Pharmacology 101

Author: Jeff Moss, PharmD, BCCP- Invited Guest Contributor

Pharmacokinetics Overview-(What the Body Does to the Drug)

·       Absorption (Bioavailability)

o   Extent and rate from drug delivery system

o   Small, non-ionized, lipophilic molecules tend to have greatest enteral absorption

o   First pass metabolism = metabolism that occurs when passing through portal circulation prior to systemic distribution

·       Distribution (VD)

o   Delivery of drugs, metabolites & toxins from systemic circulation to target organs

o   Influenced by protein binding affinity (α-1 acid glycoprotein (AAG) & albumin), lipid/water solubility, ionization state and molecular size

o   Volume of distribution = hypothetical volume to achieve plasma concentration, VD = D/ΔC

o   May distribute into one or more “compartments”

·       Metabolism

o   Biotransformation to polar, water-soluble compounds for elimination

o   Primarily occurs in liver, but also in plasma, kidney, intestine, lungs, adrenal gland and skin

o   Often limited by organ/liver flow or capacity

§  Context-sensitive half-life refers to redistribution of medication from additional compartments or reservoirs, and often prolongs half-life

o   Order pharmacokinetics: relationship between plasma concentration and rate of drug elimination

§  In zero-order models metabolic pathways are saturable and increasing dose may exponentially increase plasma concentration

§  In 1st-order model, rate of drug elimination is constant and independent of plasma concentration

o   Phase I – oxidation, reduction, hydrolysis & hydroxylation (CYP)

§  Drug-drug interactions may inhibit or induce metabolism of other medications

o   Phase II - conjugation

o   Prodrugs = medications in which parent form is not active, but metabolite has therapeutic effect

o   Active or toxic metabolites

·       Excretion

o   Clearance (Cl) of polar, water-soluble compounds via biliary, renal and pulmonary systems

·       Desired pharmacokinetic parameter depends on medication

o   For maintaining constant level of sedation/analgesia, goal is to maintain drug exposure within therapeutic range, where the amount of drug infused is equal to the drug being cleared. A continuous infusion or frequent intermittent doses may be used to achieve steady state.

o   The efficacy of antimicrobials is dependent on the mechanism of action.

o   Beta lactam antibiotics (penicillin, carbapenem antibiotics) demonstrate time-dependent killing (the time above the Minimum Inhibitory Concentration/MIC) and may attain the desired pharmacokinetic parameters with frequent dosing, extended or even continuous infusions

o   Aminoglycosides display concentration-dependent killing with a post-antibiotic effect that allows single-daily dosing and targeting peak levels as a surrogate for efficacy (and trough levels as a marker of toxicity).

o   The efficacy of vancomycin and fluoroquinolones are dependent on overall exposure

(From Sandritter et al, Ped in Rev 2017)

Peak (ie aminoglycosides)  vs. Time (ie vancomycin) Dependent Killing for Antibiotics 

Pharmacokinetic Changes in Pediatrics

·       Increased gastric pH may increase absorption of acid-labile medications and decrease absorption of weak acids

·       Changes in gastric emptying may delay time to peak concentration (Tmax)

·       Alternation in intestinal surface area and splanchnic blood flow may affect absorption

·       Changes in the gut microbiota may affect absorption of medications that require microbial breakdown for absorption

·       The composition and perfusion to the striatum corneum and skeletal muscle capillaries may affect absorption and rate of transdermal, subcutaneous/intramuscular injections

·       Changes in body compositition may affect the volume of distribution

·       Decreased protein synthesis may increase the faction of unbound drugs

·       Alterations in distribution between compartments may impact therapeutic effects.

·       Changes in phase I and phase II isoforms in the liver, gut and other organs may non-uniformly affect metabolic capacity

·       Changes in glomerular filtration and tubular secretion may affect renal clearance of medications

Pharmacokinetic Changes in Critical Illness

·       Decreased gastric pH may affect ionization state and impact absorption or elimination

·       Feeding tubes may interact with medications directly or bypass the primary site of absorption

·       Decreased splanchnic blood flow due to critical illness or vasopressor use may decrease enteral absorption

·       Fluid shifts and “third-spacing” may affect the volume of distribution

·       Hepatic dysfunction may directly impair metabolic capacity; hepatic hypoperfusion may decrease drug delivery to the liver for high extraction-ratio drugs that are dependent on hepatic blood flow.

·       Hypothermia may decrease enzyme activity

·       Renal dysfunction may decrease excretion of renally-cleared medications

o   Some patients may experience “Augmented Renal Clearance” in which critical illness is associated with supraphysiologic renal function

·       Urinary acificiation may affect drug ionization state and impact elimination

·       Cardiovascular disease may impair blood flow to end organs

·       Extracorporeal modalities may interact directly with medications, increase VD and affect overall clearance

Pharmacodynamics-(What the Drug Does to the Body) 

·       Describes the relationship between the drug and receptor (Structure-Activity Relationship)

·       Agonists mimic endogenous compounds

·       Antagonists block interaction between molecule and receptor

·       Competitive interactions are dependent on concentration of drug, compound and target receptor

·       Non-competitive interactions may structurally alter the conformation of the receptor

·       Interactions may be reversible or irreversible

·       Relationship between concentration and therapeutic (and toxic) effect