Pharmacology of Botulinum toxin and its therapeutic uses

Introduction:

German physician Justinus kerner was the first to conceive the therapeutic uses of botulinum toxin. He also coined the term "sausage poison" to indicate the toxigenic nature of Botulinum.

Botulinum toxin type A has been used as a therapeutic agent to treat:

1. Focal dystonias of head and neck

2. Spasmodic dysphonia

3. Oromandibular dystonia

4. Cervical dystonia

5. Intractable cervical pain

6. Cricopharyngeal dysphagia

7. Gustatory sweating

8. Hyperhiderosis

9. Blepharospasm

10. To treat wrinkles of face

11. Achalasia cardia

12 Paediatric incontinence due to over active bladder

The basis of using this drug as a therapeutic agent is based on its ability to locally block exocytosis from neurons there by blocking the release of acetyl choline. Hence this chemical belongs to the neuro toxin group.

Secretion of Botulinum toxin:

This toxin is synthesized and secreted by a variety of neurotoxigenic C. botulinum. Clostridium. The neurotoxigenic C. Botulinum are divided into 4 groups depending on the type of toxin they secrete. Seven different botulinum neurotoxin serotypes have been identified.

Types of C. Botulinum:

GroupI: This group synthesizes botulinum toxin serotypes A,B and F

Group II: Organisms synthesize serotypes B,E, and F

Group III: Organisms synthesize serotypes C and D

Group IV: Organisms synthesize serotype G

Molecular structure of Botulinum neurotoxin:

These neurotoxins are synthesized as 150 kDa single chain protein molecules. These molecules when secreted are inert and must be cleaved by proteases for them to become active. These neurotoxin botulinum molecule when acted upon by proteases generates a dichain molecule. This dichain molecule is composed of a heavy chain about 100 kDa and a light chain which measures about 50 kDa. These two chains are held together by disulfide bond.

The active di-chain molecule is made up of the following functional domains:

1. Binding domain at the C terminal portion of heavy chain

2. Translocation domain at the N-terminal portion of the heavy chain

3. Catalytic domain at the N -terminal portion of light chain

Mechanism of action:

1. Inhibits calcium dependent neurotransmitter exocytosis. This is a multistep process.

2. Inhibits release of acetyo choline at the neuromuscular junction

3. Inhibits neurotransmitter release from gamma motor neurons - This can lead to temporary atrophy of muscle fibers.

4. Exhibits antinociceptive action by inhibiting peripheral sensory nerve sensitization to pain

Botulinum toxin binds to the neuronal cells, exclusively to cholinergic neurons. On binding the botulinum toxin is translocated into the neuronal cytosol by a process known as endocytosis. On reaching the cytosol of the neurons, it blocks the release of acetylcholine by closing down the calcium channels. It has been shown that the duration of action of Serotype A is the longest when compared with that of other serotypes.

The effects of Botulinum toxin on the neurotransmitter release is reversible and hence reinjections are necessary to sustain the beneficial effects of the drug. Neurons recover from the effects of botulinum toxin by: 1. Sprouting of nerve endings - causing temporary re-innervation during early recovery phase

2. Increase in turnover of acetylcholine vesicles with retraction of neuronal sprouts - occurs during late recovery phase.

Uses of Botulinum toxin:

1. Due to its blocking effects on the release of acetylcholine it is very useful in the managment of cervical dystonia, spasmodic dysphonia, oro mandibular dystonia and Gustatory sweating.

2. It may be used for providing pain releif in patients with cervical dystonia, head ache, migraine and back ache. This effect is produced due to the ability of botulinum toxin to inhibit peripheral sensory nerve sensitization to pain.

Adverse effects:

Most common adverse effect caused by this drug is dryness of mouth