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