Lecture 5: Migraines and NSAIDS Flashcards
Common causes of headaches
Neck and jaw tension
Nasal pressure
Lack of sleep
Caffeine withdrawal
Eye strain
What are the pharmacological effects of NSAIDS? How are they mediated?
Non-steroidal anti-inflammatory drugs
Analgesic (anti-pain)
Antipyretic (anti-fever)
Anti-inflammatory (except acetaminophen)
All seem to be mediated by common mechanism: inhibition of prostaglandin
Synthesis of prostaglandins
See figure
NSAIDS act on COX enzymes
Cyclo-oxygenase isoforms
COX-1: non inducible, found in many cell types, has critical functions such as maintaining stomach lining
COX-2: induced in immune cells, responsible for pain inflammation and fever
COX-3: highest content in brain and heart, splice variant of COX-1
What is inflammation caused by?
infectious agents
ischemia
antigen/antibody reaction
thermal and other damage
Three phases of inflammation
1) Acute transient phase: local vasodilation, increased capillary permeability (where NSAIDS can control)
2) Delayed subacute phase: infiltration of leukocytes and phagocytes
3) Chronic proliferative phase: tissue degeneration and fibrosis
What does injection of PGs cause?
local inflammation
increased blood flow
Severe pain
Uses of PGs and PG inhibitors on uterus
PGs cause uterine cramping
PGs used in abortions
inhibitors used in dysmenorrhea and to delay delivery
What is temperature set point regulated by?
Hyopthalamus
Delicate balance between heat loss and heat production
How do PGs induce pain?
Stimulating local pain fibres
Inflammation induces hyperalgesia (increased pain sensitivity)
What are other effects of PGs other than pain?
Critical for platelet aggregation (formation of clots) - Aspirin (ASA) used for this reason
Modulate stomach acidity and mucous lining
Important for uterine contraction
How aspirin inhibits COX-1
Aspirin is the only NSAID that permanently blocking COX-1 (destroys enzyme)
Body secretes more COX-1
Exception: Aspirin gets to the platelets via the portal vein. Platelets do not make more COX-1, they are permanently unable to make PGs.
Aspirin is more effective than ibuprofen (advil) when it comes to platelets
How does aspirin work?
Irreversibly acetylates COX enzymes
Effect lasts as long as it takes to replace the COX enzyme
What does caffeine do to analgesic drugs
Increases analgesic effect of all non-opioid analgesic drugs
Cause of effect is unknown, may be cortical vasoconstriction
Required dose of caffeine for coanalgesic effect
60-120 mg
What should you take to cure a headache?
NSAID \+ Tylenol \+ Coffee \+ ice water (causes contents of stomach to dump into intestine)
In what population is salicylate overdose common?
Children
Acetominophen is most common
Drugs that are known to cause salicylate overdose
Pepto-bismol (bismuth salicylate)
Methylsaliculate (oil of wintergreen)
Why shouldn’t you take pesto bismol if you have a aspirin-induced stomach ache?
It is a salicylate and will make your stomach ache worse
Signs and symptoms of salicylate overdose
Tinnitus (typical of elderly using enteric coating)
Marked increase in metabolic rate (SA overdose interferes with oxidative metabolism)
What happens when there is an increase in metabolic rate
Initial hyperventilation: due to futile cycle burning of oxygen, overproduction of CO2
Metabolic acidosis (too much CO2)
Severe hypoglycaemia: futile cycle uses up glucose
Treatment of salicylate overdose
Immediate danger = hyperthermia, dehydration, hypoglycaemia
Parenteral fluids and glucose
parenteral sodium bicarbonate (caution: K+ depletion)
acetazolamide if parenteral bicarbonate does not alkalinize the urine (want urine pH to be above 7)
Activated charcoal (only effective within 2 hours of overdose)
Polyelectrolyte lavage solution
Hemodyalysis (severe overdose)
NSAID classes
Salicylates (methylsalicylate, bismuth salicylate, aspirin)
Proprionic acid (Ibuprofen/Advil, Naproxen/Aleve)
Diclofenac
Indomethacin
Effects of Ibuprofen
Propionic acid
Similar effects to other non-selective COX inhibitors
Less GI effects (but still major problem)
Dosing of Naproxen (aleve)
Has half life of 12-18 hours
Can be dosed only twice a day
Indomethacin
Used for gout pain and swelling
Less common for chronic conditions than diclofenac
What is the primary problem with non-selective COX inhibitors?
GI side effects
PGE2 and PGI2 (products of COX-1) ae made by gastric mucosa. These PGs suppress acid production, increase gastric blood flow, increase secretion of mucin
Inhibition of COX-1: increases acid production, decreases mucous protection
Adverse effects and drug interactions of NSAIDS
Reye’s syndrome (fatal hepatic encephalopathy in children with viral infection (chicken pox, influenza) *only children with mitochondrial diseases
Hypertension, Angina (increase in circulating volume)
Bleeding disorders (inhibition of COX, alcohol, warfarin and rofecoxib)
Distinguishing features of Acetominophen
Tylenol
Analgesic
Acts centrally, no ceiling effect (NSAIDS have ceiling effect)
Anti-pyretic
Not anti-inflammatory
Works in the brain
Acetominophen overdose mechanism
Minor clearance pathway for highly reactive metabolite of acetaminophen at low doses: Glutathione (GSH) in lover
GSH is crucial antioxidant
At high doses of acetaminophen, the reactive metabolite depletes GSH
Causes oxidative damage to liver cells from loss of anti-oxidant and direct damage to liver cells from the highly reactive intermediate
Signs and symptoms of acetominophen overdose
No obvious signs or symptoms
Severely elevated serum transaminase levels (AST, ALT)
Hepatic encephalopathy
Jaundice
Prevalence of migraine headache
18% women, 6% men (more common in boys than girls, reverses after puberty)
Symptoms of migraines
Unilateral or bilateral
Throbbing
Nausea
Often preceded by an aura (usually visual)
Variable duration (hours-days)
Variable incidence (few per year to a few per month)
Triggers for migraines
Weather
Missing a meal
Stress
Alcohol
Food
Menses
Crying
Migraine attack steps
Prodrome
Aura
Headache
Postdrome (exhaustion)
See figure
Management of acute headache
Non-opioid analgesics (NSAIDS) will be effective, should be tried first
Combination of acetaminophen, acetylsalicylic acid and caffeine (excedrin)
Opioid drugs may be used as a last resort
Mechanism of action of ergot alkaloids, ergotamine and dihydroergotamine, side effects
Nonspecific serotonin agonists
Arteriolar vasoconstriction
Caution with ergot alkaloids
Liver disease
Rebound headache with frequent use
Cardiovascular disease - arteriolar vasoconstriction
Poor peripheral circulation
What is Raynaud’s?
Poor peripheral circulation
St Anthony’s Fire
People overdosed on Ergot, vasoconstriction of limbs which caused limbs to rot
Also, ergot made people crazy so there were basically zombies walking around
What we actually use to control acute headache
Triptans
Sumatriptan, naratriptan, risatriptan, zolmitriptan
Available as pill, nasal spray, sublingual (fast and effective)
Relieve nausea and headache
Mechanism of action of triptans
Agonist at 5HT1-1B and 1D (serotonin) receptor agonists
Side effect of Triptans
Simliar to ergot alkaloids
Disadvantage of triptans
Expensive
Caution with triptans
Do not use with MAOI or SSRI antidepressants
Could cause serotonin syndrome
Restlessness, muscle twitches, myoclonus, hyperreflexia, sweating, shivering, tremor -> possible seizures and coma
Prevention of migraines
Propanolol (and other beta blockers) - regulate blood flow, reduce BP
Amytriptyline (and other TCAs) - lower dose than depression
Gabapentin - anticonvulsant, possible modulates GABA receptors
Candesartan - angiotensin II receptor antagonist, reduces BP
Dietary supplements (Riboflaxin, coenzyme Q10, magnesium, citrate)
Side effects of propanolol
Tiredness, dizzyness, decreased libido, dream effects, exacerbate asthma
Side effects of amitriptyline
dry mouth and eyes, drowsiness
