Explanation of why a certain drug, taken as a tablet, did not reach adequate blood levels in the patient

(4)

1. The drug was a substrate for an enzyme found in hepatocytes

2. The patient had a condition that caused GI hypermotility

3. The drug did not dissolve completely until it reached the colon

4. The drug exhibits significant degradation in acidic conditions

Enterohepatic Cycling

[image]

TRUE or FALSE

1. The clumping of particles tends to slow down their dissolution

2. Small particles tend to dissolve faster than large particles

3. Taking medication with a glassful of water tends to slow down drug dissolution in the body

4. Agitation can decrease the stagnant boundary layer and speed up dissolution

5. Increasing the dissolution medium viscosity tends to decrease dissolution rate

1.true

2.true

3.false

4.true

5.true

Phosphate ester vs Phosphate salt

Functional group not susceptible to hydrolysis

a. lactone

b.amide

c. lactam

d.tertiary amine

e.ester

1. demonstr safety and efficacy

2. demonstr process control and validation

Time

Drug discovery/preclinical=

Clinical=

FDA Review/lrg scale mfg=

1. 3-6 yrs

2. 6-7 yrs

3. 0.5-2 yrs

IND is___________

CLinical trials are studies in_______________

1. investigational new drug application

2. Human studies

Target

(usually macromolecule,protein,nucleic acid)

Receptor identified

molecules/structures linked to a particular disease

enzymes, receptors, ion channels, membrane transporters, DNA/RNA and ribosome, Targets of monoclonal antibodies, physicochemical mechanisms(iv mannitol osmotic agent,  topical zinc oxide)

prototype chemical has desired bio/pharm activity

may need chemical mod

Candidate

[image]

Pharmacodynamics

[image]

biochemical/physiological effects of drugs

mech of action

preformulation

[image]

physical / chemical drug properties investigated

[ADME depends on physicochemical properties]

1. protect rights / safety of human subjects

2. ensure investigate plan is sound

[investigation=30 days by FDA(drug cannot be given to humans at this time]

[animal studies/ mfg info]

1. saftey/dosage, also ME studies, healthy 20-100,1.5 yrs, 67%rx

2. effectiveness/short safety, 100-500 sufferers 2 years, 45%rx

3. 1000-5000, 3.5 yrs, 5-10%rx

The NDA consists of [3 things] (AID)

1. application=presents pre/clin data,label proposal, 100,000 pages ,10 months to review

2.inspection= facilities, cGMP good mfg

3. decision= complete response letter(deficiencies,actions needed, not ready rx)

continued monitroing (rph.md,post studies) [fda's medwatch]

adr reporting

annual reports

rare disease / condition fewer than 20,000 people in U.S

money for rx cant be recovered by sales in U.S

pt w/ life threatening/ severelly debilitating disease where no alt exists

facilitates get rx to pt

[AIDS, Alzheimers, advanced Parkinsons]

for expanded access 

filed during phase 1 or 2 to allow tx of the desperately ill

1. abbreviated NDA

2. supplemental NDA

1. NDA used for generic rx approval

2. Supp NDA= label change, method of synth, formulation, etc...new indication

Fast track= serious cond,nonclin/clin data pot to fill unmet med need[reduced dis progress/improved compliance]

Breakthrough Ther= ser cond/ prelim clin evid. indicates drug may demonstarte substantial improvementover whats avail

Accelerated approval= ser cond. fills unmet med need to be approved based on a surrogate endpoint

Priority review=sig improv in safety and fx of Tx, Dx, prevention of serious cond compared to standard app

shortened from 10 to 6 mths

can be requested in additon to one of other expeditions

FDA responds w/ in 60 days

Request made by company, during IND/clinical phase

intravenous[in veins injection]

100% bioavailable

oral, buccal, rectal IM, etc

[image]

incomplete dissolution

incomplete absorption through epithelia (efflux)

bypassing absorptive area (GI hypermotility)

acid degradation

presystemic metabolism(enterocytes & hepatocytes)

conc of rx in no polar org fase compared to polar aqeuos

-useful predicting passive diff across membrane lipid

-non ionized less polar greater membrane passing

1. multiple layers-eyeballs, skin

2. single layers-epithelium

3. lipid bilayers in cells

drugs mostly cross membrane through _________diffusion

through fenestrated cappilary endothelia (kidney glomerulus)

passive (move down conc gradient)

[image]

Active transport mechs

use drug transprtrs [agnst conc grad]

facilitated diff= with conc grad

1. play role in resistance(efflux transprtrs in cancer)

2. play roles in adverse effects(uptake trnsprtrs cause drug accumulation)

3. affects ADME [renal,hepatic,epithelial,endothelia,brain&placenta]

eukaryotes

for efflux

active trnsprtrs/use ATP for E

EX: p-glycoprotein, MRP,breast =cncer res protien

some are efflux, some are uptake

includes facilitated transprtrs and ion coupled active transprtrs

EX: organci anion transporting polypetides,OATs, OCTs

1. calcium binding to drugs in GI tract

2. Bind albumin

3. free unbound drug can,.....

1. limits absorpton OF:tetracycline, levofloxacin, alendronate

2. binds acidic and neutral rxs

3. cross cell membrane, interact w/ othr molecules,renally excreted, bloodstrmto cappilaries to intersttial fluid[protein too big to pass through glomerulus]

rx administrd as aqueous solution are ready to be absorbed

[crystals must dissolve 1st]

1st in enterocytes(intestinal epithelium)

2nd in hepatocytes after being transported via hepatic portal vein

[happens on 1st pass b4 reaching systemic circulation]

True or false

Skin and lungs can exhibit 1st pass effect

TRUE 

but to much lesser effect

faster to well profused organs [liver, kidney, brain]

slow to [muscle,fat,skin]

after cappilary beds traverse to interstitial fluid

only free drug can leave vasculature

protein bound drugs leave to maintain ewuilibrium(binding to plasma proteins is reversible)

1. endothelial cells of capilaries supplying brain and spine held by tight junc

-fat=anesthetics can accumulate in adipose

- placenta

glomerular filtration

primarily to transport rx into more hydrophylic forms/excretable

pathway phase 1/2

1=add or uncover polar group

2=conjugationrxn.covalent conjugat of polar group on parent compound

liver

[extrahepatic excretion sites = intestinal epithelieal & kidneys, lugns, skin, placenta]

1. most rx filtered through fenstrated caps of glomeruli wether or not polar or ionized

2. protein bound drugs cant filter bc proteins too large too pass fenestration

3.polar/ionized drugs stay in filtrate and leave in urine

actively secrete rx into bile

[somre rx excreted in feces some reabsorbed]

water solubility imp for....

lipid solubility for..........

liberation of rx

for rx to traverse lipid

repeating arrangement within solid

1. diff arrngments posible w/in solid

amorphous

[image]

bioavailability

melting point

percent drug reach systemic circ

function of molec strnghth

metastable=unstable but long lived state of sytem [more soluble than stable polymorphs]

Hydrates vs anhydrous [[dissolution differs]

anhydrous better dissolutions

arranging in layers

causes uniformity issues bc dif particles have dif flow properties

mixing / pouring

speed of processingduring mfg

settling,handling

Are all affected by

Hydrophylic substituents

-NH3 =

-OH = 

-COO- = 

-CHO = 

-NH2 = 

-COOH =

-NH3 = very hydrophilic

-OH = Very hydrophilic

-COO- = Very hydrophylic

-CHO = Hydrophilic

-NH2 = hydrophilic

-COOH = Slightly Hydrophylic

5mcg/ml

steroid ring structure

Henderson Hasselbach eq

pH = pKa + log[A-]/[HA]

A=salt,base

HA= acid,salt

99.9%

3 pH units

50%

 [saltcrystallized from solvent,ionized drug forms ionic inrxn w/ countreion insolvent containing strong acid or base]

salt examples

[can inc or dec drug solubility]

terbutaline sulfate w/ free base and H2SO4

oxymetazoline HCl w/ free base and HCl

salts inc rx solubility

[can inc soluble by making ionic dissociation]

phenytoin and ampicillin slightly soluble

phenytoin sodium and ampocillin sodium very soluble in water

Basic drugs use ______salts

Acidic drugs use _________salts

1.ANIONIC = HCl, Sulfate, Tartrate, Maleate, Citrate, Mesylate, Succinate

2.CATIONIC = Sodium,potassium, Calcium

PRODRUG

[prolongaction, target, solubility]

1. phosphate group

2.phosphate-ester derivative

Noyes-WHitney equation

[describes dissolution rate of a solid in a liquid]

seperating molecules one phase to the other 

[polar vs non-polar]

partition

[rxs that pass lipid membrane partition into it]

Partition ADME (passive diffusion in...)

1. microorgs too = some antibiotics

2.plastics too =drug into iv set

A= through enterocytes

D = into cells of tissues or into the CNS

M = into enterocytes and hepatocytes

E= reabsorption into tubules

1. colonic absorption of babriturates (better crossing colon)

2. neurotoxicity of penicillins(increased pass through BBB in some pts)

Citrate

lactate

tartrate

acetate

phosphate

11.6

increase

Solvents and their dielectric constants

Water

glycerin

propylene glyxol

ethanol

PEG 400

Water = 81

glycerin = 42.5

propylene glycol = 32

ethanol = 24.3

PEG 400 = 12.5

MICELLES

[surfactants have low solubility but with polar rxs can combine to have balance]

(surfactants)

Lipophilic drus dissolve in_______

(surfactants)

amphiphilic drugs are interspersed among the ______________

surfactant type and examples

1.sodium dodecy; sulfate (SDS)

2. Benzalkonium Chloride

3. Dipalmitoylphosphatidycholine (DPPC)

4.Polyoxyehtylenes.....

1.sodium dodecy; sulfate (SDS) = anionic

2. Benzalkonium Chloride = cationic

3. Dipalmitoylphosphatidycholine (DPPC) = amphoteric

4.Polyoxyehtylenes = nonionic

Cyclodextrins

[image]

glucose units

-have hydrophilic entrances, imp for interaction w/ water 

-poorly soluble drugs fit into  the hydrophobic core with a noncovalent interaction [easily dissociate]

voriconazole (VFEND)

Ziprasidone mesylate [Geodon]

[they are solubilized by the cyclodextrin]

epinephrine oxidizing to therapeutically active but intensly colored prod

erythromycindheydrate to ther activ but bad tasting

Tetracycline epimerizing/dehydrates tofatal nephrotoxin (rare Fanconis syndrome)

Penicillin decompose in acid sol to allergenic prod

Hydrolysis occurs in what func groups

LELA

Lactams (penicillin,cephs,chlordiazepoxide) 

Esters (aspirin,procaine,cocaine)

Lactones (pilocarpine, spironolactone)

Amides (dibucaine,chloramphenicol)

[esters like phosphoric acid,sulfonic acid,carbamic acid too]

superooxide [O2.-]

hydrogen peroxide [H2O2]

hydroxyl radical [OH.]

free radical mechanisms [3]

TIP

termination [R.+ROO. to inert products]

initiation-hydrogen abstraction [light,heat,transition metals]

propogation [ROO.>>>ROOh+R.]

Polyunsaturated hydrocarbons [vitaminA,lipids,Vit D, Zocor]

Phenols [morphine]

Thiols [captopril,cysteine]

Tertiary amine [clopidogrel]

Catechols [dopamine,isoproterenol, epinephrine]

photolysis =breakdown caused by light

wavelength of 300nm has how much E?

400kJ/mol of E

[can make or break bonds]

photooxidation

[creates ln.]

ex:sodium nitropruside (lasts 1yr in dark, 4hrs wen exposed to light)

Deliquesence

[can start at certain RH]

ex: metformin HCl - 80% RH at 25 degrees C

Rate equation

molar concentrations and k is rate constant

First order degredation

[image]

Varies as first power of cocentration of substrate and is independent of conc of any other substance

-dC/dT = kC¹ =k₁C

the actual order of hydrolitic reactions is calculated using ______________________

[water is in such excess. real life]

Pseudo first-order degradation 

[deg rate apparently independent of conc of one of reactants.even tho its consumed in rxn]

10% (t90)

3% (t97)

formulate at pH of max stability (dip in graph)

[push to more neutral pH]

stability

ionization

solubility

pt comfort

Arrhenius equation used 

k = Ae^-Ea/RT

k= reaction rate constant

A = frequency factor

Ea energy of activation

R = gas constant

reduce temps

formulate at stable pHs(strong acid or base)

dry product (dessicants like silica gel)

Freeze drying to make solvent loving.

Vacuum for sublimation and create spongy matrix.

Lyophilization

[uses excipients like sugar]

1.alpha tocopherol, butylated hydroxytoluene, propyl gallate

2.ascorbic acid, sodium sulfite(allergenic in 0.2% of population)

1. Oil soluble anti oxidants

2. water soluble antioxidants

these help creat chain initiating radicals

ex; citric acid, tartaric acid, EDTA

protect from light 

so NO MORE THAN ____% of the light at any wavelength between 290 and 450nm may be transmitted

10%

Fluorescent

incandescent

1. includes some uv 320-380nm

2.>380nm

1. rotation

2.storage

3.observing

4. proper Tx

5.informing

Muscle

subcutaneous tissue

Dermis

and epidermis are _______________routes

parenteral

[IM,IV,SC,Intradermal]

[needles n catheters]

Central IV(have multiple lumens)

[peripheral includes catheter going to central site from peripjheral vein]

high volume

or

viscous fluids

Hand, lower arm and upper arm, antecubital fossa

(scalp for infants under 6 months)

SHU L.A.

piggyback

[add secondary admin set]

administered directly into vein w/ syringe and needle 

[concentrated and fast]

IM

[speed:3-5 min onset. 2nd to IV]

Gluteus (large muscle area)

Deltoid (smaller muscle mass but good w/ circ))

Vastus lateralis (children under three)

usually 1-3 ml but can be up to 10 ml in divided doses

[easier admin than IV w/ more diverse forms]

avoid major nerves

Subcutaneous

[sc tissue relativley poorly perfused]

fat adipose tissue

O-HAT [inj sites]

Outer arm

Abdomen 

Hip area

Thigh

SC speed

[up to 2 ml inj]

SLower than  IM or IV

[poor blood supply]

Low risk of hittting nerve

Most common route for self inj

Intradermal

[little available fluid]

{bout 0.1 ml injections}

poorly perfused

between dermis and epidermis

not systemis(mainly vaccine/diagnostics)

-artery site (intrahepatic chemotherapy)

Epidural

[opiods/anesthetics w/ lower doses]

Directly into CSF. Into subarachnoid space in spinal cord

[low dose analgesia, cerberal palsy,cancer,infections,anesthesia]

SYnovial sacs of joints

[infections,arthritis, and pain and inflammation]

Intraarticular

[for local action]

pleural cavity 

[infections for cancer and local action]

Intrapleural

[image]

Injections into tibia for admin of emergncy meds or fluids to child under 6

[w/ bone marrow cavity,it is a non collapsible vein]

in or around a lesion for local action [PSORIATIC LESIONS]

several sites within the eyeball(local action,intravitreal inj)

for infection deep in the eye

embolus

[pulmonary embolism leading death in hospital]

These IV fluids Cause 

Electrolytes,antibiotics,chemotherapeutic agents, vasopressors

infection under skin

infection systemically

1. cellulitis

2. septicemia

bacterial endotoxin LPS [Lipopolysacharride]

fragment of cell wall that is water soluble

10-20kD

[too small for sterilizing filters]

Nothing growing in product

free of living microorg

filter 0.22 um=fungi/bacteria*****

1-5um=particulates

Nothing growing in product

free of living microorg

filter 0.22 um=fungi/bacteria*****

1-5um=particulates

moist= 121 C for 15 mins(in igh pressure autoclave)

dry heat = 170 C for more than 120 mins

UV light of 253.7 for sterilizing

1) direct transfer of sample to sterile culture

can be thioglyolate or sobein for 14 days to test growth

2)membrane filtration = filter concentrates microbes[especially for antibiotics and preserved products]

7 days to check bac growth

Bacterial endotoxins ridding.

product given to rabbits(imprecise and expensive)

rectal temp collected

Freedom from particulates

may have size up to ___um****

environment

packaging materials

solution and formulation components

product packaging interxn

process-generated particles

large vs

small volume parenterals

large: >100ml

[no more than 50 particles per ml equal to or larger than 10 um]

small: <100ml

[no more than 10,000 particles per container equal to or larger than 10 um]

3-10.5

[5-9 if peripheral]

NaCl = 0.86

KCl = 0.03

CaCl2 = 0.033

Lactated Ringers Isotonic %

(Hartmanns)

NaCl = 0.6

KCl = 0.03

Sodium Lactate = 0.3

CaCl2 = 0.02

1. mini bags contain drugs

2. mini bags w/ adapters fordrug prod

[ADD vantage sys by ABBOTT has 2 parts]

3. Parenteral  nutrition seperate but attached bags(baxter)

SC self administered TNF alpha blocker

prefilled disposable syringe

solu-medrol and solu-cortef are examples of 

[seal must be broken between vials for recon]

pareteral manufacturing proceeds from dirty to clean room in what order?

SCAC

Supply storage

controlled env

aseptic area

clean area

Supply storage

controlled env

aseptic area

clean area

important properties of parenteral packaging

PAL

1. permeation (of gas/water)

2. leaching (container breaking down into fluid)

3. Adsorption (drug stick to container)

important properties of parenteral packaging

PAL

1. permeation (of gas/water)

2. Adsorption (drug stick to container)

3. leaching (container breaking down into fluid)

most common plastic

[plastics are cheap and durable]

Polyvinylchloride

PVC

high O2 permeation

[but less leaching]

Container types (how many times can u use them?)

Ampule

Vials

Plastic Bags

Large volume bottles

Ampule = once [contents filtered after breaking]

Plastic Bags = once [flexible]

Large volume bottles = once [plastic orglass,glass not collapsible]

Vials = once or multiple [rubber stopper,glass or plastic]

Keeps veinready for next infusion.

Small intermittent device prevents clotting.

-cross cell membranes

-interact with other molecules

-transfer from the bloodstream through the capillaries into interstitial fluids

-administration technique

-reflex vasoconstriction

-drug product

P Glycoprotein

[located on apical side]

Neutral amino acids use LAT1

Hydrophilic substances may use__________

Functionalization=CYP p450 catalyzing oxidation of organinc rx (reveals polar groups)

Conjugation=combining w/ polar molecules