and pharmacodynamics of antibiotics
Pharmacokinetics mathematically describe the relationship of antibiotic concentration to time.
Terminology that is typically associated with pharmacokinetics includes: absorption, distribution, metabolism, elimination, half-life, volume of distribution, and area under the concentration-time curve (AUC).
Pharmacodynamics describe the relationship of antibiotic concentration to pharmacologic effect or microorganism death. The three main pharmacodynamic parameters that are used are the peak to minimal inhibitory concentration ratio (peak/MIC), the AUC to MIC ratio (AUC/MIC), and
the time the drug concentration remains above the MIC (T>MIC).
What is Concentration independent versus concentration dependent with regards to abx?
Concentration independent (time dependent) means that the rate and extent of microorganism
killing remain unchanged regardless of antimicrobial concentration. The pharmacodynamic
parameter that is most often predictive of outcome for concentration independent drugs is
T>MIC, although the AUC/MIC can be used because the AUC takes both the antimicrobial
concentration and time into account. Examples of concentration independent antimicrobials
include: beta-lactams, vancomycin, macrolides, aztreonam, carbapenems, clindamycin,
tetracyclines, quinupristin/dalfopristin, flucytosine, and azole antifungals.
Concentration dependent (time independent) means that the rate and extent of microorganism
killing are a function of the antimicrobial concentration (increase as the concentration
increases). The pharmacodynamic parameter that is most often predictive of outcome for
concentration dependent drugs is peak/MIC, although the AUC/MIC can be used because the
AUC takes both the antimicrobial concentration and time into account. Examples of
concentration dependent antimicrobials include: fluoroquinolones, aminoglycosides, and
amphotericin B
What is Bacteriostatic activity versus bactericidal activity?
Bacteriostatic activity refers to the inhibition of bacterial growth, while bactericidal activity refers to killing the bacteria.
Minimum inhibitory concentration (MIC) – The MIC is defined as the lowest concentration of antibiotic that completely inhibits growth of the specific organism being tested.
Minimum bactericidal concentration (MBC) – The MBC is defined as the lowest concentration of antibiotic at which bacteria are killed
How is vancomycin dosed?
Vancomycin is considered to be a concentration independent or time dependent killer of
bacteria. Therefore, increasing antibiotic concentrations beyond the therapeutic threshold will
not result in faster killing or eliminate a larger portion of the bacterial population.
Vancomycin dosing should be based upon actual body weight (ABW), is generally used at doses of 10-20
mg/kg, and dosing intervals should be renally adjusted.
