Question | Answer |
Modified Noyes-Whitney Equation | dC/dt = kS (Csat-Ct)
dissolution rate equation |
crystalline form | substances with definite identifiable shapes and it is chemically stable |
amorphous form | particle without definite shape and it is more soluble than crystalline but less stable and may have different biological activity |
dissolution | the process by which particle dissolve; before a drug can go thru absorption it must go thru this |
diffusion layer | it is a saturated drug layer around a particle when the drug molecules first enter into solution layer;
the molecules from this layer will enter into solution and get absorbed thru body membrane
then the layer is replenished from the particle |
absorption | process by which UNCHANGED drug moves from site of administration to site of measurement
thru passive and carrier mediated transfer processes and the drug must be in soluble in solution and no in particle form |
distribution | a reversible transfer of drug from and to site of measurement |
metabolism | conversion of a drug into another chemical entity by a biochemical process |
excretion | irreversible loss of chemically UNCHANGED drug from the body |
salt form of drugs | their dissolution rate is higher than its parent acid or base drug form |
biopharmaceutics | the study of relationship b/w some of the physical & chemical properties of drug & its dosage form & biological effects observed
important for bioavailability
purpose: optimize biological response of drug product |
disposition | all processes that occur subsequent to absorption of the drug, so include DISTRIBUTION & ELIMINATION |
elimination | the loss of drug from the site of measurement include both METABOLISM & EXCRETION, sites include: liver (metabolism), kidney (urine), intestine (gut, feces), skin |
First Pass Effect | the loss of drug as it passes thru sites of elimination for the 1st time during the absorption process
these sites include: liver, intestine, skin, NOT KIDNEY |
intravascular | placement of drug directly into blood
IV or IA
avoid first pass effect |
extravascular | placement of drug at a site that requires an absorption step to enter the blood stream
PO, PR, SL, IM, SQ, etc |
possible routes of drug administration | oral
Parenteral: IV, IM, IA, SC, etc
respiratory & intranasal
transdermal/topical
ocular
rectal
vaginal,
sublingual
aural
conjunctival |
therapeutic range | the range b/w minimum effective dose and maximum safety dose
the narrower it is the more dangerous the drug |
physiological factors affecting oral absorption | pH of GI fluid (vary b/w ppl)
perfusion
permeability
gastric emptying rate (vary by food)
surface area for absorption
metabolism (hepatic & extrahepatic) |
different physiologic pH values | gastric: fasted (<2-3); fed (4-5)
Intestinal: varies regionally (5-7)
colon: (7-7.5) |
Factors that determine a Dosage Regiment | the drug's toxicity & activity
ADME
patient's health factor
therapy's ease factor
others: DDI, tolerance etc |
organic acid drugs | those containing an ionizable carboxyl group (R-COOH) |
organic base drugs | those containing an ionizable amino group ( R-NH2, R2-NH, R3-N) |
organic neutral drugs | non-ionizable drugs |
large drug molecule | drugs that are polypeptide and proteins |
passive transfer processes | include passive diffusion and filtration |
carrier mediated transfer processes | include active transport, receptor mediated endocytosis |
passive diffusion | required lipid solubility (more nonpolar than polar group)
ionization (organic acids/bases) increase polarity
requires concentration gradient
only nonionized form of a drug can diffuse across the lipid membrane |
filtration | depends on molecular size
requires concentration gradient
use channel protein |
active transport | 1) discrete transporter proteins, finite number, therefore saturable
2)structurally selective, competitive inhibition
3)require energy; can go against concentration gradient |
receptor mediated endocytosis | 1) involves membrane receptor
2) transport large polypeptides & proteins
3) likely to become increasingly important with the use of bio engineered proteins as drugs
4) forms an endosome around molecule to be transfer |
acid drugs | tend to be concentrate on the high pH (basic) side of the membrane |
basic drugs | tend to concentrate on the low pH side of the membrane |
pKa | the ionization tendency of the drug but it does not tell if the drug is acidic or basic
pKa is the pH at which the drug is half ionized
for each pH unit away from pKa, the ratio increases 10 fold
pH has no effect on nonionizable drugs |
alimentary tract route of administration | 1) oral mucosa - rapid absorption, small surface area, used for potent drug to relieve anginal pain; avoid immediate exposure to liver
2) rectal mucosa - suppository for nauseated patients; 50% pass liver immediately |
skin route administration | few drugs can penetrate intact skin
oily vehicle to enhance penetration
CR topical patches |
drug distribution | drug concentration at the site of action determines the pharmacologic effect
can be measured by examining blood or urine |
apparent volume of distribution (Vd) | volume the drug appears to be distributed in, at the same concentration as in blood:
Vd = (amount drug in the body) / (concentration of drugs in the blood)
show where the drug is, available for therapeutic manipulation
large Vd = longer drug stays in b |
distribution of drugs within the blood | drug can be free in solution or bound to plasma proteins
only free drugs can cross membrane to enter other tissues
acidic drugs bind to albumin
basic drugs bind to α1-acid glycoprotein
only finite # of protein binding sites = saturation and competitio |
distribution of drugs within the tissues | lipophilic drugs are highly bounded, and tend to accumulate in adipose tissue
basic drugs tend to move into cell due to lower pH in cell; they can accumulate in acidic intracellular organelles
highly vascularized tissues tend to equilibrate [drug] fir |
blood brain barrier | tight junctions b/w endothelial cells of brain capillaries
1)passive diffusion - highly lipid soluble & polar drugs
2) active transport - for amino acid type drugs
3) endocytosis - engineered chimeric proteins |
placental barrier | all modes of transfer shown, but passive diffusion most important
no protective barrier |
biotransformation (drug metabolism) | structural alternation of the drug molecue by action of various enzymes and general facilitates excretion of lipid soluble drugs by making them more water soluble
it is biphasic metabolism (2 steps)
oxidation and conjugation |
Phase I biotransformation | chemical modification of the drug & results in:
1)inactivation - detoxification
2)conversion of active drug to active drug metabolite
3) conversion of inactive drug to active - prodrug |
Phase II biotransformation | add conjugating group to drug molecule which almost always results in
1) pharmacological inactive metabolites
2) highly ionized, polar, water soluble metabolites
exception: acetylation yields less soluble metabolites |
presystemic/first-pass hepatic elimination | when hepatic clearance sufficiently high enough to remove most of the drug from the blood passing thru the liver
can be measure by extraction ratio:
(Cin - Cout)/Cin
hepatic clearance depends on activity of drug metabolizing enzymes & hepatic blood f |
Liver microsomal metabolism | microsomes are isolate smooth ER
Smooth ER contains two important drug metabolizing enzyme systems:
1) cytochrome P-450 complex
2)UDP-glucuronyl transferase |
Cytochrome P-450 (CYP) Complex | iron-heme monoxygenase enzyme and NADPH-CYP oxidoreductase; needs molecular O2 and NADPH
a lot of CYP ISOENZYMES
wide range of substrates; each isoenzyme oxidize particular structural types
exodogenous and endogenous metabolism |
UDP-glucuronyl transferase | forms glucuronic acid conjugates during drug metabolism |
nonmicrosomal enzymes | found in the liver, certain tissues, & plasma
responsible for drug metabolism
1) phenolsulfotransferases - form sulfate conjugates
2) alcohol dehydrogenase
3) mitochondrial monoamines oxidase (MAO)
4) esterase
5) amidases |
variability in biotransformation in different ppl | 1) genetic differences in CYP isoenzymes; test with debrisoquin polymorphism test or gene chip tests
2) age differences: newborns are deficient in glucuronidation ability, elder's rate differ due to diff rate of deterioration
3)diff among individuals |
variability in biotransformation among individuals | 1)sex: females metabolize many drugs slower
2) pathology: liver disease
3) species differences
4) enzyme induction/inhibition due to other drug usage
5) enantiomers of drugs: Nexium is single enantiomer of Prilosec |
cimetidine | anti-ulcer
inhibits the metabolism of warfarin |
certain antifungal and antibiotics | inhibit CYP3A4 which oxidizes terfenadine leading to excessive blood levels and arrhythmias |
Fluoxetine (Prozac) | inhibitor of microsomal oxiidation (CYP2D6) |
grapefruit juice | inhibits metabolism of cyclosporin |
renal excretion of drugs | 1)Glomerular iltration: only unbound (free) drug
2)Proximal tubular transport: secrete into urine; two systems, one for acid & base; competition (probenecid & penicillin to retain penicillin in body)
3)Distal tubule: reabsorption; use pH to vary results |
Biliary Excretion of drugs | 1)active transport of polar molecules, esp anionic (+ & -) into bile
2)the metabolites tend to be large molecules like glucuronicacid conjugates
3)enterohepatic recirculation |
enterohepatic recirculation | tends to prolong duration of drug;
can be interrupted by diarrhea
glucuronide conjugate reenter intestine with bile and turn back to free drug by bacterial glucuronidase |
treatment of drug overdose | 1)supportive treatment: treat patient not poison
2)antidotal: available for only few drugs
3)alter drug dispotion: slow absorptions
4)alter distribution: little can be done
5)alter biotransformation: slow down toxic metabolite
6)inc urine: diuresis & |
powder | intimate mixtures of dry, finely divdided drugs and/or chemicals that may be intended (oral powders) for internal or external (topical powders) use
as a dosage form it is a mixture of powdered drugs and excipients (this dosage form has limited usage) |
why powders | API & excipient are in powder form
topical powder or sterile powder in vial
starting material for solid dosage (tap & cap), liquid dosage (reconstituion), semisolid dosage (oint & cream) |
characterization for powder | morphology
purity
solubility
stability
particle size & distribution
uniformity
compatibility in blends |
common issues with powders | dissolution rate
suspension
uniform distribution
inhalation
poor flow
appearnace |
characterize powder particle size | sieve analysis: sieve # or mesh size 8 is very coarse, 80 is very fine
granules are coarse to very coarse
microscopy, sedimentation rate, light scattering, cascade impact (for inhalation |
How to reduce particle size | mortar & pestle, levigation, mills, pulverizer |
how to blend powers | blending: mixing powders to uniform by:
spatulation, trituration, sifting, tumbling, geometric dilution |
medicated powder | oral powder for reconstitution: for ease to swallow & large dose, good for 2weeks, need to mask taste
dry powder inhalation
sterile dry powder: mix w/water for injection
vaginal douche: mix with water, "external use only" |
medicated powder application | p.o. aerosol, suspension, injection, external usage |
dusting powder | powder in topical application
common diluents: starch & talc
sifter-top shaker container not a tight seal
not for volatile/sensitive to moisture powder
particles smaller than 45um minimize mechanical irritation (pass it thru 325 mesh sieve) |
aerosols | powder for inhalation
>5um, 85% stay in upper respiratory
1-5um, 90% stay in alveolae
<0.5um, exhale out |
bulk powder, douche powders, topical powder, Brewer's yeast powder | bulk powder: non potent powders
douche powders: wash w/water, for vaginal use
topical powder: anti-infective, antifungal
Brewer's yeast powder: B complex vitmins |
divided powder | they are for unit dose or each use
pack in powder paper and dispense in powder box as charts
use waxed/glassine paper for moisture/air sensitive powder(volatile) |
granules | they are prepared agglomerates of powders; 4-12 sieve size; larger & more porous than powder; hydrophilic in nature due to pores
starting material for tab & cap & suspension |
granulation | size enlargement process |
why granules | 1)goodflow 2)compressibility (use in cap & better bind when press) 3)uniformity (granules=API+excipient+binder) 4)for high-speed equipments 5)more stable in moisture & O2 6)less likely to cake in container 7)dissolution not affected/improved due to pores |
granule's main composition | active ingredient, binder, diluent, flavor, excipient, color |
wet granulation | use high shear granulator or fluid bed granulation
1)moist and mix powder to form lumps
2)wet lumps pass thru sieve
3)wet granules dry in oven/fluid bed dryer
4)dry granules pass thru sieve |
Fluid Bed Granulation | suspend power in air to mix and moisten. then dry in hot suspending air
high inlet air temp=rapid evaporation of binder,small,griable granules
low inlet air temp=longer drying,larger,denser,strong granules
high feel rate=slow drying,large,dense,stron |
dry granulation | for drugs that are sensitive to water or heat
roller compactor or slugging roller compactor method |
dry granulation: slugging | older process and slow
mix with dry binder, compress into large cruge tab (slugs), mill to form granules |
dry granulation: compaction | powder blend compressed b/w roller to form a cake (ribbon), cake milled to granules |