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.

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

References

1. Kearns G, Abdel-Rahman SM, Alander SW, Blowey D, Leeder SJ, Kauffman RE. Developmental pharmacology—drug disposition, action & therapy in infants and children. N Engl J Med. 2003. 349: 1157-67.

2. Thakkar N, Salemo S, Hornik CP, Gonzalez D. Clinical pharmacology studies in critically ill children. Pharm Res. 2017. 34:7-24.

3. Besunder JB, Pope J. Pharmacology in the PICU. 2014. Pediatric Critical Care Medicine 1:55-74.

4. Blot SI, Pea F, Lipman J. The effects of pathophysiology on pharmacokinetics in the critically-ill patient –Concepts appraised by the example of antimicrobial agents. Adv Drug Del Rev. 2014. 77(20): 3-11

5. Stephenson T. How children’s responses to drugs differ from adults. Br J Clin Pharmacol. 2005. 59(6): 670-673.