Adjuvant analgesics rugs used to treat gout, centrally acting muscle relaxants

Adjuvant analgesics

Definition

Drugs lacking a genereal analgesic effect but reducing neuropathic pain -> their mode of action is largely unkown

Effective only on neuropathic pain

Damage of peripheral or central pain pathway due to

Polyneuropathy

Traumatic nerve lesion

Spinal cord injury

Damage at the level of the middle brain, thalamus, cortex

Types

Phantom limb pain

Traumatic neuropathy

Postherpetic neuralgia

Trigeminal neuralgia

Pain following stroke

Symptoms

Spontaneous pain

Mechanical heat or col hyperalgesia

Allodynia

Conventional analgesics don't work

Drugs used to treat gout

breakdown of purine

GMP & AMP - hypoxanthine -> xanthine - uric acid

by xanthine oxidase

Disorders of uric acid

Disturbance of metabolism and excretion -> hyperuricemia

Primary

A defect of ruic acid secretion

Overproduction of ruic acid

Secondary

urate overproduction due to malignant tumors and their chemotherapy and radiotherapy

Reduced urinary excretion of uric acid due to renal failure or drugs or ethanol

Consequence

precipitation of NA urate crystals in tissue or tissue fluid

Acute gout arhtritis

Tophus formation in tendons and bones

Interstitial nephritis and urate renal stone

Centrally acting muscle relaxant

General

Centrally acting muscle relaxant act on the brain

quality of the drugs is different

Features

Acting in the CNS

Reduce the pathological tone of skeletal msucle w/o compromising voluntary contraction

Different then peripheral muscle relaxants

Drugs

Most drugs act in the spinal cord

Typical route of administration -> oral

Side effect

sedation

Muscle relaxants

clinical efficacy

effective in spasticity only

Effective in acute muscle spasm only

Effective in both

Site of action

presynaptic inhibition (GABA)

Inhibition of excitatory transmitter from presynaptic neuron (baclofen)

Indication

spasticity

Chronic, often only partially improving condition

Evoked by impairement of the descending corticospinal inhibitory pathways regulating stretch reflex

Spasm of antigravity muscles

enhanceed stretch reflex

pain and siability

Acute muscle spasm

Reversible

Self improving condition

Muscle tone increase caused by reflex mechanism initiated by trauma or inflammation

Affecting muscle or by pain

Adjuvant analgesics

Tricyclic antidepressant

Amitriptyline

Nortriptyline

Antiepileptic

phenytoin

Carbamazepine

Oxcarbazepine

Gabapentin

Larmotrigine

Na channel blocking agent

Lidocine

Mexiletine

Capsaicin

Given locally

Transdermal patch

Selective blocking of peripheral nociceptors

Drugs used to treat gout

Prototype

Allopurinol

MOA

Analog of hypoxanthine

Act as substrate for xanthine oxidase

Converted to oxipurinol

Inhibit urate formation

Non-competitive inhibitor of xanthine oxidase

T1/2

Allopurinol 1h

Oxipruinol 24h.

Major part of allopruinol effect

Excreted by urine

Effects

Less uric acid is produced

accumulate hypoxanthine and xanthine

Have good water solubility

slightly inhibit de novo purine synthesis

Side effect

Increas risk of acute attack in the first 2 weeks

Can be prevented by cochicines or NSAID

GI disturbance

Allergic reaction

Renal failure

Interaction

Slower metabolism

Azathioprine

Mercaptopurine

Slower metabolism of coumarins/theophylline

Xanthine oxidase inhibitor

Rasburicase

Reduce uric acid lvl

Recombinant urate osidase

convert urate to allantoin which is awter soluble

Uricosuric drugs

probenecid
sulfinpyrazone
benzbromarone

Increase renal excretion of uric acid

by inhibiting urate reabsorption in proximal tubule

MOA

Given P.O

Significant plasma protein binding

Reach sight of action at luminal memb of proximal tubule

Induce secretion of urate

Effect

At lower dose

Paradoxically evoke urate retention because they competitively inhibit active secretion of urate in proximal tubule

Therapeutic dose

The sum of these opposing effect is a net increase in renal excretion uric acid

Side effect

increase risk of acute attack during the first 2 weeks

Can be prevented by colchicines or NSAID

Urate renal stone formation

can be prevented by elevating pH of urine by NA-bicarbonate or NA-citrate

Diarrhea

Urate renal stone

Drugs of acute gouty arthritis

Colchicines

MOA

Inhibit polymerization of tubulin into microtubules

Reduces chemotaxis and phagocytotic activity fo neutrophils and some function of T cells

Good oral absorption % I.v.

used for 3-5 days only

Metabolism

Partially by CYP3A4

excreted in urine and bile by enterohepatic circulation

Side effect

NSAID

Drugs of choice because they have less side effect than cohicine

COX inhibitors with less GI side effect are used

Glucocortioid

If the 2 other drugs don't work

Centrally-acting muscle relaxant

Centrally-acting muscle relaxant effective in spasticity only

Baclofen

Agonist of presynaptic GABA-b rec (Gi coupled)

MOA

Reduces transmitter release from central terminals of type Ia proprioceptive afferent

It is involved in the stretch reflex

Inhibiton of the stretch reflex

reduction of muscle tone

Orally or intrathecally

Metabolism

unchanged by the kidney

Withdrawal

Convulsion

Hallucination

Flexor reflex is also inhibited

by reducing transmitter release from central terminals of nociceptive afferents

Gabapentin

Under trial

Effective in muscle spasm only

Guaifenesin

I.m. or i.v.

inhibit polysynaptic spinal reflex

Chlorzoxazone

inhibiting polysynaptic spinal reflex

may cause dizziness and cholestatic icterus

Effective in both spasticity and acute muscle spasm

Benzodiazepine

diazepam, Tetrazepam

Anxiolytic action can contribute to therapeutic effect

MOA

Positive alloseric modulation of GABA-a rec

Enhance presynaptic inhibitory effect of spinal GABA-ergic interneurons exerted on type Ia muscle afferent

Reduce transmitter release

inhibit stretch reflex

Tizanidine

Clonidine derivative

MOA

alpha2 receptor agonist

reduce transmitter release from central terminals of type Ia afferents

Side effect

Hypotension

dry mouth

Tolperisone

MOA

Na channel block

Inhibit propagation of action potential in muscle afferents

Reduce transmitter release

Inhibiton of the stretch reflex

Enhance peripheral blood flow

Orally or I.v.

Side effect

Liver damage

hypotension

Headache

no sedation