medical therapy 2 Flashcards
” Receptors found in heart
“ Stimulation causes increase heart rate, cardiac contractility and atrioventricular conduction
beta 1
” Located in bronchial muscle, blood vessels and uterus
“ Stimulation causes dilation of bronchi and blood vessels
beta 2
” Recently identified in mammals “
Mediation of lipolysis
beta 3
Topical ocular beta blockers (OBB) are β- adrenoreceptors antagonists
! β-adrenergic antagonists are competitive inhibitors
beta adrenoreceptor antagonists
selective beta
either beta 1 or beta 2
Non-selective
both beta 1 and beta 2
Selectivity is relative at high concentrations selective β-adrenergic act on all beta receptors.
selectivity of beta receptors
Ocular beta blockers (OBBs) act by reduction in aqueous formation
! No change in outflow facility
! Aqueous formation can decrease as much as
50%
! Exact mechanism still not clear (despite 30 years of use).
! Two hypothesis ◦ Classic hypothesis
◦ Alternate hypothesis
moa of beta blocker
! Direct relationship between OBBs and cAMP not supported in all studies
! IOP can decrease in response to increase in cAMP
! Both dextro –isomer (low affinity) and levo- isomer (high affinity) of timolol decrease IOP. Which gives evidence against competitive inhibition.
evidence against classic hypothesis
Clilary process are under continuous tonic stimulation to produce aqueous (mediated by epinephrine).
! Beta- blockers interfere with tonic stimulation
! This is a speculative hypothesis ! No anatomic basis identified yet.
alternate mechanism of OBB
we have to choose a hypothesis to follow, which do we choose?
classic
! Lowering IOP ocular hypertension and open angle glaucoma
! May be used stand alone or in combination with other drugs
! Secondary glaucoma ! Angle closure glaucoma
indication of OBB
! Relative or absolute contraindication in patients with
◦ Pulmonary disease, bronchial asthma, severe COPD
◦ Betaxolol (selective OBB is not contraindicated for
above diseases)
! Any patient with sinus bradycardia (less than 60 beats resting), overt congestive heart failure
! Any patient that develops ether heart or lung problems after starting OBBs
! Patient hypersensitivity to drug or any component
glaucoma contrainidication
clinical tip: anyone we consider putting on OBB, you must measure what?
pulse rate and BP!
you put a pt on timolol, and if you notice they have lung issues they did not have before, what do u do?
take pt off it! this is too much of a coincidence, they didnt have this problem before
do beta blockers decrease heart rate?
yes
if the heart rate is
no! why? b/c it will further decrease heart rate
treatment regimen of OBB
OBBs used once or twice daily
! Twice daily may lower IOP greater than once
daily
! More and more practitioners use qd and increase to bid if needed (to minimize side effects)
! All OBBs twice daily
! Exception
◦ Isatalol qam
◦ Timoptic XE or GFS (gels) qd
◦ Betagan qd
treatment regimen of OBB
OBBs used once or twice daily
! Twice daily may lower IOP greater than once
daily
! More and more practitioners use qd and increase to bid if needed (to minimize side effects)
! All OBBs twice daily
! Exception
◦ Isatalol qam
◦ Timoptic XE or GFS (gels) qd
◦ Betagan qd
what is the most common form of timolol?
timolol maleate 0.5%
! Commonly used 0.5%
! Non selective beta-adrenergic antagonist ! No corneal anesthesia (like propranolol) ! Greater efficacy than pilocarpine
! Lowers IOP in normals, ocular hypertensive and glaucoma patients
timolol
why is timolol a good alternative to pg when used appropriately?
- when they dont like using PG due to its side effects
- PG is too expensive!
why is timolol a good alternative to pg when used appropriately?
- when they dont like using PG due to its side effects
- PG is too expensive!
why are beta blockers prescribed bid?
max effect is 12 hrs
when does aqhu production go down?
night time
Timolol AM dose reduces IOP below baseline
! Timolol PM dose does not reduce it below baseline levels.
! This casts doubt on its efficacy on PM dosing.
am/pm efficacy
Timolol AM dose reduces IOP below baseline
! Timolol PM dose does not reduce it below baseline levels.
! This casts doubt on its efficacy on PM dosing.
am/pm efficacy
short term escape of obb
Not in all patients
! Efficacy of timolol decreases over time
(several weeks)
! Response of beta receptors to constant antagonist
! There may be an up regulation of beta receptors in target tissue
! Important- not in all patients!
long term drift of obb
Over months to years
! Control of IOP not as good as once.
! Washing out and re-starting helps restore levels
! Lack of efficacy or poor adherence ??? We don’t know for sure
what does washing out mean?
stopping drug completely
what is a good wash out period for a drug?
4 weeks
obb inhibits –> beta agonist –> activation of g protein –> membrane bound adenyl cyclase –> catalyzes ATP –> cAMP –> production of aqueous from ciliary processes
moa of obb
why would u give someone 0.25 timolol?
pediatric or someone that cant handle side effects of 0.5% timolol
its important to ask patient when they took their last dosage of medication?
-if they missed dosage that day, result could be high in clinic
what is long term drift?
Over months to years
! Control of IOP not as good as once.
! Washing out and re-starting helps restore levels
are there symptoms for poag?
no. not usually
whenever you suspect drug is not working what do u do?
ask pt to drop it in their eye in front of you. sometimes you will see that they aren’t good at applying it.
whats the washout period for drugs?
Clinically a 4-week wash out period is considered acceptable
IOP lowering effects may persist for 2 weeks
! Aqueous flow up to 6 weeks.
when would you consider washout?
pt is not responding to drug; or you want a clear picture of what is going on
pros of gels
- improves bioavailability (stays where its supposed to stay)
- decrease systemic absorption (stays in conj longer)
- once a day dose instead of 2x a day (compliance may be better)
cons of gels
can blur vision if left over in morning
timoptic XE (gel) is preserved with what?
benzododecinium bromide (not BAK)
what beta blocker is applied once a day?
istalol
! Formulated with potassium sorbate
! Claims to enhance bioavailability so once daily.
! Lower BAK concentration
! Most visits IOP difference is within 1.0mmHg between groups 95% CI
! All visits within 1.5mmHg (compared to twice daily)
istalol
! Selective beta blocker
! Initially 0.5% solution (1985)
! Later 0.25% suspension of resin coated beads (gradual release) – Betoptic S (Suspension)
betaxolol hydrochloride
is betaxolol solution available in USA?
no (we only get suspension-coated and more comfortable)
! Cause less ocular irritation compared to Solution.
! Less effective when compared to Timolol
! Advantage it is selective beta blocker – can be used in patients with pulmonary disease.
betaxolol suspension (Betoptic S)
what drug can be used safely with patients with pulmonary disease due to is selectivity as a beta blocker?
betoptic s
anything that blocks calcium to cell will do what?
neuroprotection (calcium going to cell will cause death)
May possess calcium channel blocker properties
◦ Thus may have neuroprotectic effect*
◦ Highly lipid soluble, binds well with plasma
proteins
“ Significance: Lower CNS effects when compared to timolol
Betaxolol properties
if betxolol is neuroprotective, can this be our go to drug?
betxolol has less iop lowering than timolol and PG; it may provided neuroprotection, but it cant beat PG; iop lowering is proved to protect GC (good for glaucoma)
local side efects?
! Propranolol – corneal anesthesia
! Other OBBs no such effect.
! Discomfort, burning stinging ◦ Factors like
“ Active molecule, pH, preservative and vehicle.
! Preservative- BAK
◦ BAK helps with penetration of OBBs ◦ Sensitivity not uncommon
◦ Preservative free timolol is available (very expensive)
local SE of propanolol
corneal anesthesia; long run can lead to keratopathy
local SE of OBB
none
local SE of any drug
discomfort, burning, stinging
preservative used for obb, why?
breaks down corneal epithelium.
–> good for drug to pass through
what cornea barrier is the most resistant to keep drug outside?
epithelium
con of BAK
causes hypersensitivity
expensive
doesnt always penetrate as well as u like
local side effect of timolol - due to preservative
Decreased tear production
! Decreased goblet cell density
! Dry eye symptoms
! Ocular cicatrical pemphigoid (immune rxn to drug)
what disease can metipranolol cause?
granulomatous uveitis
systemic side effects of obb?
OBBs enter systemic circulation via nasolacrimal system
◦ Almost like intravenous dose of medication (bypasses first pass metabolism)
! Does not approach oral dose
typical dose of OBB?
20-60 mg PO
peak plasma value of obb
50-103 ng/ml
trough plasma value of obb
0.8-7.2 ng/ml
two drops of timolol plasma levels range; and why is it bad?
5-9.6 ng/ml; this is similar to trough plasma values; can cause systemic side effects
what do we need to make sure to do when applying timolol?
punctal occlusion to avoid systemic effects
! Detailed history is required ! Anxiety, depression, fatigue, lethargy, confusion, sleep disturbance, memory loss and dizziness ! Sexual dysfunction ! Decreased libido men and women ! Impotence in men ! CNS fewer with the use of betaxolol
cns adverse effects
which obb has fewer cns adverse effects?
betaxolol
what do beta blockers do?
◦ Lower heart rate
◦ Lower blood pressure
◦ Decreased myocardial contractility
◦ Slowed conduction time
Blocking beta-1 receptors interferes with what?
Blocking beta-1 receptors interferes with normal sympathetic stimulation of heart
topical obb heart effects
Decreased heart rate and significant bradycardia
! Reduced blood pressure
will topical obb have good effect on hypertension pt?
may not give us any further benefit; they are already taking oral obb
what do we always check before presribing obb?
◦ Always check BP and pulse rate on
patients prescribed or on OBBs
! Timoptic XE and other gels less effect-why?
Gels stay in eye and decreased systemic absorption.
! Most problems were early on due to lack of experience with OBBs
! 12 deaths in first 8 years; 50% of these had pulmonary disease
! Pulmonary effects due to- blockade to Beta-2 receptors.
! Betaxolol has been used safely in patients with pulmonary disease.
pulmonary adverse effects of obb
! Affects lipid metabolism ! Normal volunteers used timolol: ◦ 12% increase in triglycerides ◦ 9% decrease in HDL ◦ Not all studies showed this effect ! Data on OBBs and lipids inconclusive.
metabolic adverse effects of obb
what are low hdl levels?
! Depression -1960s and 1970s
! Subsequently large scale population based studies
◦ No effect
No robust evidence for use of OBBs and depression- evaluate case by case
drug disease interaction-cns
! Cardiovascular disease- contraindicated
◦ May worsen BP- potentially worsening orthostatic hypotension, cerebrovascular disease, preripheral vascular disease.
! Pulmonary disease caution
! Anyone on OBBs develops these- alter
medications
◦ May relieve symptoms/ conditions
drug disease interaction - cardiovascular and pulmonary disease
" nervousness, " sweating, " intense hunger " trembling, " weakness, " palpitations
symptoms of hypoglycemia
if diabetic has hypoglycemia, what drug could mask the effects?
beta blockers! this is bad because its a true problem in insulin dependent patients (they wont know that they need more insulin :( )
name 3 adrenergic agents
! Clonidine
! Apraclonidine
! Brimonidine
! Lowers IOP well- but
◦ Causes sedation
◦ Systemic hypotension
◦ Narrow therapeutic index
clonidine
Mechanism of action
◦ Decreased aqueous production
◦ Improves trabecular outflow
◦ Decreases episcleral venous pressure
moa of apraclonidine
More hydrophillic ◦ Does not penetrate eyes and blood brain barrier ◦ More apha-2 selective ◦ Wide therapeutic index
apraclonidine
why is lowering episcleral venous pressure good for glaucoma?
aqhu can come out easier
what is iop a function of?
production and outflow
what influences outflow?
if episcleral venous pressure is high, aqhu cant come out
! FDA approved to prevent post laser treatment spikes in IOP
! Adjunctive therapy- TID
uses of apraclonidine
Reduction of aqueous flow
moa of brimonidine
highly alpha 2 selective drug
brimonidine
! Peak effectiveness in 2 hours
! Effect present at lower amount at 8 hours ! Thus TID dose
brimonidine
! Prophylactic –to avoid post laser IOP spike
! Primary or secondary therapy glaucoma and ocular hypertension
indication of brimonidine
contraindication of brimonidine
! Allergy to drug
! Contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy (antideppresants).
can you give antiallergy meds to someone with allergies to drugs in hopes of clearing your allergy to the drug?
source of allergen will continue, but you cant get out of it; anti-allergy wont solve all problems
! Conjunctival follicles, ocular allergic reactions, and ocular pruritus (itching).
! headache, blurring, foreign body sensation, fatigue/drowsiness,
! Oral dryness,
! Ocular hyperemia, burning and stinging,
adverse reaction to brimonidine
what is combigan?
brimonidine + timolol (BID)
whats wrong with combigan?
not much logic behind this; brimonidine is supposed to be TID and timolol is BID
cosopt
dorzolamide (CAI) and timolol - BID
WHAT fixed combo drug makes sense?
simbrinza (brinzolamide and brimonidine) - both drugs are TID; and combined is TID; makes sense
Any method that prevents or slows the death of neurons is considered what? therfore?
neuroprotective; all treatments are neuroprotective
true neuroprotection
◦ Prevent destructive cellular events
◦ Enhance survival of cells after damage
what drug is approved for use in glaucoma pts that have indication of neuroprotection
NONE!!!!!!!
◦ 1) the agent must have a target in the retina;
“ Yes they are present
◦ 2) it must be neuroprotective in animal
models;
◦ 3) it must reach neuroprotective concentrations in the posterior segment after clinical dosing;
◦ 4) it must be shown to be neuroprotective in controlled clinical trials.
4 criteria for drug to be neuroprotective
if drops are given topically how readily are they getting to vitreous and retina?
not doing a good job; its hard for it to reach retina
cholinergic drug for glaucoma
pilocarpine (angle closure glaucoma with pupillary block)
moa of pilocarpine
! Anatomic relationship between anterior tendons of ciliary muscle and ◦ Scleral spur ◦ Peripheral cornea ◦ Trabecular meshwork ◦ Inner wall of schlems canal
! Contraction of ciliary muscle causes
◦ Unfolding of meshwork
◦ Widening of Schlemm’s canal
pilocarpine dosage?
1 or 2% two to 3 times in 30 minutes
! Pilocarpine nitrate
◦ 0.5% to 4% QID (four times daily)
! Pilocarpine hydrochloride
◦ 0.5% to 6%
! Preservative BAK and EDTA
! Pilocarpine gel- bed time
pilocarpine
! Absorbed by cornea
! Drug binds to iris pigment ! Light iris- 2%
! Dark iris- 6% may be needed
pharmacokinetics of pilocarpine
SE of pilocarpine
! Stinging
! Burning
! Prolonged use- risk of failure with surgeries ! Risk of hyphema during surgeries
! Ciliary spasm, temporal or supraorbital headace and induced myopia
◦ Because of drug induced contraction of ciliary muscle
pilocarpine vf effect?
problems in dark environment - less light enters the eye; pupil should dilate in dark but with pilocarpine it stays small; glaucoma pts have periphery problems to begin with
! 1% drug
! 10-30 minutes- miosis
! Max IOP reduction 75 minutes
! Miosis lasts 4-8 hours ! IOP lowering 4-14 hrs
dose effect varies with strength
Miosis vision decrease ! Intense miosis and constant
accommodation
◦ Increase risk of pupillary block
SE of pilocarpine
Decreased efficacy of lowering IOP with long term use.
◦ Mechanism unclear
◦ Increasing problems in drainage mechanism
long term escape of pilocarpine
! Extremely rare
! If occurs
◦ Sweating
◦ Salivation and ◦ Gastrointestinal over activity
◦ Atropine is pharmacological antagonist for pilocarpine
systemic toxicity of pilocarpine
if intraocular congestion like uveitis-why do we not give them pilocarpine?
if you leave iris in contracted form - chance of synechiae is increased; also we want to relieve cil muscle to decrease pain of patient
contraindication of pilocarpine
! Risk/ history of retinal detachment
! Intraocular congestion like uveitis
! Any one whom pupil size and accommodation is an issue
what can pilocarpine be combined with?
Can be combined with drugs that decrease aqueous humor production
members of sulfonamide family
CAI
MOA OF CAI
Carbonic anhydranse inhibitors causes reduction of bicarbonate ions in posterior chamber
! Subsequently prevents Na+ movement and hence water movement (LOWERS IOP)
! Acetazolamide max dose 250mg qid
! Methazolamide max dose 150 mg bid
CAI
! Sulpha allergies
! Diabetic patients susceptible to ketoacidosis
! Patients who have hepatic insufficiency and cannot tolerate the increase in serum ammonia
! Patients with chronic obstructive pulmonary disease, in whom increased retention of carbon dioxide can cause potentially fatal narcosis from a combination of both renal and respiratory acidosis
contraindications to CAI
anyone with bad kidneys, livers, lungs, should not be given what drug?
oral CAI (b/c the drug will not be metabolized and can lead to severe systemic problems)
SE of cai
numbness, paresthesias, malaise, anorexia, nausea, flatulence, diarrhea, depression, decreased libido, poor tolerance of carbonated beverages
myopia, hirsutism, increased serum urate, and, rarely, thrombocytopenia and idiosyncratic aplastic anemia
what happens when u take cai and drink soda?
unpalatable metallic taste (taste change)
Dorzolamide ! Brinzolamide
! BID or TID
! Three times daily gives better reduction in intraocular pressure approximately 1mmHg
topical agents cai
