what does the body do to the drug?

Drug into tear film, passively diffuses through the corneal epitheliumm, stroma, and endothelium (concetnration dependent).

High concetbtration of drug win tears would force drugs through the layers of cornea to get to the aquous humor. From the aquous drung can travel to lens, iris,CB.  Can't get it back!

Aqueous humor dilutes the drug and romoves it throug aqueous humor drainage (Trabecular Meshwork, schlemm's canal).

Once drug drains with tears into the nasolacrimal drainage system or the angle outflow, with aqueous, the drug is GONE to systemic circulation.

1. production & volume
2. drainage
3. composition of the tears

Production and Volume:

1. how much lacrimal flow/production?
2. how much of the volume of lacrimal lake replaced?
3. what is normal volume of the lacrimal lake?
4. Maximum lacrimal lake?
5. size of 1 drop

1) 1µL replaced/min

2) 15% of the vol replaced 3) normal vol: 7µL

4) max: 25-30µL

5) drug: 40-75µL

1) 80% of drug lost to nasolacrimal drainage and overspill on cheek.

2) conjunctival vessels can absorb the drug

3) blinking, pumps out tears and drugs.

Conjunctival vessel absorption(non productive absorption, esp if inflammed, the conj vessels will absorb more of drug than normal.) so a pt with conjunctivitis given drug, drug will not enter cornea but will be absorbed by the conj vessels.

drop washes out everything lacrimal lake, within ~10 sec, the drug is dilated,

the drop coming in contact with the cornea can cause reflex tearing which increaes rate of lacrimation and speeds up turnover of tears.

Wihin 5 mins most of drug (>50%) eliminated

Withing 10 mins only 20% of drug is left in lacrimal lake

Decreased concentration of proteins = icreased absorption of drug in cornea.

drug cannot cross the cornea if it is protein bound; lost to nasolacrimal drainage

0% protein = highest amount of drug entering the aqueous humor

3% protein: least amount of drug that is able to enter the aqueous.

thru passive diffision and is concentration dependent.

Increasing tear flow causes Decreased drug concentration leads to decreased absorption (concentration) gradient.

2 imp things: corneal contact time, concentration of drug.

increases corneal contact time b/c tear turnover time is slower so increased absorption into cornea.

But if dry eye is irritating and stimulates lacrimal production then dry eye will decrease absorption of the drug.

damages epithelia tissue making for better absorption into the corena, because epithelial layer is the most significant barrier to absorption.

Cuased decreased blinking so longer corneal contact time &absorption.

Using a local anesthetic before a dilating drop allows better absorption of the dilating drop.

Epithelium (LIPID): main Barrier to absorption for drugs across the cornea

Stroma (water)

Endothelium (lipid?): good absorption in either water soluble/lipid soluble.

Drugs are mostly weak bases. Ionized: don't move thru membranes well (cos not lipid soluble)

Non-ionized: more lipid soluble

Physiological state 7.4pH

ph < 7.4, more acidic, says non-ionized.

pH >7.4, more basic, gets ionized. 

non-ionized form (B), we are 2 pH units below pKa so 100 : 1 ratio of ionized: non-ionized form (in tear film) and the nonionized form, B moves across the membrane.

N

which will be slower?

 a) a drug that is 50 ionized :50 nonionized

b) a drug that is 100 ionized: 1 nonionized

which of the follwoing that affect epithelial integrity will NOT increase absorption?

a) benzalkonium chloride

b) inflammation with diffuse keratitis

c) discrete ulcer

d) contacts lens overwear,

e) local anesthetics

c) discrete ulcer.

all the others will cause breaks in epithelium and increase absorption

The cornea maintains concentration of drug like a reservoir, will declne but slower decline!

Slow release to aqueous or slow release back to tears

vehicle

viscosity effects

drop size

other features of ophthalmic formulations

which has the longest contact time and increased stability and less risk of contamination?

a) solution

b) suspensions,

c)ointments

which vehicle has easy and rapid absorption, is homogenous and does not interfere with vision?

a) solution,

b)suspensions

c) ointments

which vehicle has longer contact time but is hard to dissolv e(bioavailability), is non-homogeonus amd has a foreign body sensation? when is it good to use it.

a) solution,

b)suspensions

c) ointments

b) suspension.

solid drug particles float in soln, good to use when drug is NOT very water soluble

when we want to get a very lipid soluble drug in eye w/w irritation. it melts in eye becomes a fluid but does not mix with tears very well; as viscosity increases corneal contact time increases and amount of drug absorbed through the cornea increases.

It is more stable,

icrease viscosity --> increases contact time and absorption.

Increase viscosity by 100 fold will increase absorption into the cornea bu 2X.

generic may have the same active drug but MAY NOT have the extra stuff to make it more viscous.

Polyvinyl alcohol (PVA) increases viscosity but at lower level than methyl cellulose!

Tropicamide and Phenylephrine for eg. put 1 drop only: most effective.

1 drop then another drop: the 1st drug has less of an effect because it is washed out by the 2nd drug.

Best to wait 5mins b/w drops for the best effect, shorter time between drops means more of the first drop is washed out!!

preservatives can cause harm to epithelial tissues:

1. benzalkonium Cl (icreases carbachol corneal absorption)

2. Thimerosal: non-toxi, used in proparicaine/fluorescein but not in toher soln cos allergy-like sensitivity in pt.

1. make sure tonicity of drug is close to tears at 0.9%. Drugs can range from 0.6% (hypotonic, dry eye pt.) to 1.8% (hypertonic, corneal edema pt)

1. make sure pH is close to physiological pH 7.4: buffer soln w/ NaOH (increases pH) or HCL (decreases pH).
2. Low [drug]: buffer drug to increase stability in soln. There is high tear turnover that can buffer drugs to increase its stability in solution.
3. High [drug] difficult to buffer

Effect of temperature 25 C (room temp) & 120 C (autoclave temp): if drug is a weak base, can stabilize by lowering pH and ionizing the compounds. Heating a drug makes it less stable.

Procaine & Tetracine: at pH 5, inoiczed and more stable, longer half life at autoclave temp.

Chlorobutanol: long half life at pH 5 an room temp, but only 5 min half life at pH 6.8 and 120 C.

Phenylephrine: detoriates with exposure to air (more irritating then!)

Preservatives: no effect on drug stability.

1. Reservoir technique: OTC antibiotic ointment on eyes, easier for old people to apply to fingers an rub across ointment,
2. lid scrubs (blepharitis pt. apply on lid margins)
3. Gel (pilopine H.S); apply to eyes across canthi at bedtime for longer contact time and hihh concentratopm/ Timoptic-XE interacts with Ca2+ on tear film: longer contact time w/cornea and incr. absorpt. duration. once a day.
4. cotton pledget: dilating drop on cotton tuft into lower cul de sac for tear drop dilation; see posterior view without full dilation (worried about closing angles)
5. Lacrisert: solid chunk of viscosity building compd in lower cul-de-sac and dissloves with tears; long duaration of drop. only bad thing, dry eye pt with little tears so solid never dissolves (foreign body sensation); lubrication immediately after insertion may help.
6. OcusertL w?pilocarpine in plastic like CL: constant concen. deliver, decreased administration frequency, great compliance. problems: can fall out, FBS, pilocarpine not favored.
7. soft CL: longer release than drobs: 6-8 hrs, not viable commercially; irrigation of eyes with saline remove foreign body, decrease pH due to chemical exposure, could hook IV drip under lids for constant irrigation.

• to maintain therapeutic response re-adminster every 2-6 hrs (4-5x daily)!

IF 0.5% given every 6 hrs; therapeutic range reached but fluctuations keeps it under therapeutic range most of the time.

Increasing to ever 2 hrs will maintain higher steady state within therapeutic levels but poor compliance

lower pH

ionize the compoind,

stable at room temp 25 C

which of the following is true?

A) icreased frequency (same dose) will increase the steady state level

b) decreased frequency with same dose, will decrease the steady state level

c) taking 2 tablets instead of 1 tablet at same frequency will increase the steady state

d) it takes 2 half lifes to reach steady state

e) repeated doses in blood leves reach a plateau for topical and systemic adminsitration

Yes!

•  esp for infxns and inlammatory disease (treat the underlying sytemic prob and releive ocular sx_
• concern = increased systemic toxicities,

concern= absorption from GIT,

food, drug stability, first-pass effects, easy to do and advantageous for chronic tx.

last resort: Allows significatn absorption of drug for long time. Absorption is directly across the sclera into the tissue of the eye closest to the injection site.

1. Sunconjunctival: depot for long-term absorption into anterior parts of eye.
2. Subtenons: depot of slowly absorpted into tissues of posterior eye
3. retrobulbar: infilatrate nerve and EOMs

intracameral: inject into aqueous humor

intravireal: into vitreous

used for severe inflammation/infection

Risk: large!contaminants can get in and could lose eye

1. proeper patient selection
2. ptoper pt medical history
3. all medications pt is taking: e.g. Anti-depressants & anti-psychotics can interact with phenylephrine, oral contracetpive- dry eye
4. allergies
5. systemic diseases

1. VAs: always check VA's before adding drops for legal reasons.
2. pupil evaluation: cycloplegic/anti-muscarinic agent will alter pupil response
3. refraction: cycloplegic drugs will disrupt normal refraction
4. amplitude of accomodation
5. binocularity
6. biomicroscopy: looking at anterior chamber-- there could be pigment dispersion  due to strong dilation from phenylephrine administration, CB epithelium could make pigment in anterior chamber.
7. tear film evaluation
8. tonometry (phenyl decrease IOP, antimuscarinic will increase IOP)
9. Blood pressure: (adrenergic agonists will raise BP)

1) toxic: easy to predict e.g COPDpt gets no beta blocker

2) Allergic toxicites: unpredictable

alergy: mins to days see reactions, related to previous experience.

anaphlyactic reactions are immediate 9rare that topical drug gives systemic anaphylactic reactionl generally limited to eye and adnexa.

Delayed allergic hypersensitivities: more common; hours to days later,

decreased response to repeated use of same drug at the same dose.

drug/drug interaction could potentiate the effects of other drugs

laryngeal edema (difficult to breathe), bronchospasm, air hunger,

significant risk of death

epi pen : epineprhine injection.

ocygen (probs beathing).

pt with atopic history, of being allergic to other things, have more likely severe response.

if no immediate allergic rxn w/ 20-30 mins after drug administration= no risk of life threatening reaction.

cardiopulmonary arrest : AED (defibrillators)

1.  keep all meds out of reach of children
2. ointment, less reisk systemicall (slowly absorbed)
3. lowes dose, shortest time
4. lower dose in bionates and ifnants (low body mass & low rate of metabolism in liver)
5. inflamed conjunctiva (systemic absorption)
6. use only as directed
7. light complextion/light irrides - often greater drug effect( not much pigment for drugs to bind so they don't bind isteead, act at receptor sites more)
8. topical LA's increase drug absorption
9. environmental conditions
10. punctual occlusion

50µL = average drop size

20 drops in 1ml.

To go from % to mg: move the decimal place one to the right and divide by 20.

because 1ml = 20 drops.

1% soln = 0.5mg/drop