role of calcium channel blockers in management of migraineium cnannel blockers vascular headaches

8/12/2019 Role of Calcium channel Blockers in management of Migraineium Cnannel Blockers Vascular Headaches

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Calcium Channel Blockers — Vascular HeadacheT.J. Carlov, H.D.

I. Pathophysiology of Vascular Headache

A. Vascular Theory

l. classic migraine

a. decreased posterior cerebral blood flow (CBF)

1. spreading depression 2-3 mm/min P.>+ -s>&c“t2. non—major blood vessel distribution

b. extracranial vasodilation — HA

2. common migraine — no change in CBF

B. Neural Theory-

l. carotid blood flow increases + stimulation__

“af itrigeminal nerve -‘Pe@~¢AmJ

b. lotcuta ce‘ru1eps5+e1.,~,n.. . . . . - . r b . . . _ . ; , . . 4 < 7 1 , - , ¢ , . » » . ; t v t m - s4.,.,.x., a-“A-r»—_c. raphe nuclei ymcdaebe.

2. locus ceruleus stimulation

a. decreasedACBFKr — *e — ~—*

LjL,4k——J? b. increasedrexternal carotidflow4- steady increase

4 1 . -Par: (_L,) ‘fifth{ ¢1'ea5ed_§tim\l13'5i_9 1 H 2t/rZ%*fiC*Uu&”/ c. changes are ipsilateral

II.

C. Current Theory — Lance

1. spontaneous activation spinal tract 5 _ _

2. vascular changes - discharge of brainstem nuclei

3. _excess monoamines_(serotonin-norepinephrine)\i>

reflect changes in central neurotransmitters

Calcium Channels - Vascular Smooth Muscle

A. Increased Intracellular Ca - Contraction §fi‘&”“”X¢1n“¢'VCZ.

1. extracellular Ca - moves intracellular

a. membrane depolarization — opens Ca channelsb. receptor operated — B adrenergic agonist - opens

Ca channels

2. stored intracellular Ca — released

a. endoplastic reticulum

b. mitochondriaB. Elevated intracellular Ca - muscle contracts

1. Ca - binds to calmodulin—(Pru4-2»u\*€Qn~)

2. Ca + calmodulin stimulates myosin kinase

3. myosin kinase phosphorylates myosin

4. myosin interacts with actin

5. muscle contraction

C. Relative value of extracellular Ca for contraction

1. smooth muscle +++

2. cardiac muscle ++

3. skeletal muscle +

.I?'



III Pharmacology Calicum Channel Antagonists

Ca Channel antagonist drugsdihydropyridine

a. nifedipinef

_ L A E “: ~ _ . i l : . £ |

b. _nimodipinefiphenylalkylamine

verapamil*

dipEenyIaIEylamine

flunarizine 5/“J41 0'24 ‘A’ 1 ’l“ 'benzothiazepine

II U

diltiaaem _

9 »

cyproheptadine* __

amitriptyline*Block Voltage Dependant Ca Channels

1 multiple binding sites

2 frequency of channel openings reduced

Brain Ca Channels Blockedmultiple Ca channel subtypes - brain

selective subtypes blocked - drug specific

inhibits Ca dependant serotonin releasedoesn't resolve - vascular vs neural issue for migraine

Approved CC B - Cardiac

r 1 __ _~n%n-II -_

“ €0* _ \_.-I ? * ___

Clinical Pharmacology FDA Approved

Calcium Channel Blockers (CCB)

nifedipine (Procardia)verapamil (Calan, Isoptin)

diltiazem (Cardizem)

route administereda. al oral

ii:. IV - verapamil

c. SL - nifedipine,--- ‘ MM

Principal Metabolic Route — liver

Side Effects

nifedipine - 17 2verapamil - 9

3 diltiazem —

Cardiovascular

hypotension +++A V block

heart failure

edema

&Z

Nifedipine Verapamil Diltiazem

0

O

+

Neurologic *

headache C;Eg:::>§k

Gastrointestinal

constipation 0 (Q; >

nausea <i§%j€:>

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|I- — — — - _—

F

D. Drug Interactions

1. B blockers — hypotension

2. cimetidine — reduced hepatic function — increasedI CCB

i 3. digoxin — increased digoxin levels

4. overdose - calcium gluconate IV and catecholaminesTmeourse for Beneficial Response

1. aura - 2 weeks

2. headache 953; ‘ _ , , _ _ k[Lou Q

3. ma y become refractory

I V. Nifedipine

1. 10 mg. t.i.d

2. decreaseda. freq - 742

I b. severity - 712B. Meyer

1. dose 30 -180_mg.

2. improvement II a. common migraine 5/8

b._ classic migraine 5/6 _

N -PQ (Lo. *EfH§:er 825 D

A. Kahan - 8 patients - 1 month

3. side effects 60

B-edemab. dizziness 1aJ£Lr;y n

V. pot Released FDA I

; ___,-1. ’ 1,

I A. Maybe Most Effective CCB M4l§/-@L/1. hi hest aff' ' sites

W 2 - srtssissj _ P ° = ¢ n < = > {n13P£8_v9 ;-9sfluxI 3. most marked selectivity for cerebralvasculaturefl 9%;

B. Gelmers - 28 Patients - 3 mo. ' ts t **“*' Jo 1. improvement - 12 weeks

I a. 40 mg. t.i.d

b. treated 54

c. placebo 9

C. Meyer — 34 Patients - 2 mo.

I 1. two doses 60 and 12 0 mg./day

2. frequency reduceda. common migraine 71 - 9 32

I b. classic migraine 85 92

c. cluster _63 - 682 y a

3. severity and duration unaffected

4. side effects

I a. muscle cramps

b. dysmenorrhea

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D. Havanka—Kanniainen — 30 mg. q.i.d - 2 mo.

1. common migraine 13

2. classic migraine 20

3. improved

a. frequency 28 2b. severity 25

I _

§#lEkf¢’ VII. Verapamil

Jiyaba-a@tf_ A. Solomon — 80 mg. q.i.d - 4 mo.

/f¢a¢;jgA4¢4 1. 12 patients _ _

a. 7 common migraine

b. 5 classic migraine

2. improvement — decreased

a. frequency 492

b. severity 28

c. maximum benefit 1 mo. Wyuf

B. Markley — 80 mg. t.i.d - 2 mo.

1. 14 patients ébfly,

a. 7 common migraine

b. 7 classic migraine Vwn. , T

2. improvement 564

3. increased benefit 160 mg. q.i.d.’;%&// Au‘

4. major side effect - constipation

C. Meyer - 80 mg. t.i.d - 7 patients

1. al improved

2. 4 cluster

3. 2 classic migraine

4. 1 common migraine

VIII. Diltiazem /6442/1:6‘ ,rL2r‘1~¢¢<»</4 K’/it Ht/ Jim

A. Smith - 9 patients - 2 mo.1. 60 - 90 mg. q.i.d

2. failed nadolol

3. statistica improvement only at 8 weeks

B. Riopelle - 15 Patients 90 mg./day ___—_§__

1. improvement decreased

frequency - 86

5} severity - 552

C. Saunders - Increase Bleeding Time 3 Patients

1. cerebral vasospasm - SA H

2. decrease platelet aggregation

3. diltiazem more potent than other CCBs



IX. Comparison

A. Drug Efficiacy Z improved

Nifedipine 75

Nimodipine 93

Verapamil B1

Diltiazem 86

B.

C.

D.

h_ _

No Significant Difference

Therapeutic Daily Dose — mg.

1.

2.

3.4.

nifedipine - 40

nimodipine - 120

verapamil — 320 - 480diltiazem 9 0

Non—cardiac Uses CCB

1.

II. , . . . . , . . _ .

Q . . . \ L / ‘

--

In

migraine

pulmonary arterial hypertensioncerebral arteria spasm

dgta vasospastic disease'%§

bronchial asthma-i;

esophageal hypermotility

uterine hyperactivity H-_ ?

bladder hyperactivity

potentiates oncologic drugs rm

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eferences

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iiIIIIIIIIIII



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role of calcium channel blockers in management of migraineium cnannel blockers vascular headaches

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