Pharmaceutics Exam 2

pH effect on gastric emptying

low pH will slow it down

how do you measure rate of absorption (Ka)

Tmax and Cmax

how do you measure extent of absorption (bioavailability (f))

AUC and Cmax

Noyes Whitney equation measures...

rate of dissolution and is responsible for the sink condition

sink condition

Concentration of drug in bulk solution is always significantly lower than the saturated solubility

high solubility is considered

soluble in 250mL or less

high permeability is considered

bioavailability greater than 85%

class I drugs

high permeability, high solubility

class III drugs

-low permeability, high solubility
-small partition coef (k)

class II drugs

-low solubility, high permeability
-low [drug] in lumen/ gut (Cd) causing smaller flux (J)

Ficks law measures

drug flux

class IV drugs

-low permeability, low solubility
-low Cd and K

glynase

glyburide - micronized formulation to increase SA and improve solubility (class II drug)

purpose of micronized forms

small particles give large surface area to improve dissolution and solubility

Acetazolamide

class IV drug

estrogen - rate of passive diffusion permeability

fast

acetic acid at a pH1.5 and glycerol - rate of passive diffusion permeability

slow

sucrose and acetic acid at a pH7 - rate of passive diffusion permeability

does not pass through the membrane

drugs that cause esophageal irritation

antibiotics, NSAIDs, bisphosphonates, chemo regimens, pills with poor texture or large in size

gastric emptying

materials from the stomach are transported into the small intestine through the pylorus

digestive phase includes:

cephalic and gastric phase

cephalic phase definition

in preparation for a meal the stomach comes out of the interdigestive phase and begins low level motor and secretory activity

gastric phase definition

when food arrives in the stomach and gastric motor and secretory activity are fully turned on

which dosage form is affected most by gastric emptying?

enteric coated and delayed release
-should be taken before meals
-sprinkled dosage forms are not affected by gastric emptying

migrating motor complex (MMC)

occurs between meals
· 1. No activity at first with rare contractions (45-60 min)
· 2. Intermittent contraction and increasing intensity (30 min)
· 3. Intense and regular contractions keep pylorus open; known as "housekeeper waves" (5-15 min)
· 4. Short period of transition before phase 1 starts again

pH during fasting and fed state

fasting: pH between 1-3
fed: pH between 2-5 due to food neutralization

the gastric pH affect the dissolution rate of which drugs

weak bases

small intestine

contains large surface area with high blood flow which improves permeability, dissolution and absorption of drugs
- housekeeper wave/ MMC occurs every 2 hours unless fed

duodenum

bile acids and enzymes released (most active uptake occurs here)

jejunum

most passive absorption of nutrients occurs here

illeum

bile acids absorbed before emptying contents into ileal-cecal region

colon

-high water absorption/ neutral pH
-rich in bacteria and bacterial enzymes

Azulfidine (Azo)

-sulfasalazine uses bacteria in the colon to convert prodrug into active drug (mesalamine)
-creates localized effect

Azulfidine EN-tabs

delayed release and enteric coated to protect against upset stomach

GI transit times

o Stomach 0-3 h
o Small intestine 2-5 h
o Large intestine up to 18 h

enterohepatic recycling

biliary excretion of the drug and intestinal absorption
- hepatic conjugation and deconjugation

passive diffusion

-follows first order kinetics and Ficks's law (flux)
-high solubility=large Cd= high flux
-concentration gradient driven
-drugs must be non ionized
-alcohol, urea

convective transport

uses small pores to allow drug to pass through
-small molecules depending on shape and size

active transport

o Requires ATP to pump against concentration gradient
o Saturation of transport and competitive inhibition can occur
o Examples: iron, levothyroxine, methotrexate,

facilitated transport

o Uses carrier transporters to go from high to low concentrations
o Carriers can be saturated or inhibited
o Examples: levodopa, OCT (metformin, trimethoprim, morphine, cimetidine, ranitidine) OAT (valacyclovir, fexofenadine, statins), dipeptide transporters (b-lactams, ace inhibitors)

transcytosis (endocytosis/ pinocytosis)

-fairly uncommon
-fats glycerin, starch, vitamins
-Examples: auryxia (ferric citrate) and antibiotics (colistimethate and polymyxin B)
-fats, glycerin, starch, vitamins

efflux transport

o Pumps drugs out of cell
o Examples: taxols, steroids, immunosuppressants, antibiotics

gap junctions

allow small, hydrophilic molecules to pass

which drugs are more prone to efflux transport

hydrophobic drugs

what affects the degree of passive absorption?

how ionized the drug or molecule is

rifampicin metabolism

undergoes enterohepatic circulation via intestinal microflora

if the absorption rate is slowed due to food, what happens to tmax, Cmax, and AUC?

-tmax delayed
-Cmax dec
-AUC may not be affected

if food causes decreased absorption, what happens to tmax, Cmax, and AUC?

AUC is dec
Cmax dec
tmax may not be affected

if food causes increased absorption, what happens to tmax, Cmax, and AUC?

-AUC inc
-Cmax incr
-tmax may not be affected

examples of drugs that are instable in gastric fluids

azithromycin, erythromycin, isoniazid
-gastric residence time increased which increased acid degradation

drug chelation

o Drug food interactions form insoluble complex (often with dietary supplements like Ca, Fe)
o Examples: bisphosphonates, estramustine, -floxacins, penicillin, tetracycline

effect of eating fatty foods while taking lipophilic drug

more bile will be released and will increase absorption of drug

food inhibiting CYP enzymes

o causing higher drug concentrations (atorvastatin and grapefruit juice, ketoconazole, clarithromycin)
o Increases blood flow and bioavailability
o Slows gastric emptying and increases dissolution rate

when are delayed-release/enteric-coated tablets or capsules best taken?

Before meals
- the capsules may be sprinkled on soft foods and should be consumed immediately after opening

keratinized parts of the mouth

· dorsal tongue, gingiva, hard palate

non keratinized parts of the mouth

· cheeks, inner lip, ventral tongue, floor of mouth, soft palate

is drug absorption faster from keratinized or non keratinized region?

non keratinzed because it is easier for the drug to cross and penetrate tissue

saliva composition

o 99.5% water
o Remaining: electrolytes, buffers, mucins, digestive enzymes, statherins and histatins

oral transmucosal drug delivery (OTDD)

o Applied to oral mucosa / mucus membrane for rapid absorption and quick onset of action
o Saliva can effect drug release via dilution/ buffering, salivary washout, and via digestive enzymes
o Disadvantage: high doses can NOT be administered due to small surface area for absorption and limited residence time

this OTDD provides rapid onset of action

sublingual

this OTDD provides sustained release

mucoadhesives

Transmucosal absorption is rapid due to:

-good permeability of the oral epithelium
-paracellular and transcellular transport (passive diffusion)
-oral mucosa is well vascularized (blood supply)

Drugs that are suitable for an OTDD are:

-low dose, non-irritating
-soluble and stable in saliva
-preferably lipophilic (good permeability)

Nitrostat (nitroglycerin) indication

sublingual for angina

ergotamine indiacation

sublingual for migraines

Buccal vs Sublingual absorption

buccal has slower absorption since the mucosa is thicker and less permeable

significance of sublingual dosage form

-under the tongue is highly vascular and thin mucosa so fast absorption and increased AUC

Belbuca (buprenorphine) indication

buccal film for opioid analgesic

buprenorphine buccal film vs sublingual tablet

film= opioid analgesic
sublingual= opioid dependency

type I mucoadhesive

drug loaded bioadhesive layer; releases in all directions

type II mucoadhesive

impermeable backing layer so the majority released to mucosa (most common)

Suboxone (buprenorphine/naloxone) indication

mucoadhesive sublingual film for buccal use of sublingual

Sitavig (acyclovir)

mucoadhesive buccal tablet

Oravig (miconazole)

mucoadhesive buccal tablet

Fentora (Fentanyl citrate)

-mucoadhesive buccal tablet
-salt form makes more soluble
-65% bioavailable

clotrimazole lozenge

local effect to mouth and throat

Fentanyl citrate lozenge (OTFC)

-systemic effect for pain relief
-salt form makes more soluble
-50% bioavailability

Nitrolingual (nitroglycerin)

translingual solution pump spray

Subsys (Fentanyl)

-sublingual spray
-free base
-76% bioavailable

medicated chewing gum (nicotine)

chewing releases drug and mostly absorbed from buccal cavity

BCS class of naproxen

class II (good permeability poor solubility)

does naproxen or naproxen sodium show a pH dependent water solubility

naproxen
(the salt is already ionized)

aleve

salt form of naproxen provides faster onset of action due to improved solubility

food effect on naproxen

food increases the pH of the stomach and therefore improves the solubility by generating ionized form of drug to make more water soluble

why does naprelan show no significant effect from food

it is an ER formulation achieved through coated microbeads that will be small enough to leave the stomach even during the fed phase so there is no delay in gastric emptying

benefits of naprelan

once a day dosing and ER and SR reduce GI irritation

why shouldn't you take antacids with EC-naprosyn

it can raise the pH and cause the dosage form to disintegrate in the stomach causing and immediate effect rather than delayed effect

extent of absorption is measured by

AUC

which oral dosage forms are most affected by food

enteric coated or delayed release because it will delay gastric emptying

A patient keeps an OTFC lozenge in the mouth and tries not to swallow the saliva would cause

An increased AUC
and A faster absorption rate (tmax)

a patient chews and swallows a OTFC instead of letting it dissolve in the mouth. how does this affect bioavailability?

decreases

why do we want drugs that show linear PK

easier for dose adjustments / titrations

what oral delivery product is most likely to show an application site adverse effect

mucoadhesives such as fentora

Fentora: OraVescent® technology

Citric acid help shift pH down so it can ionize and dissolve (improve solubility)
Sodium bicarbonate shifts pH up by neutralizing acid to favor non ionized form of drug and increase permeability

why are mesalamine products preferred over sulfasalazine

-sulfa is a prodrug that contains active mesalamine and another agent that causes ADE

mesalamine site of action

-local in the GI at site of disease state

why wouldn't an IR mesalamine product work

the drug is highly water soluble and wouldn't be able to reach targeted disease site

Canasa rectal suppository

will melt in the rectum since it contains hard fats the base
- indication ulcerative proctitis/distal ulcerative colitis

carbomer 934P and xanthan gum

suspending / thickening agent

edetate disodium (EDTA)

chelating agent