Hyperhidrosis

Question 1

What drugs are approved for on-label use of Hyperhidrosis?
• which are used off-label?

Answer 1

On label: Aluminum chloride, Botulinum toxin.

Off label:
• Anti-muscarinics: Glycopyrrolate, Oxybutynin, Propantheline
• Alpha (clonidine) and Beta (propanolol) blockers
• CCB’s Dilatizem

Question 2

What system and neurotransmitter controls sweating through Eccrine and Apocrine glands?

Answer 2

Sweating: controlled via Ach postganglionic stimulation for Eccrine glands (note the unique use of Ach by the sympathetic NS, we also see this in dilator fibers in vascular smooth muscle in skeletal muscle vasculature) and Catecholamine postganglionic stimulation for Apocrine glands

Question 3

What ligand receptors recieve signals to sweat?

Answer 3

Sweat glands are stimulated by alpha-1receptors for local effects and M2 (Gi GPCR), M3 (Gq GPCR) receptors for generalized effects.

Question 4

What receptors control the constriction and dilation of Skin and Mucosal blood vessels?

Answer 4

Skin and mucosal blood vessels: Vasoconstriction via alpha-1 and alpha-2 effects via the SYMPATHETIC Nervous System with any parasympathetic dilation occurring from NO release.

Question 5

What symptoms would you see in someone that you gave too much of an AchE inhibitor to?

Answer 5

Question 6

Explain the physiology that causes sweat to leave the gland.

Answer 6

Shown here is the mechanism of Ach stimulation in sweat glands. The following steps happen with Ach binds to M3 (Gq) receptors.
1. Intracellular Ca2+ increases leading to efflux of H2O and Cl-.

2. Cell shrinkage then causes Na2+/K+/2Cl- co-transporter to get activated

3a. Na/K ATPase then gets activated to restore Na+/K+ balance.
3b. Cl- flows unopposed into the lumen of the gland

4. Na+ follows PARACELLULARLY into lumen to follow Cl-

Question 7

How should you approach the treatment of Hyperhidrosis?

Answer 7

• *General Treatment of Hyperhidrosis should progress as follows:**
  1. Try antiperspirants
  2. Botulinum toxin injections
  3. Try anticholinergics
  4. Ablate

Question 8

Aluminum Chloride
Administration
MOA
Side effects

Answer 8

Aluminum Chloride

Administration – Topical

MOA
Short-term occlusion of eccrine and apocrine sweat gland ducts – combines with keratin to produce fibrillar contraction of duct

SIDE EFFECTS
Minimal Systemic Absorption

Renal Elimination of What is absorbed

Question 9

Botulinum Toxin
Administration
MOA
RESISTANCE
SIDE EFFECTS

Answer 9

Botulinum Toxin
Administration - SC

MOA

• *2 portions - Heavy and Light Chains:
• Heavy Chain*: Binds Cell membrane allowing for Endocytosis
• Light Chain:* Cleaves SNAP25 that is needed for exocytosis of vesicles containing Ach AND PAIN NEUROPEPTIDES too**

RESITANCE
• Sprouting of new nerve endings that reconnect with the muscle

SIDE EFFECTS:
• Blocks BOTH nicotinic (Nm receptors = ion channels for muscle movement) and muscarinic receptors
• SYSTEMIC EFFECTS rare but include Respiratory arrest and death
• Anti-Ach effects: Dry mouth, tiredness, blurred vision, dry eyes, urinary retention

Question 10

Of the anticholinergics used to treat Hyperhidrosis, which is most likely to cause CNS effects?
• what would these effects be?

Answer 10

Oxybuterin crosses the BBB so its most likely to cause symptoms of tiredness, diplopia, etc.

(glycopyrrolate and propantheline are the others used)

Question 11

Why do CCBs have the potential to work in hyperhidrosis?

Answer 11

• CCBs like diltiazem can block Ca2+ needed in the initiation of sweat gland activation

Question 12

Glycopyrrolate
MOA
Indication
Side Effects

Answer 12

MOA
Antimuscarinic that can be used to prevent stimulation of eccrine glands by AcH
• cannot pass BBB

INDICATION
Failed therapy with botulinum toxin and Aluminum chloride

SIDE EFFECTS
Dry mouth, Dry Eye, Urinary Retention, Gastrointestinal non-motility

Question 13

Propanthelin
MOA
Indication
Side Effects

Answer 13

MOA
Antimuscarinic AND anti-nicotinic that can be used to prevent stimulation of eccrine glands by AcH
• cannot pass BBB

INDICATION
Failed therapy with botulinum toxin and Aluminum chloride

SIDE EFFECTS
Dry mouth, Dry Eye, Urinary Retention, Gastrointestinal non-motility
• Anti-nicotinic abilities of this drug could cause muscle weakness

Question 14

Oxybutynin
MOA
Indication
Side Effects

Answer 14

Oxybutynin
MOA
Antimuscarinic that can be used to prevent stimulation of eccrine glands by AcH
• cannot pass BBB

INDICATION
Failed therapy with botulinum toxin and Aluminum chloride

SIDE EFFECTS
• more likely to have CNS associated affects (tiredness etc.)
Dry mouth, Dry Eye, Urinary Retention, Gastrointestinal non-motility