DDPharm2

Question 1

Factors Influencing Drug Membrane Passage

Answer 1

Molecular size; Lipid solubility; Degree of ionization; Concentration gradient

Question 2

Passive Diffusion

Answer 2

Driven by concentration gradient. Either via aqueous diffusion or lipid diffusion

Question 3

Aqueous diffusion

Answer 3

Limited capacity. Channel size varies (generally for drugs of molecular weight

Question 4

Lipid diffusion

Answer 4

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.

Question 5

Carrier-Mediated Diffusion

Answer 5

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

Question 6

Endocytosis/Exocytosis

Answer 6

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.

Question 7

Bioavailability (extent of absorption)

Answer 7

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)

Question 8

F for IV administration

Answer 8

100% as no absorption step is involved. AUC for IV route is taken as the 100% value)

Question 9

F of oral administration? What does it depend on?

Answer 9

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

Question 10

How is rate of absorption estimated?

Answer 10

peak Cp or time to attain peak Cp plasma levels

Question 11

Rate of absorption comparison

Answer 11

IV = inhalation

Question 12

Bioequivalent

Answer 12

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)

Question 13

General factors affecting drug absorption

Answer 13

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)

Question 14

Routes of administration for systemic effects

Answer 14

Oral or Rectal (both enteral); sublingual; IV; IM; Subcutaneous; Inhalation (all parenteral)

Question 15

Onset of action/bioavailability for oral route

Answer 15

Relatively slow onset of action. Bioavailability varies widely (0-100%)

Question 16

Location of absorption in oral route

Answer 16

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).

Question 17

Gastric motility effects on absorption time

Answer 17

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

Question 18

Enteric coating effects

Answer 18

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

Question 19

How controlled-release drugs work

Answer 19

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.

Question 20

Pros/cons of controlled-release drugs

Answer 20

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.

Question 21

Onset of action/bioavailability for rectal route

Answer 21

Onset not rapid. Bioavailibity variable; but generally greater than oral

Question 22

Pros of rectal route

Answer 22

Useful when oral route precluded by vomiting; unconsciousness; post-GI surgery; presence of GI irritation; or uncooperative patient.

Question 23

Cons of rectal route

Answer 23

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.

Question 24

Onset of action/bioavailability for sublingual (buccal) route

Answer 24

Onset of action within minutes; bioavailability generally high

Question 25

Why sublingual works so well

Answer 25

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

Question 26

Types of drugs that work well for sublingual

Answer 26

Lipid soluble and relatively potent (

Question 27

Onset of action/bioavailability for IV route

Answer 27

Most rapid onset of action (

Question 28

Pros of IV

Answer 28

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

Question 29

Cons of IV

Answer 29

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

Question 30

Onset of action/bioavailability for IM route

Answer 30

Generally approaches bioavailability of IV route (? 100%); aqueous solutions absorbed rapidly with rapid onset (5-10 min)

Question 31

Pros of IM route

Answer 31

High bioavailability and rapid onset. Useful if drug is too irritating for subcutaneous admin.

Question 32

Cons of IM route

Answer 32

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

Question 33

Onset of action/bioavailability for subcutaneous route

Answer 33

Generally approaches bioavailability of IV route (? 100%); route often utilized to provide slower; constant rate of absorption

Question 34

Pros of subcutaneous

Answer 34

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)

Question 35

Limits of subcutaneous administration

Answer 35

Only for non-irritating drugs; volume of dose is limited

Question 36

Onset of action/bioavailability for inhalation route

Answer 36

Rate of onset (

Question 37

Which types of inhalants are used to have systemic effects?

Answer 37

gas; volatile liquids - molecules in gaseous state

Question 38

Pros of inhalation

Answer 38

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

Question 39

Transdermal route

Answer 39

Patch on skin for treatment of systemic conditions. 1st pass metabolism is avoided.

Question 40

Types of drugs for transdermal route

Answer 40

Drug must be potent (doses

Question 41

Cons of transdermal route

Answer 41

Prolonged drug levels can be achieved - potential for unexpected drug accumulation and toxicity

Question 42

Routes for local effects

Answer 42

Inhalation or topical

Question 43

Inhalants used for local effects of inhalation

Answer 43

aerosol/microparticles - molecules in suspension

Question 44

How does particle size determine effects of inhalation?

Answer 44

Effects dependent on particle size: 10 uM means particles deposited in oropharynx (side effects)

Question 45

Locations of topical application

Answer 45

Skin or mucous membranes (vaginal/conjunctival/nasal/throat)

Question 46

When does systemic absorption of topical application increase?

Answer 46

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

Question 47

Loading dose

Answer 47

1st dose