DDPharm2 Flashcards
Factors Influencing Drug Membrane Passage
Molecular size; Lipid solubility; Degree of ionization; Concentration gradient
Passive Diffusion
Driven by concentration gradient. Either via aqueous diffusion or lipid diffusion
Aqueous diffusion
Limited capacity. Channel size varies (generally for drugs of molecular weight
Lipid diffusion
Favored if drug has high lipid:water partition coefficient. Often pH dependent. Unionized moiety crosses membrane down concentration gradient. Most important mechanism for majority of drugs with molecular weights of 500-800.
Carrier-Mediated Diffusion
Done by specialized transporters that regulate entry and exit of important physiologic molecules (sugars/amino acids/neurotransmitters) but some also transport foreign chemicals (xenobiotics) including drugs with structural similarity
Endocytosis/Exocytosis
Minor importance to drug passage. Endo: Substance bound to receptor at cell surface; engulfed by membrane; taken into cell in newly formed vesicle; then released (vitamin B12 and iron). Exo: Secretion. Many neurotransmitters released from vesicles into extracellular space upon neuronal activation.
Bioavailability (extent of absorption)
F or f[%] for fraction bioavailable. Defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route. It is determined by comparing the AUC (area under the curve from Cp vs time) obtained following a single dose of drug given by any route (most commonly the oral route) to the AUC obtained following a single dose by the IV route. F = (AUCroute)/(AUCiv)
F for IV administration
100% as no absorption step is involved. AUC for IV route is taken as the 100% value)
F of oral administration? What does it depend on?
F varies from 100% to 0. Depends on: survival of drug in GI; ability to cross GI membranes (drug lipid solubility/size/% in un-ionized state); first-pass effect (efficiency of drug metabolism by the gut wall or in liver). Note: Pt compliance is also a factor here
How is rate of absorption estimated?
peak Cp or time to attain peak Cp plasma levels
Rate of absorption comparison
IV = inhalation
Bioequivalent
Drugs are considered bioequivalent if the 90% confidence interval of the mean AUC (bioavailability) and the mean Cmax (rate) of the generic product (T-test) is within 80-125% of the brand product (R)
General factors affecting drug absorption
Drug solubility in biologic fluids (must be partly hydrophilic but also lipophilic enough to cross membranes). Rate of dissolution. Concentration of drug at site of administration. Circulation at site of absorption (can be altered by disease state or exercise). Area of absorbing surface (stomach vs intestine vs lungs)
Routes of administration for systemic effects
Oral or Rectal (both enteral); sublingual; IV; IM; Subcutaneous; Inhalation (all parenteral)
Onset of action/bioavailability for oral route
Relatively slow onset of action. Bioavailability varies widely (0-100%)
Location of absorption in oral route
Either in stomach or upper intestine. One might predict that weak acid drugs would be absorbed better from the stomach than intestine and vice versa for weak bases (ionized vs. un-ionized states). BUT b/c of extremely large surface area of the intestine relative to the stomach; the rate of absorption of a drug from the intestine will be greater than that from the stomach. Even for drugs predominantly ionized in the intestine and largely unionized in the stomach (weak acids).
Gastric motility effects on absorption time
Increased GI motility generally increases speed of emptying & rapidity of absorption (b/c drug reaches the small intestine faster). Food delays absorption of most drugs by delaying gastric emptying
Enteric coating effects
Drugs that cause GI irritation or drugs destroyed by gastric secretions can be administered with an enteric coating that prevents dissolution until the more basic intestine is reached
How controlled-release drugs work
Rate of drug absorption is slowed by slowing rate of product dissolution allowing a slower; sustained; and uniform absorption of drug lasting 8 hours or longer.
Pros/cons of controlled-release drugs
Pros: Decrease frequency of administration (increase compliance); maintenance of therapeutic effect overnight; and elimination of peaks (decreased incidence/intensity of undesired effects) and nontherapeutic troughs in plasma levels. Cons: greater interpatient variability in systemic levels obtained and dosage form failure resulting in dose-dumping and drug toxicity.
Onset of action/bioavailability for rectal route
Onset not rapid. Bioavailibity variable; but generally greater than oral
Pros of rectal route
Useful when oral route precluded by vomiting; unconsciousness; post-GI surgery; presence of GI irritation; or uncooperative patient.
Cons of rectal route
Pt acceptance is not high. Approximately 50% of dose will bypass the liver (first pass metabolism is less than for the oral route). Absorption is irregular and incomplete; solutions absorbed more reliably than suppositories in children.
Onset of action/bioavailability for sublingual (buccal) route
Onset of action within minutes; bioavailability generally high
Why sublingual works so well
After absorption from oral mucosa; venous drainage from mouth is to the superior vena cava protecting drug from rapid hepatic first pass metabolism plus faster onset of action
Types of drugs that work well for sublingual
Lipid soluble and relatively potent (
Onset of action/bioavailability for IV route
Most rapid onset of action (
Pros of IV
Most direct route of administration; factors relevant to absorption (membrane passage) are circumvented. Accuracy and immediacy of drug delivery exceeds all other routes. Often used for drugs with narrow therapeutic index
Cons of IV
Bypasses absorption barriers (can result in introduction of infectious agents). Most hazardous route: easy to reach toxic levels rapidly and reversal of effect often difficult
Onset of action/bioavailability for IM route
Generally approaches bioavailability of IV route (? 100%); aqueous solutions absorbed rapidly with rapid onset (5-10 min)
Pros of IM route
High bioavailability and rapid onset. Useful if drug is too irritating for subcutaneous admin.
Cons of IM route
Onset/absorption can be effected by blood flow/degree of muscle activity at site of injection. Absorption may be erratic and incomplete if drug solubility is limited (e.g.; diazepam). Pain; tissue necrosis (if high pH); and microbial contamination
Onset of action/bioavailability for subcutaneous route
Generally approaches bioavailability of IV route (? 100%); route often utilized to provide slower; constant rate of absorption
Pros of subcutaneous
Period of drug absorption can be altered intentionally as with insulin preparations (varying particle size; protein complexation; and pH); local anesthetics (addition of vasoconstrictor) or contraceptives (pellet implantation under skin)
Limits of subcutaneous administration
Only for non-irritating drugs; volume of dose is limited
Onset of action/bioavailability for inhalation route
Rate of onset (
Which types of inhalants are used to have systemic effects?
gas; volatile liquids - molecules in gaseous state
Pros of inhalation
Route utilized for rapid onset of systemic drug effects (general anesthetics; nicotine; crack cocaine; marijuana). Rapid rate of absorption due to large surface area and high blood flow in pulmonary tissue
Transdermal route
Patch on skin for treatment of systemic conditions. 1st pass metabolism is avoided.
Types of drugs for transdermal route
Drug must be potent (doses
Cons of transdermal route
Prolonged drug levels can be achieved - potential for unexpected drug accumulation and toxicity
Routes for local effects
Inhalation or topical
Inhalants used for local effects of inhalation
aerosol/microparticles - molecules in suspension
How does particle size determine effects of inhalation?
Effects dependent on particle size: 10 uM means particles deposited in oropharynx (side effects)
Locations of topical application
Skin or mucous membranes (vaginal/conjunctival/nasal/throat)
When does systemic absorption of topical application increase?
Application over large area; to denuded area; use of occlusive dressings; or with highly lipid soluble drugs. Greater potential for systemic availability in children due to greater ratio of body surface area to weight
Loading dose
1st dose
