routes of drug administration and conditions for use
enteral = GI: oral, sublingual, rectal
-most common, easy, cheap, must survive 1st pass metabolism
parenteral: subcutaneous, IV, intramusc.
-IV: need fast or can’t do GI, can be unconscious, stable
other: inhalational, topical, transdermal
general considerations:
-drug: size, solubility, pH/pKa,
-patient: condition, age, compliance
-therapy goals: urgency, location, effect
factors that influence drug absorption and availability
- pKa and pH -> charge, solubility (best absorbed in unionized HA or B form); size; solubility
- bioavailability = fraction absorbed. F=(in circulation)/(dose given)
Vd
volume of distribution: the theoretical compartment the drug is dissolved in
-large Vd= mostly in tissues, small Vd=more in blood/ECF
recall: body 60% H2O (42L), 2/3 ICF, 1/3 ECF–> 2/3 interstitial, 1/3 plasma
factors that influence drug distribution in blood
- protein binding: less free drug in blood
- perfusion: brain, heart, liver, kidneys first
- conc gradient, pKa/pH, liposolubility
mechanisms of drug metabolism
usu in liver: goal= make more excretable
Phase I: Redox/hydrolysis
-CYP450: add/uncover polar groups
Phase II: conjugation
-non P450 enzymes, covalent add’n of large polar molecules
-urine excretion: must make more polar/charged
some drugs metabolized extensively by gut bacteria
drug excretion
- may occur unchanged, or after phase I or phase II
kidney: passive (small), tubular secretion (large, protein complexes), tubular reabsorption ( uncharged drug follows conc gradient back to blood) t limit). subject to enterohepatic recirculation
enterohepatic circulation
- gut bacteria hydrolyze phase II conjugates -> no longer polar -> reabsorbed
- antibiotic use can effect
AUC
area under the curve, measure of F (fraction absorbed)
- useful for comparing administration routes
- bioavailability= AUC oral/ AUC injected x 100%
CYP450 inducers
alcohol (esp chronic) cigarettes Rifampin Phenytoin, carbamazepin (epilepsy drugs) St John's wort
CYP450 inhibitors
grapefruit juice
fluconazole, ketoconazole (-azole antifungals)
fluoxetrine (antidepressant)
erythromycin (macrolide antibiotics)
therapeutic range
range between MEC (min effective conc) and MTC (toxic),
Css
5 half lives=time taken to reach
rate of infusion = rate of clearance
peak and trough levels fluctuate around
can give loading dose to reach faster, follow with smaller MD
time required for drug washout
5 half lives
first vs zero order kinetics
first order = normal, constant fraction of drug eliminated per unit time (%), does not depend on dose.
zero order = elimination process saturated, constant amount of drug (mg/mL) per unit time (linear) depends on dose. more danger of OD
ex. alcohol, high dose aspirin, phenytoin,
* some 1st order drugs show during high/OD
factors contributing to variability in drug response between patients
- compliance
- drug interactions
- disease (ADME)
- gender, ethnicity: metabolism differences?
- AGE
- start low and go slow
pediatric differences for drug absorption
- higher gastric pH: affects abosorption of weak acids/bases, more acid labile drug
- stratum corneum thinner: percutaneous absorbed more
geriatric differences for absorption
- higher gastic pH: more acid labile drugs, changed absorption of week acid/base drugs
- faster GI emptying and less blood flow = decreased absorption
geriatric differences for distribution
- more adipose tissue: lipophilic drugs lower in plasma
- less TBW: hydrophilic drugs have higher conc
- less serum albumin = more free drug
geriatric differences in metabolism and excretion
- decreased liver mass and hepatic blood flow, decreased phase I enzyme activity -> longer half life
- phase II rxns generally unchanged
- decreased renal function (size, functioning nephrons, blood flow)
paediatric differences in drug distribution
- larger % body water: may larger mg/kg dose of hydrophilic drugs
- less protein binding in plasma = more free drug
paediatric differences for drug metabolism and excretion
- decreased hepatic metabolism (Phase I enzymes immature)
- decreased renal function (especially pre term)
Factors to consider when assessing the impact of drug interactions
- toxicity profile: margin of safely width and nature or toxicity
- Regimin: dose, frequency, duration
- extent of interaction: weak/strong, exclusive to one enzyme?, genetic factors
- frequency of interaction in population: genetics, patient factors
Pharmacokinetic drug interactions: absorption
- chelation: binds to free ions, can reduce plasma levels
- binding: directly bind another drug
- indirectly reduce absorption: gastric pH, GI motility,
- P-glycoprotien: (pump drug out, BBB and GI) induced or inhibited
Pharmacokinetic drug interactions: distribution
-displacement of protein binding very rarely has clinically significant effects, must be combined with decreased metabolism etc
