Wk 14 - Alpha Adrenergic Agonists

Question 1

Glaucoma Treatment Drug Classes

Answer 1

1) Autonomic agents
a) Cholinergic agents: miotics
- Parasympathomimetics
- increase aqueous outflow
b) Adrenergic agents
i) Sympathomimetics
- Decrease aqueous production (major) and increase outflow (minor)
- Alpha adrenergic agonists (typically alpha-2 selective)
ii) Sympatholytics
- Decrease aqueous production
- Beta-adrenergic blockers/antagonists

2) Prostaglandin analogs
– increase uveoscleral aqueous outflow

3) Hyperosmotic agents
– rapidly lower IOP through osmosis

4) Carbonic anhydrase inhibitors
– decrease aqueous production

5) Marijuana
– increases uveoscleral outflow by unknown MOA

Question 2

Epinephrine and Dipivefrin

Answer 2

• Classic medications, not used today

MOA: Nonselective adrenergic agonists – stimulate both alpha and beta receptors
o Alpha-2 stimulation lowers IOP
o Alpha-1 stimulation causes mydriasis and vasoconstriction/HTN
o Beta-1 stimulation causes tachycardia
o Beta-2 stimulation causes bronchiolar dilation

Ocular side effects

• Burning, mydriasis
• Allergy in ~15% of patients
• Red eyes – initial vasoconstriction and blanching of conj with rebound hyperemia
• Cystoid macular edema in non-phakic patients

Systemic side effects

• Headache, palpitations, tachycardia, hypertensive crisis
• Worse systemic side effects with Epinephrine

Question 3

Alpha 2 Adrenergic Agonists

Answer 3

Modern Adrenergic Glaucoma Treatment

MOA: Selective for alpha-2 receptors, which are located both pre-synaptic and post-synaptic
o Pre-synaptic: inhibits release of norepinephrine from the neuron
- decreases production of aqueous from the ciliary processes
o Post-synaptic: decreases levels of cAMP leading to ciliary body contraction
- increases uveoscleral outflow

Question 4

Apraclonidine (Iopidine)

Answer 4

•Derived from oral clonidine (a drug for HTN)
o Greater affinity for alpha-2 receptors, but some alpha-1 activity as well
o Can cause vasoconstriction and mild mydriasis

•FDA category C

Preparations: 0.5% and 1.0% solutions
o Both are equivalent

Dosing: TID when used alone

Clinical uses
1) Treatment of acute angle closure glaucoma and acute pressure spikes
• 20-25% reduction of IOP*
2) Pre- and post- anterior segment surgical procedures to prevent pressure spikes
• Shown to be more effective than drugs in other classes
• Brimonidine later shown to be equivalent to apraclonidine

Question 5

Apraclonidine use in Diagnosis of Horner’s Syndrome

Answer 5

• Will dilate the affected eye because of weak alpha-1 activity and denervation hypersensitivity
• Horner’s eye lacks sympathetic stimulation, so the iris upregulates NE receptors, making it very sensitive to apraclonidine’s normally weak mydriatic effect
• No dilation in the unaffected eye
• Anisocoria is improved

Question 6

Apraclonidine Side Effects

Answer 6

1) Tachyphylaxis
•IOP lowering effect wanes over a few months
•Poor choice for long term treatment
2) Allergy
•High rate: ~20% of patients develop allergy to drug
3) Systemic side effects
•Dry mouth and nose
•Decreased BP
•Lethargy, esp in young children
4) Contraindication: avoid in patients taking MAOI
•May cause HTN crisis, esp in patients with severe cardiovascular disease

Question 7

Brimonidine (Alphagan P)

Answer 7

•30X more affinity for alpha-2 receptors than apraclonidine
o Much more selective – no alpha-1 effects

FDA category B

Preparations
1) Alphagan and generic brimonidine 0.2% and 0.15%
•BAK preserved, lower pH
•Less comfort and more toxicity
2) Alphagan P* 0.15% and 0.1%
•PURITE preserved with pH closer to that of tears
•Gentler to cornea and more comfortable

Dosing
o	TID when used alone
o	BID when combined with another IOP lowering medication
o	Max effect is 2 hours after dosing
o	Maintains effect over 10-12 hours

Clinical uses
1) Primary or adjunct treatment for primary open angle glaucoma
• No tachyphylaxis
• Approved as chronic, long-term treatment
• 20-30% reduction of IOP
2) Possibly neuroprotective for optic nerve and retinal ganglion cells, but not yet well understood or decisively proven
3) Scotopic miosis following refractive surgery or ortho-K
• Pupils may become larger than zone of treatment in dim illumination
-Causes halos, starbursts, glare, etc.
• Brimonidine relaxes the iris dilator muscle so that pupil stays slightly smaller
-Binding pre-synaptic alpha-2 receptors inhibits release of NE at the iris dilator muscle
-Onset in 30 minutes, lasts 4-6 hours

Question 8

Brimonidine Safety and Efficacy

Answer 8

1) Brimonidine 0.2% proven to be as effective as timolol 0.5% (old gold standard for IOP reduction)
• Better safety profile than timolol
• No cardiopulmonary contraindications like with beta-blockers
• Remember you don’t give beta-blockers to asthma patients because of the bronchoconstriction risk

2) Alphagan P (brimonidine-PURITE 0.15%) has fewer adverse events than original Alphagan (brimonidine 0.2%)

Question 9

Brimonidine Side Effects

Answer 9

1) Allergy in 5-10% of patients (less than apraclonidine)
• The longer a patient uses brimonidine, the more likely they are to develop an allergy
• If a patient is on multiple glaucoma drugs and having an allergic reaction, assume it’s the alpha agonist

2) Systemic side effects
• Dry mouth and nose
• Decreased BP
• Lethargy, esp in young children

3) Contraindication: avoid in patients taking MAOI
• May cause HTN crisis, esp in patients with severe cardiovascular disease

Question 10

Combigan

Answer 10

0.5% Timolol + 0.2% brimonidine
o Beta-blocker + alpha agonist

Dosing BID

Fewer allergies than Alphagan

Not quite as good as using the two medications separately, but still better than either alone

Question 11

Simbrinza

Answer 11

0.1% Brinzolamide + 0.2% brimonidine
o	Carbonic anhydrase inhibitor + alpha agonist
•	Dosing
o	TID when used alone
o	BID when used with another drug

Question 12

Cosopt

Answer 12

Timolol + dorzolamide
• Beta blocker + CAI

Dosing = BID