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Neuro exam 2 > Treatment of headaches > Flashcards

Treatment of headaches Flashcards

1
Q

Biological effects of Brady kinin and Kallidin

A

autocoids that induce inflammation, pain and vasodilation

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2
Q

Synthesis of kinins

A
  1. Kininogens → Kallikrein → Kinins
  2. Kininogens are precursors of kinins
  3. Kallikreins are serine proteases that cleave Kininogens into kinins
  4. High Molecular Weight Kininogen (HMWK) is cleaved by Plasma
    Kallikrein into bradykinin
  5. Low Molecular Weight Kininogen (LMWK) is cleaved by Tissue Kallikrein
    into kallidin which is then cleaved by an Aminopeptidase into Bradykinin
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3
Q

The plasma kinin forming system

A
  1. Autoactivation of factor XII (Hageman Factor) to factor XIIa. Factor XIIa
    converts Plasma Prekallikrein to Plasma Kallikrein, Plasma Kallikrein
    converts High Molecular Weight Kininogen (HMWK) to Bradykinin. Plasma
    Kallikrein activates factor XIIa. This is a positive feedback loop, and the first
    step in the intrinsic clotting cascade that enhances Bradykinin synthesis.
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4
Q

The tissue kallikrien-kinin forming system

A
  1. Tissue Kallikrein is different than Plasma Kallikrein.
  2. Tissue Kallikrein converts Low Molecule Weight Kininogen (LMWK) to
    Kallidin. Aminopeptidase converts Kallidin to Bradykinin
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5
Q

Metabolism of Kinins

A

1.Carboxypeptidase N and M (CPN, CPM) (Also known as Kininase I) are
metallopeptidases that cleave Kinins into active kinin metabolites (des-Arg9-
Bradykinin/ des-Arg10-Kallidin).
2. *Angiotensin I-Converting Enzyme (ACE) (also known as Kininase II)
hydrolyzes Bradykinin into inactive products. The cardioprotective and blood
pressure lowering effects of ACE inhibitors (like Captopril) may in part be
due to increases in Bradykinin.

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6
Q

Kinin Receptors

A

1.B1 and B2 are G protein coupled receptors
2. Native Bradykinin and kallidin activate the B2 receptor.
3. Bradykinin and kinin active metabolites (des-Arg9
-Bradykinin/ des-Arg10-
Kallidin) activate the B1 receptor
4. B2 receptor constitutively expressed in most tissues
5. B1 receptor is induced by tissue damage, inflammation
6. Activation of B receptors stimulates increases in the synthesis of
prostaglandins, NO, EDHF

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7
Q

Drug interactions of Kinins

A

1.NSAIDS reduce bradykinin and Kallidin-induced increases in PG production
by inhibiting cyclo-oxygenase
2. Corticosteroids reduce bradykinin and Kallidin-induced PG production by
stimulating increases in Lipocortin. Lipocortin is a phospholipase A2
inhibitor

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8
Q

Effects of kinins

A

1.Pain: kinins can induce the excitation of sensory neurons, which induces the
release of neuropeptides, substance P, neurokinins, and calcitonin gene related
peptide (CGRP). *CGRP is the most potent vasodilator peptide in the
trigeminal system (important for Migraine).
2.Inflammation: Kinins increase permeability of microcirculation which can
promote edema
3. Respiration: Kinins can induce bronchospasms and kinin levels can be
elevated in asthma
4. Cardiovascular: Kinins induce vasodilation and lower BP

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9
Q

Serotonin (5-HT): Biological effects. Platelets, cardiovascular, GI, and CNS

A

1.Platelets
a) Platelets do not synthesize serotonin but actively take up and store
serotonin. Serotonin release during platelet aggregation promotes platelet
aggregation and vasoconstriction.
2.Cardiovascular
a) Induces vasoconstriction and has positive inotropic and chronotropic
effects on heart
3.GI
a) Enterochromaffin cells release 5-HT in response to vagal stimulation and
stretching with food ingestion. 5-HT will regulate GI motility. 5-HT
producing carcinomas will induce diarrhea and abdominal cramps.
4.CNS
a) 5-HT neurons in raphe nuclei of brain stem and project throughout the
brain and spinal cord.

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10
Q

Synthesis and inactivation of 5-HT

A
  1. Serotonin is preferentially inactivated by monoamine oxidase A (MAO-A)
    isoform, platelets only express the MAO-B isoform
  2. 5-Hydroxyindoleacetic acid (5-HIAA) is the urinary metabolite of 5-HT
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11
Q

*5-HT1 Receptors

A
  1. There are seven 5-HT receptor subtypes some of which have defined
    functions including the 5-HT1 family.
  2. The role of 5-HT1B/1D receptors in migraine
    a) *5-HT1D induce vasoconstriction of cranial blood vessels. *5-HT1B is an
    autoreceptor and its activation inhibits nociceptive trigeminal afferents,
    which reduces migraine pain.
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12
Q

Role of 5-HT in Migraine

A
  1. Urinary and platelet 5-HT levels decrease during Migraine attacks
  2. *Triptans are 5-HT1B/1D agonist to treat migraine pain.
  3. Intravenous infusion of 5-HT aborts spontaneous headache
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13
Q

Migraine Headaches overview and types

A

1.Afflict over 23 million individuals each year.

Common migraine: Has no aura and has headache.

Classic Migraines: Have aura and HA

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14
Q

Aura

A

Sensory disturbance in brain prior to headache
• Visual disturbance → scintillating scotoma
• Sensory disturbance → Focal paresthesia
• Motor disturbance → Weakness or paralysis
• Auditory Disturbance → Excessively sensitive to noise or light

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15
Q

Migraine stages

A

a) Prodome (1 – 2 days prior to attack) GI effects Mood changes
b) Aura (20- 60 min prior to attack)
c) Attack 4hrs – 3 days
d) Postdrome

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16
Q

Characteristics of migraine attack

A

a) POUND (Pulsating Headache lasting 4-72 hOurs that is Unilateral,
Nauseating and Debilitating)

17
Q

Pathophysiology of Migraine (Working Model)

A

a) Genetically susceptible patients
b) Triggers include: stress, certain foods, odors, change in sleep habits
c) Neurovascular headache: a disorder in which neural events results in
further dilation of cranial blood vessels, which in turn, results in pain
and further nerve activation
d) Migraine is not caused by a primary vascular event
e) Migraine is likely caused by brain-stem nuclei that normally

18
Q

*Drug therapy for Migraine:

Goals

A

a) Reduce the number of Migraine attacks with Migraine prophylactic drugs
(*if attacks are occurring frequently)
b) Reverse Migraine Attack with Rescue/Abortive Migraine Drugs.

19
Q

Types of Drugs

A

a) Prophylactic drugs that reduce the migraine frequency
b) Drugs used to treat Migraine attacks (“rescue or abortive
drugs”) once they occur. These can be further divided into
nonspecific pain-reducing drugs and migraine-specific drugs.

20
Q

Prophylactic agents: Beta blockers

A

Propranolol and Atenolol taken orally (FDA approved)
• May take three weeks to be effective
• Relatively well tolerated and effective
*Mechanism by which beta blockers reduce migraine attacks is not
clear. Hyperfunctioning of the sympathetic nervous system has been
suspected in patients with migraines.
• Side effects are reduced energy, tiredness
• Contraindicated in patients with asthma

21
Q

Prophylactic agents: Tricyclic Antidepressants

A

Amitriptyline and Nortriptyline are taken orally
• The precise mechanism of the anti-migraine effects of tricyclic
antidepressants is not clear, however, could be attributed to
inhibition of serotonin reuptake.
• *Side effects limit use and include significant antimuscarinic
properties, weight gain and tiredness.

22
Q

Prophylactic agents: Anticonvulsants

A

• Valproic acid, Topiramate, Gabapentin & Levetiracetam taken
orally
• Effective in some patients. Mechanisms of anti-migraine activity not
clear. Increases in gamma-aminobutyric acid (GABA) signaling
could play a role.
• Valproic Acid is contraindicated in pregnancy because of
teratogenicity. Side effects include drowsiness, anorexia, nausea,
ataxia, alopecia, tremor as well as liver toxicity.
• Used especially in migraine patients with epilepsy or anxiety
disorders

23
Q

Prophylactic agents: Calcium channel blockers

A

Verapamil
• Antihypertensive drug that reduces the incidence of migraine
through mechanisms that are not clear
• Side effects include negative inotropic cardiac effects, hypotension

24
Q

Prophylactic agents: Cyproheptadine:

A

Potent antagonist of histamine, acetylcholine, and serotonin
• Used for seasonal allergy and pruritus from histamine release
• Cyproheptadine has proven effective in the prophylaxis of migraine
headache
• Side effects include high incidence of CNS depression and
sleepiness

25
Q

Prophylactic agents: BOTOX:

A

Prophylaxis - Migraine (Chronic)
• Multiple injections given in head/neck muscle areas
• Mechanism: blocks neuromuscular conduction by binding to
receptor sites on motor nerve terminals, entering the nerve terminals,
and inhibiting the release of acetylcholine. When injected
intramuscularly in therapeutic doses, causes muscle paralysis

26
Q

*Migraine “Rescue/abortive” drugs

A

a) Taken just before a migraine attack or as soon as possible after onset of
migraine attack
b) Nonspecific agents that treat pain and are used to abort a migraine
attack include:
i. INSAIDS, Ibuprofen, naproxen, acetaminophen, ketorolac
ii. Mild to Moderate Migraine: Acetaminophen, Aspirin,
ibuprofen, naproxen. Combinations of acetaminophen, aspirin
and caffeine can also help
iii. Moderate to Severe Migraine: Ketorolac (IV or oral) use for a
max 5 days
iv. Children: Acetaminophen and ibuprofen
v. Pregnant women: Ibuprofen and acetaminophen can be used in
pregnancy. *All NSAIDs should be avoided in the last trimester
due to increased bleeding and premature closure of the ductus

27
Q

Migraine “Rescue/abortive” drugs: Ergot alkaloids

A

i. Ergotamine and Dihydroergotamine
ii. Used for moderate to severe migraine attacks and can be
combined with an antiemetic to curve nausea
iii. *They are rescue agents that are not used for prophylactic
therapy
iv. Mechanism: The anti-migraine activity of ergot alkaloids are
likely to be attributed their agonist effects at 5-HT1 receptors,
however they also have partial agonist and antagonist activity at
serotonergic, dopaminergic and adrenergic receptors

28
Q

Migraine “Rescue/abortive” drugs: Ergot alkaloids 2

A

v. Routes of administration: Ergotamine sublingual (extensive
first pass effect). Dihydroergotamine: nasal spray, or injection
(sc, im, or iv)
vi. **Side effects: Nausea and vomiting induced by Ergots are a
problem given that nausea and vomiting are associated with migraine. Significant generalized vasoconstriction can also be a
significant problem (Myocardial infarction, Peripheral ischemia,
Vasoconstriction, Coronary, Vasospasm). Ergots cannot be
used in pregnancy (Pregnancy X drug) they may cause fetal
stress and miscarriage.
vii. **Contraindicated in: (1) pregnancy (2) peripheral vascular
disease (tingling, peripheral vasoconstriction) (3) Ischemic
Heart Disease because can induce angina, coronary vasospasms
viii. *Cannot be used in combination with Triptans (must have 24 hr
delay).

29
Q

Migraine “Rescue/abortive” drugs: Triptans

A

i. There are several Triptans including Sumatriptan, Rizatriptan,
Zolmitriptan, Naratriptan and Frovatriptan
ii. Triptans are used to abort a migraine attack and they are not
used for migraine prophylaxis
iii. *Triptans cause significantly less nausea and generalized
vasoconstriction as compared to the Ergot alkaloids
iv. Triptans have a more selective mechanism of action relative to
the Ergots given that they are selective 5-HT1B/1D Receptor
Agonists
v. *Antimigraine Mechanisms of the 5-HT1B/1D Receptor Agonists

30
Q

Migraine “Rescue/abortive” drugs: Triptans MoA

A

Vascular: Vasoconstriction of cranial vessels

Neurogenic: Reduction of trigeminal sensory nerve activation
and inhibition of vasoactive neuropeptide
release

Central: Inhibition of neurotransmitter release from
activated trigeminal nerves in the brainstem and
upper cervical spinal column

31
Q

Migraine “Rescue/abortive” drugs: Sumatriptan

A

• Prototype triptan and has a short onset and short duration of
action.
• Administered subcutaneously, orally or via nasal spray and
provides relief within approximately 1 hr and has a half-life of 2
hrs.
• Onset of action for SQ

32
Q

Migraine “Rescue/abortive” drugs: Naratriptan and Zolmitriptan

A

• Given orally, onset of action of approximately 1hr
• Lipophilicity may result in greater distribution to the brain
stem.
• Greater bioavailability (70%) relative to sumatriptan (15%)
• More effective then sumatriptan with a lower instance of
recurring headaches.
• Longer duration of action (half-life of 6 hrs) compared to
sumatriptan
• P450 metabolism and 50% of drug excreted in urine unchanged
• Lower dose in renal dysfunction

33
Q

Migraine “Rescue/abortive” drugs: Frovatriptan

A

longest acting Triptan (half-life of more than 24 hrs).
Highest affinity for 5-HT1B/1D receptor. Slower unset to action than other
triptans.

34
Q

Migraine “Rescue/abortive” drugs: Rizatriptan

A

Available as quick dissolving tablet (sublingual)
• Rapid onset of action, high bioavailability, Faster onset than
sumatriptan
• Less nausea than sumatriptan
• Half-life 2 hrs
• Metabolism MAO

35
Q

Migraine “Rescue/abortive” drugs: AE and Contra

A

Adverse effects
• * Headache Recurrence
• Tingling, paresthesia, dizziness, flushing, neck pain and
drowsiness

Contraindications
• Use of ergot alkaloid within 24 hrs
• peripheral vascular disease
• ischemic heart disease

36
Q

Migraine “Rescue/abortive” drugs: Drug interactions

A

Should avoid concurrent use with Serotonin Selective Reuptake
Inhibitors as it could induce serotonin syndrome that manifests
as restlessness, hallucinations, loss of coordination, diarrhea

37
Q

Cluster Headaches

A 
1.Episodic severe unilateral stabbing headaches that tend to appear at the same
time each (circadian rhythm)
2.Acute Treatments for cluster headache attack include:
a) Oxygen
b) Triptans (rapid onset Triptans)
3.Prophylactic
a) High dose prednisone
b) Calcium channel Blockers (Verapamil)
38
Q

Tension Headaches:

A

1.Headache pain is a squeezing sensation or pressure felt around the head that is
not associated with nausea or vomiting.
a) Abortive medications
• Acetaminophen and NSAIDS
b) Prophylactic medications include: tricyclic antidepressants such as
amitriptyline and the antiepileptic gabapentin

39
Q

. Idiopathic Intracranial Hypertension (IIH)

A
  1. Pain due to increases in intracranial pressure and the disorder occurs most
    frequently in obese young women
  2. Treatments include weight loss and removal of drugs that could be
    responsible for IIH (including: tetracycline containing drugs, oral
    contraceptives and hypervitaminosis)
  3. Drug therapy includes the use of carbonic anhydrase inhibitors:
    a) *Acetazolamide and Topiramate
    b) Mechanisms: Function as carbonic anhydrase inhibitors that reduce CSF
    production
    c) Side effects: nausea, fatigue, tingling in the hands and feet and altered
    taste, distal paresthesia, concentration difficulties and weight loss

Neuro exam 2 (35 decks)

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