Pharmacology Flashcards
4 factors that affect a drug’s ability to cross biological membranes
1) Molecular size (Can be affected by plasma protein binding)
2) Lipid solubility- estimated by oil:water partition coefficient
3) Degree of ionization - affected by tissue pH, affects lipid solubility
4) Concentration Gradient - created at site of administration
Bioequivalence
(a) rate of generic and brand name must be similar - estimated by Cmax and bioavailability
(b) Drugs are considered bioequivalent if the 90% CI of mean AUC and mean Cmax of generic product is within 80-125% of the brand product.
Bioavailability (F)
Fraction of unchanged drug reaching the systemic circulation following administration by any route
AUC (route)/AUC (iv)
First-pass effect
Drug metabolism of po drugs that occurs in liver before drug enters systemic circulation
Estimate of rate of absorption
Difficult to measure, typically estimated by the peak Cp or teh time needed to attain the Cp
Affect of drug formulation on rate of absorption by oral route
Liquid preparations/ rapidly disintegrating tablets –> fast!
enteric coated products or sustained release preparations - slower
General factors affecting drug absorption (5)
Solubility in biologic fluids (need some hydrophilicity and some hydrophobicity)
Rate of dissolution of solid for oral dosage formulation or suspended particles (parenteral)
Concentration of drug at site of administration
Circulation at site of absorption
Area of absorbing surface
Acid/base effect on oral absorption
weak acids are neutral at lower pH’s (should absorb better in stomach)
weak bases are uncharged at higher pH’s (should absorb better in upper small intestine)
BUT Surface area trumps it!!!
Effect of gastric emptying time on drug absorption
increased GI motility increases speed of stomach emptying and hence rapidity of absorption (drugs get to small intestine faster!)
Food delays absorption of most drugs
Is the food guideline to protect the stomach or the drug?
Take without food–> protects drug
Take with food–> protect stomach
Enteric coatings can prevent dissolution in stomach
Pros and cons of controlled release preparations
Pros - > overnight, decreased frequency of administration (better compliance) , elimination of peaks and troughs
Cons- greater interpatient variability in systemic levels obtained and dosage form failure resulting in “dose dumping”
Rectal admin
useful in unconscious, vomiting, post-GI surg, or uncooperative patients
~50% o f dose will bypass liver, so first pass metabolism is less than oral
Sublingual/buccal
Fast onset, high bioavailability
Drugs drain directly into superior vena cava, bypassing first pass metabolism
Useful for lipid soluble and potent drugs (small surface are a for admin)
Intravenous
Most direct, 100% bioavailability
Good for narrow therapeutic index drugs
bypasses absorption barriers
Most hazardous route
Intramuscular
onset and extent of absorption are affected by bloodflow at site of injection
Suspensions have a slower, more sustained absorption
Absorption can be erratic with limited solubility
Pain, tissue necrosis and microbial contamination possible
Subcutaneous
generally approaches bioavailability of IV route
Slower, constant rate of absorption
Only for non-irritating crugs
Inhalation
Fast rate of onset, Bioavailability of ~100% for systemic
Transdermal
Application of patch for systemic conditions, avoids first pass metabolism.
Prolonged drug levels achieved, potential for toxicity
Drug must be potent and able to permeate skin
Inhalation - local vs. systemic
For Local admin - aerosolized particles
Systemic- Molecules should be administered
Topical
Localized application to skin, minimal systemic absorption
Ion Trapping
At equilibrium, UNIONIZED concentration of drug is the SAME on both sides of the
membrane, but TOTAL concentration of drug is greater on side where ionization is
greater - drugs are trapped where they are predominantly ionized
• Acidic drugs are trapped in the more basic solutions
• Basic drugs are trapped in the more acidic solutions
Clinical significance of ion trapping
- alkalization of urine can trap weak acid aspirin in overdose situations
- greater potential to concentrate basic drugs in acidic breast milk (opioids)
Drug binding proteins in blood
Albumin binds acidic drugs
Alpha 1 acid glycoprotein binds basic drugs
Example of displacement drug-drug interaction
salicylates displace methotrexate (narrow TI cancer drug)
Phase I metabolism reactions
redox, hydrolysis
Activation of opioids
Codeine –> Morphine
Hydrocodone –> Hydromorphone
Phase II conjugations
Glucuronidation
N-Acetylation
Glutathione conjugation
Sulfate conjugation
Phenobarbital
Inducer; Pharmacokinetic tolerance
Phenytoin
Inducer
Carbamazepine
Inducer; pharmacokinetic tolerance
Rifampin
Inducer
Ethanol
inducer, induces CYP 2E1 to metabolize acetominophen to a hepatotoxic metabolite
St. John’s Wort
Inducer
Tobacco/ marijuana smoke (not nicotine)
Inducer
Cimetidine
Inhibitor
erythromycin/clarithromycin
Inhibitor
Ketoconazole/ azole antifungals
Inhibitor
Fluoxetine, other SSRI’s
Inhibitor
Grapefruit Juice
Inhibitor
HIV protease inhibitor
Inhibitor
Omeprazole
Inhibitor
Cyp 2D6
Metabolizes Codeine, genetic variation is important
N-Acetyl Transferase
Metabolizes Isoniazid (TB drug), genetic variation can lead to peripheral neuropathy
Chronic alcohol exposure
without liver damage, leads to induction of certain disease states.
p-glycoproteins
Transport drugs out of the body. In intestines they decrease absorption, and in kidneys they enhance excretion. There’s a potential for consequences of genetic variation
Glomerular Filtration
120 ml/min drug clearance
Any drug smaller than albumin will be filtered out
Only free drug (NOT protein bound) will be cleared
1-4 hr half life, affected by renal function
Active tubular secretion
120- 600 ml/min
Stronger acids and bases
Saturable transporters
plasma protein binding does not affect rate
Tubular reabsorption
Lipid soluble molecules are reabsorbed. A key purpose of metabolism is creating more water soluble metabolites that will not be reabsorbed.
Low extraction drug
Drug is not significantly metabolized in the liver and hepatic clearance does not contribute to total clearance
High extraction drug
Drug is significantly metabolized in the liver and hepatic clearance contributes significantly to total clearance
Treatments for methanol/ ethylene glycol poisoning
Ethanol (competitive inhibition of alcohol dehydrogenase)
fomepizole - direct AD inhibitor
Hemodialysis/gastric lavage
Sodium bicarb to correct acidosis
Risk factors for hepatocellular damage by acetaminophen
-enhanced CYP2E1 function
-Decreased hepatic glucothione
Both risk factors are more severe in heavy drinkers
Acetaminophen poisoning treatment
Activated charcoal and gastric lavage
N-Acetylcysteine (provides precursor for glucothione synthesis (IV or oral)
When to use hemodialysis
1) Toxin has small Vd
2) Toxin does not have any significant protein binding capacity
Hemoperfusion
Useful for high molecular weight drugs with poor water solubility
