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pharmacology winter 2013
General principles of ocular drug usage
77
Pharmacology
Graduate
02/02/2013

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Cards

Term
ocualar pharmocokinetics model: what is pharmacokinetics? describe topical application
Definition

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.

Term
what are the tear film dynamics?
Definition
  1. production & volume
  2. drainage
  3. composition of the tears

 

Term

 

 

Definition
Term

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
Definition

1) 1µL replaced/min

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

4) max: 25-30µL

5) drug: 40-75µL

 

Term
what are the 3 ways drug is drained
Definition

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.

Term
Production &volume: how long does drug last in lacrimal lake tears?
Definition

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

Term
what will slow drug loss thru the nasolacrimal drainage system?
Definition
punctual occlusion:  fingers over the puncta and press gently while eye is closed.
Term
how does protein component in tears affect drug concentration in the aqeuous humor?
Definition

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.

Term
how does corneal absorption and penetration occur?
Definition

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.

Term
dry eye: decreased tear turnover will do what to corneal contact time?
Definition

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.

Term
CL effect on corneal contact time
Definition
if drug put in with CLs on it could increase corneal contact time.
Term
Local anesthetic effect on corneal contact time
Definition

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.

Term
Age effect on corneal contact time
Definition
older pt with droopy lids; lacrimal lake increases in volume, slower tear turnover, increased corneal absorption, more flaccid eye means longer corneal contact time.
Term
Hypersecretion effect on corneal contact time
Definition
more tears coming in dilutes drug, drug washes out faster, less corneal contact time, decreased absorption into the cornea.
Term
Punctual Occlusion effect on corneal contact time
Definition
decrease nasolacrimal outflow, increase time drug stays in cornea, increases corneal contact time
Term
Corneal structure related to absorption, distribution and elimination of drugs.
Definition

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

Stroma (water)

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

Term
Differential solubility of durgs into eye= weak electrolytes
Definition

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. 

Term
Tear film, what form moves through
Definition
Drug in tear film: ionized form (BH+).
Term
Non-ionized.
Definition
B: when it does  not have H+ for bases only
Term
drug moving across lipid epithelial membrane is non-ionized or ionized?
Definition

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

 

Term

which will be slower?

 a) a drug that is 50 ionized :50 nonionized

b) a drug that is 100 ionized: 1 nonionized

Definition
a) the drugh that is 50:50 ionized to nonionized.
Term
which form of drug will move through stromal layer?
Definition
drug in ionized form BH+ will diffuse more easily.
Term
Which form of drug will go through Endothelium --> aqueous humor
Definition
EITHER ionized OR non-ionized form moves easily from endothelium to aqueous humor.
Term

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

Definition

c) discrete ulcer.

all the others will cause breaks in epithelium and increase absorption

Term
Corneal Reservoir allows for what?
Definition

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

Slow release to aqueous or slow release back to tears

Term
what physical features corneal absorption?
Definition

vehicle

viscosity effects

drop size

other features of ophthalmic formulations

Term

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

a) solution

b) suspensions,

c)ointments

Definition
c) ointments
Term

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

a) solution,

b)suspensions

c) ointments

Definition
a)solution
Term

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

Definition

b) suspension.

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

Term
when is it good to use an ointment?
Definition

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,

Term
what is a disadvantage of  ointment vehicle for durgs
Definition
interferes with vision, not as easily absorbed in cornea, risk of allergy to ointment
Term
what does increase in viscosity of solution do to corneal contact time?
Definition

icrease viscosity --> increases contact time and absorption.

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

 

Term
what is the difference b/w brand name and generic?
Definition

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!

Term
As viscosity increases, what happens to drainage rate?
Definition
as viscosity increases,  drainage  rate decreases and contact time increases and there is better absorption of drug across cornea.
Term
As viscosity increases, what happens to blinking?
Definition
with increased viscosity drops are more comfortable to put in eye; blinking decreases, less drug pumped out thru nasolacrimal system--> increases contact time.
Term
what happens if drop size too large?
Definition
drop size too large, drug washed out right away runds down cheek and overdose pt.
Term
with multiple drops what is the wash out effect?
Definition

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!!

Term
what are the factors to consider when formulating compounds into solution applied to the eyes?
Definition

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.

Term
what do you have to make sure for tonicity of solution compared to tears?
Definition
  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)
Term
what do you have to make sure of drug PH and tears?
Definition
  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
Term
how does temp and pH affect stability of ophthalmic drugs?
Definition

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.

Term
Other drug delivery systems: Reservoir technique
Definition
  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.
Term
for routine multiple dosinf drugs how to get and maintain therapeutic levels.
Definition
  • 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

Term
how many half lifes before steady state is reached?
Definition
reached after 4-5 half lifes ( 94-97% plateau level
Term
what does increased frequency of administration do to drug levels?
Definition
increasing the frequency of administration will decrease fluctuations in drug levels
Term
how do you improve stability by changing pH and temperature?
Definition

lower pH

ionize the compoind,

stable at room temp 25 C

Term

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

 

Definition
d) false because its takes 4 to 5 half-lifes to reach steady state
Term
can you use oral meds to treat  ocular conditions?
Definition

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.

Term
what are the advantages of periocular injections?
Definition

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
Term
what are the disadvantages of periocular injections?
Definition
increased toxicities, can damage the globe.
Term
what are the ways to give intraocular injections and what is the advantage/disadvantages?
Definition

intracameral: inject into aqueous humor

intravireal: into vitreous

used for severe inflammation/infection

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

Term
how does a systemic drug enter the eye?
Definition
throught the uveal bload vessels because they are the most permeable; blood-retina barrier does not get much to go across the retinal vessels
Term
what does uveiits (inflammation of the uveal tissue) do to drug absorption?
Definition
will increase drug absorption since inflammation disrupts the normal barriers.
Term
how do you get drugs directly into the eye?
Definition
periocualr or intraocular injection: into iris, lens,
Term
where does topical drug enter the eye?
Definition
via the tear film
Term
how do you prevent or predict possible toxic events?
Definition
  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
Term
which tests should be performed before dilating pts because DPAs can affect them?
Definition
  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)
Term
what are 2 types of toxic reactions?
Definition

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

2) Allergic toxicites: unpredictable

Term
what is difference bewteen allergies and delayed allergic hypersensitivities?
Definition

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,

 

Term
allergic
Definition
acquired after repeated exposure; can't be allergic to drug untill you've been exposed to it multiple  times.
Term
idosyncratic
Definition
genetic dispostion causing unusal response to a drug e.g significantly reduced vision w/ ibuprofen
Term
tolerance
Definition

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

drug/drug interaction could potentiate the effects of other drugs

Term
hyper-reactivity
Definition
pt responds with an expected drug effect at a very low dose. eg cycloplegia and dilation for a full day with one drop of tropicamide
Term
negative placebo effect
Definition
pt could faint when you touch his/her eyes.
Term
emergency treatment: anaphylaxis
Definition
allerge response; immediate & life threatening. Sx: utricaria (hives), pruritus (itching) within mins of intake
Term
emergency treatment: pulmonary
Definition

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

significant risk of death

Term
emergency treatment: cirulatory
Definition
hypotension, syncope (fainting), collapse b/c no blood flow to brain.
Term
management fo emergency reactions
Definition

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)

Term
who should never take beta blockers?
Definition
pt with: COPD, asthma, congestive heart failure, cardiac rhythm disturbance.
Term
what is the most importang thing with risk assessment to prevent adverse reactions?
Definition
knowledge of the drug and patient history.
Term
what are risk assesment things to do to prevent adverse reactions?
Definition
  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
Term
conversion factor from % to mg
Definition

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

 

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