Color Atlas of Pharmacology (Part 17): Drugs Acting on Motor Systems

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Drugs Affecting Motor Function

The smallest structural unit of skeletal

musculature is the striated muscle fiber

It contracts in response to an impulse of

its motor nerve In executing motor pro-

grams, the brain sends impulses to the

spinal cord These converge on a-moto-

neurons in the anterior horn of the spi-

nal medulla Efferent axons course, bun-

dled in motor nerves, to skeletal mus-

cles Simple reflex contractions to sen-

sory stimuli, conveyed via the dorsal

roots to the motoneurons, occur with-

out participation of the brain Neural

circuits that propagate afferent impuls-

es into the spinal cord contain inhibit-

ory interneurons These serve to pre-

vent a possible overexcitation of moto-

neurons (or excessive muscle contrac-

tions) due to the constant barrage of

sensory stimuli

Neuromuscular transmission (B) of

motor nerve impulses to the striated

muscle fiber takes place at the motor

endplate The nerve impulse liberates

acetylcholine (ACh) from the axon ter-

minal ACh binds to nicotinic cholinocep-

tors at the motor endplate Activation of

these receptors causes depolarization of

the endplate, from which a propagated

action potential (AP) is elicited in the

surrounding sarcolemma The AP trig-

gers arelease of Ca* from its storage or-

ganelles, the sarcoplasmic reticulum

(SR), within the muscle fiber; the rise in

Ca“ concentration induces a contrac-

tion of the myofilaments (electrome-

chanical coupling) Meanwhile, ACh is

hydrolyzed by acetylcholinesterase

(p 100); excitation of the endplate sub-

sides If no AP follows, Ca2* is taken up

again by the SR and the myofilaments

relax

Clinically important drugs (with

the exception of dantrolene) all inter-

fere with neural control of the muscle

cell (A, B, p 183 ff.)

Centrally acting muscle relaxants

(A) lower muscle tone by augmenting

the activity of intraspinal inhibitory

interneurons They are used in the treat-

ment of painful muscle spasms, e.g., in

spinal disorders Benzodiazepines en- hance the effectiveness of the inhibitory transmitter GABA (p 226) at GABAa receptors Baclofen stimulates GABAg receptors a2-Adrenoceptor agonists such

as clonidine and tizanidine probably act presynaptically to inhibit release of excitatory amino acid transmitters The convulsant toxins, tetanus tox-

in (cause of wound tetanus) and strychnine diminish the efficacy of interneu- ronal synaptic inhibition mediated by the amino acid glycine (A) As a conse- quence of an unrestrained spread of nerve impulses in the spinal cord, motor convulsions develop The involvement

of respiratory muscle groups endangers life

Botulinum toxin from Clostridium botulinum is the most potent poison known The lethal dose in an adult is approx 3 x 10-6 mg The toxin blocks exo- cytosis of ACh in motor (and also para- sympathetic) nerve endings Death is caused by paralysis of respiratory muscles Injected intramuscularly at minus- cule dosage, botulinum toxin type A is used to treat blepharospasm, strabis- mus, achalasia of the lower esophageal sphincter, and spastic aphonia

A pathological rise in serum Mg?+ levels also causes inhibition of ACh release, hence inhibition of neuromuscular transmission

Dantrolene interferes with electromechanical coupling in the muscle cell

by inhibiting Ca?* release from the SR It

is used to treat painful muscle spasms attending spinal diseases and skeletal muscle disorders involving excessive release of Ca2+ (malignant hyperther- mia)

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An

Myotonolytics

Antiepileptics tiparkinsonian drugs

Xa>>

Muscle relaxants

Benzodiazepines Tetanus

e.g., diazepam GABA \ | Glycine Toxin

Inhibition

Strychnine

| {+ Baclofen antagonist

(GABA =

y-aminobutyric acid)

A Mechanisms for influencing skeletal muscle tone

Botulinum toxin inhibit generation inhibit of action ACh-release potential

Sarcoplasmic reticulum

Action potential t-Tubule

Depola-

rization

Membrane potential

l———

Muscle ton ACh receptor usere tone

(nicotinic) JN

ms 10 20

Dantrolene inhibits

Ca®* release

Motor

Gontraction

B Inhibition of neuromuscular transmission and electromechanical coupling

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Muscle Relaxants

Muscle relaxants cause a flaccid paraly-

sis of skeletal musculature by binding to

motor endplate cholinoceptors, thus

blocking neuromuscular transmission (p

182) According to whether receptor oc-

cupancy leads to a blockade or an exci-

tation of the endplate, one distinguishes

nondepolarizing from depolarizing

muscle relaxants (p 186) As adjuncts to

general anesthetics, muscle relaxants

help to ensure that surgical procedures

are not disturbed by muscle contrac-

tions of the patient (p 216)

Nondepolarizing muscle relaxants

Curare is the term for plant-derived ar-

row poisons of South American natives

When struck by a curare-tipped arrow,

an animal suffers paralysis of skeletal

musculature within a short time after

the poison spreads through the body;

death follows because respiratory mus-

cles fail (respiratory paralysis) Killed

game can be eaten without risk because

absorption of the poison from the gas-

trointestinal tract is virtually nil The cu-

rare ingredient of greatest medicinal

importance is d-tubocurarine This

compound contains a quaternary nitro-

gen atom (N) and, at the opposite end of

the molecule, a tertiary N that is proto-

nated at physiological pH These two

positively charged N atoms are common

to all other muscle relaxants The fixed

positive charge of the quaternary N ac-

counts for the poor enteral absorbabil-

ity

d-Tubocurarine is given by i.v in-

jection (average dose approx 10 mg) It

binds to the endplate nicotinic cholino-

ceptors without exciting them, acting as

a competitive antagonist towards ACh

By preventing the binding of released

ACh, it blocks neuromuscular transmis-

sion Muscular paralysis develops with-

in about 4 min d-Tubocurarine does not

penetrate into the CNS The patient

would thus experience motor paralysis

and inability to breathe, while remain-

ing fully conscious but incapable of ex-

pressing anything For this reason, care must be taken to eliminate conscious- ness by administration of an appropri- ate drug (general anesthesia) before us- ing a muscle relaxant The effect of a single dose lasts about 30 min

The duration of the effect of d-tubocurarine can be shortened by adminis- tering an acetylcholinesterase inhibitor, such as neostigmine (p 102) Inhibition

of ACh breakdown causes the concentration of ACh released at the endplate

to rise Competitive “displacement” by ACh of d-tubocurarine from the receptor allows transmission to be restored Unwanted effects produced by d-tubocurarine result from a nonimmune- mediated release of histamine from

mast cells, leading to bronchospasm, ur-

ticaria, and hypotension More com- monly, a fall in blood pressure can be attributed to ganglionic blockade by d-tubocurarine

Pancuronium is a synthetic compound now frequently used and not likely to cause histamine release or ganglionic blockade It is approx 5-fold more potent than d-tubocurarine, with

a somewhat longer duration of action Increased heart rate and blood pressure

are attributed to blockade of cardiac M2-

cholinoceptors, an effect not shared by newer pancuronium congeners such as vecuronium and pipecuronium Other nondepolarizing muscle relaxants include: alcuronium, derived from the alkaloid toxiferin; rocuroni-

um, gallamine, mivacurium, and atra- curium The latter undergoes spontane- ous cleavage and does not depend on hepatic or renal elimination

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z=

J, Jase

&

Arrow poison of indigenous South Americans

0œ (no enteral absorption) Sow 3

0

Blockade of ACh receptors

No depolarization of

endplate

Relaxation of skeletal muscles ventilation cholinesterase

(Respiratory paralysis) ——————————> (plus general e.g., neostigmine

A Non-depolarizing muscle relaxants

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Depolarizing Muscle Relaxants

In this drug class, only succinylcholine

(succinyldicholine, suxamethonium, A)

is of clinical importance Structurally, it

can be described as a double ACh mole-

cule, Like ACh, succinylcholine acts as

agonist at endplate nicotinic cholino-

ceptors, yet it produces muscle relaxa-

tion Unlike ACh, it is not hydrolyzed by

acetylcholinesterase However, it is a

substrate of nonspecific plasma cholin-

esterase (serum cholinesterase, p 100)

Succinylcholine is degraded more slow-

ly than is ACh and therefore remains in

the synaptic cleft for several minutes,

causing an endplate depolarization of

corresponding duration This depola-

rization initially triggers a propagated

action potential (AP) in the surrounding

muscle cell membrane, leading to con-

traction of the muscle fiber After its iv

injection, fine muscle twitches (fascicu-

lations) can be observed A new AP can

be elicited near the endplate only if the

membrane has been allowed to repo-

larize

The AP is due to opening of voltage-

gated Na-channel proteins, allowing

Nat ions to flow through the sarcolem-

ma and to cause depolarization After a

few milliseconds, the Na channels close

automatically (“inactivation”), the

membrane potential returns to resting

levels, and the AP is terminated As long

as the membrane potential remains in-

completely repolarized, renewed open-

ing of Na channels, hence a new AP, is

impossible In the case of released ACh,

rapid breakdown by ACh esterase al-

lows repolarization of the endplate and

hence a return of Na channel excitabil-

ity in the adjacent sarcolemma With

succinylcholine, however, there is a per-

sistent depolarization of the endplate

and adjoining membrane regions Be-

cause the Na channels remain inactivat-

ed, an AP cannot be triggered in the ad-

jacent membrane

Because most skeletal muscle fibers

are innervated only by a single endplate,

activation of such fibers, with lengths

up to 30 cm, entails propagation of the

AP through the entire cell If the AP fails,

the muscle fiber remains in a relaxed state

The effect of a standard dose of succinylcholine lasts only about 10 min It

is often given at the start of anesthesia

to facilitate intubation of the patient As

expected, cholinesterase inhibitors are

unable to counteract the effect of succinylcholine In the few patients with a genetic deficiency in pseudocholineste- rase (= nonspecific cholinesterase), the succinylcholine effect is significantly prolonged

Since persistent depolarization of endplates is associated with an efflux of

Kt ions, hyperkalemia can result (risk of cardiac arrhythmias)

Only in a few muscle types (e.g., extraocular muscle) are muscle fibers supplied with multiple endplates Here succinylcholine causes depolarization

distributed over the entire fiber, which

responds with a contracture Intraocular

pressure rises, which must be taken into

account during eye surgery

In skeletal muscle fibers whose mo-

tor nerve has been severed, ACh recep-

tors spread in a few days over the entire

cell membrane In this case, succinyl-

choline would evoke a persistent depolarization with contracture and hyperkalemia These effects are likely to occur

in polytraumatized patients undergoing follow-up surgery

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0~CHz—CHzÝN—CH;

Acetylcholine

CHạ

x

H3C CHạ O

HẠC—O—C—CH¿—CH;—f 07CM

9 HạC x„.CHì

Succinylcholine yc ‘cus

a“

ữ-R—9 Depolarization

Ke

ACh Propagation of

action potential (AP)

Contraction

1 Rapid ACh cleavage by

2 Repolarization of end plate

ACh

New AP and contraction

can be elicited

Succinylcholine

Contraction

Succinylcholine not degraded

by acetylcholine esterases

—,

Persistent depolarization of end plate

{

“cv AP and contraction camnot be elicited

Membrane potential

Nat-channel

Open Closed

ý (opening not possible)

Repolarization

Closed

(opening possible)

Persistent depolarization

No repolarization, renewed opening of NaT-channel impossible

A Action of the depolarizing muscle relaxant succinylcholine

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Antiparkinsonian Drugs

Parkinson’s disease (shaking palsy) and

its syndromal forms are caused by a de-

generation of nigrostriatal dopamine

neurons The resulting striatal dopa-

mine deficiency leads to overactivity of

cholinergic interneurons and imbalance

of striopallidal output pathways, mani-

fested by poverty of movement (akine-

sia), muscle stiffness (rigidity), tremor

at rest, postural instability, and gait dis-

turbance

Pharmacotherapeutic measures are

aimed at restoring dopaminergic func-

tion or suppressing cholinergic hyper-

activity

L-Dopa Dopamine itself cannot

penetrate the blood-brain barrier; how-

ever, its natural precursor, L-dihydroxy-

phenylalanine (levodopa), is effective in

replenishing striatal dopamine levels,

because it is transported across the

blood-brain barrier via an amino acid

carrier and is subsequently decarboxy-

lated by DOPA-decarboxylase, present

in striatal tissue Decarboxylation also

takes place in peripheral organs where

dopamine is not needed, likely causing

undesirable effects (tachycardia, ar-

rhythmias resulting from activation of

B1-adrenoceptors [p 114], hypotension,

and vomiting) Extracerebral produc-

tion of dopamine can be prevented by

inhibitors of DOPA-decarboxylase (car-

bidopa, benserazide) that do not pene-

trate the blood-brain barrier, leaving

intracerebral decarboxylation unaffect-

ed Excessive elevation of brain dopa-

mine levels may lead to undesirable re-

actions, such as involuntary movements

(dyskinesias) and mental disturbances

Dopamine receptor agonists Defi-

cient dopaminergic transmission in the

striatum can be compensated by ergot

derivatives (bromocriptine [p 114], lisu-

ride, cabergoline, and pergolide) and

nonergot compounds (ropinirole, prami-

pexole) These agonists stimulate dopa-

mine receptors (D2, D3, and D; sub-

types), have lower clinical efficacy than

levodopa, and share its main adverse ef-

fects

Inhibitors of monoamine oxi- dase-B (MAOg) This isoenzyme breaks down dopamine in the corpus striatum and can be selectively inhibited by selegiline Inactivation of norepinephrine,

epinephrine, and 5-HT via MAQag is un-

affected The antiparkinsonian effects of selegiline may result from decreased dopamine inactivation (enhanced levodopa response) or from neuroprotective mechanisms (decreased oxyradical for- mation or blocked bioactivation of an unknown neurotoxin)

Inhibitors of catechol-O-methyltransferase (COMT) L-Dopa and dopamine become inactivated by methyla- tion The responsible enzyme can be blocked by entacapone, allowing higher levels of L-dopa and dopamine to be achieved in corpus striatum

Anticholinergics Antagonists at

muscarinic cholinoceptors, such as

benzatropine and biperiden (p 106), suppress striatal cholinergic overactivity and thereby relieve rigidity and

tremor; however, akinesia is not re-

versed or is even exacerbated Atropine- like peripheral side effects and impair- ment of cognitive function limit the tol- erable dosage

Amantadine Early or mild parkin- sonian manifestations may be tempo- rarily relieved by amantadine The underlying mechanism of action may involve, inter alia, blockade of ligand- gated ion channels of the glutamate/ NMDA subtype, ultimately leading to a diminished release of acetylcholine Administration of levodopa plus carbidopa (or benserazide) remains the most effective treatment, but does not provide benefit beyond 3-5 y and is fol- lowed by gradual loss of symptom control, on-off fluctuations, and develop- ment of orobuccofacial and limb dyskinesias These long-term drawbacks of levodopa therapy may be delayed by early monotherapy with dopamine receptor agonists Treatment of advanced disease requires the combined administration of antiparkinsonian agents

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Selegiline

N=œn

CHạ

CH,

Inhibition of

dopamine degradation

by MAO-B in CNS

Normal state

Predominance

Leprol

of acetylcholine Parkinson’s disease

H._ H Amantadine N

NMDA

receptor:

Blockade

of ionophore: attenuation

of cholinergic neurons

Dopa- decarboxylase

Carbidopa

H3C N£NH;

H GOOH

Inhibition of dopa-

decarboxylase

Dopamine

Stimulation of peripheral dopamine receptors

Adverse effects

2000

Entacapone

Q

HO nz Calls

02H;

N

HO

NO»

Inhibition of catechol-

O-methyltransferase

Dopamine substitution

Bromocriptine

5c CHạ

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NAG

H OH

k N

H N

| N

H QO

| H ° Hạ@Z = ^CHạ

/

NN Dopamine-receptor

HBr agonist

L-Dopa

H

a

COOH

HO

Dopamine precursor

Benzatropine

LÊN

Mic

H

Acetylcholine antagonist

A Antiparkinsonian drugs

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Antiepileptics

Epilepsy is a chronic brain disease of di-

verse etiology; it is characterized by re-

current paroxysmal episodes of uncon-

trolled excitation of brain neurons In-

volving larger or smaller parts of the

brain, the electrical discharge is evident

in the electroencephalogram (EEG) as

synchronized rhythmic activity and

manifests itself in motor, sensory, psy-

chic, and vegetative (visceral) phenom-

ena Because both the affected brain re-

gion and the cause of abnormal excit-

ability may differ, epileptic seizures can

take many forms From a pharmaco-

therapeutic viewpoint, these may be

classified as:

— general vs focal seizures;

- seizures with or without loss of con-

sciousness;

- seizures with or without specific

modes of precipitation

The brief duration of a single epi-

leptic fit makes acute drug treatment

unfeasible Instead, antiepileptics are

used to prevent seizures and therefore

need to be given chronically Only in the

case of status epilepticus (a succession of

several tonic-clonic seizures) is acute

anticonvulsant therapy indicated —

usually with benzodiazepines given i.v

or, if needed, rectally

The initiation of an epileptic attack

involves “pacemaker” cells; these differ

from other nerve cells in their unstable

resting membrane potential, i.e., a de-

polarizing membrane current persists

after the action potential terminates

Therapeutic interventions aim to

stabilize neuronal resting potential and,

hence, to lower excitability In specific

forms of epilepsy, initially a single drug

is tried to achieve control of seizures,

valproate usually being the drug of first

choice in generalized seizures, and car-

bamazepine being preferred for partial

(focal), especially partial complex, sei-

zures Dosage is increased until seizures

are no longer present or adverse effects

become unacceptable Only when

monotherapy with different agents

proves inadequate can changeover to a

second-line drug or combined use (“add on”) be recommended (B), provided that the possible risk of pharmacokinet-

ic interactions is taken into account (see below) The precise mode of action of antiepileptic drugs remains unknown Some agents appear to lower neuronal excitability by several mechanisms of action In principle, responsivity can be decreased by inhibiting excitatory or ac- tivating inhibitory neurons Most excitatory nerve cells utilize glutamate and most inhibitory neurons utilize y-aminobutyric acid (GABA) as their transmitter (p 193A) Various drugs can lower

seizure threshold, notably certain neu- roleptics, the tuberculostatic isoniazid,

and p-lactam antibiotics in high doses;

they are, therefore, contraindicated in

seizure disorders

Glutamate receptors comprise three subtypes, of which the NMDA subtype has the greatest therapeutic importance (N-methyl-D-aspartate is a synthetic selective agonist.) This receptor is a ligand-gated ion channel that, upon stimulation with glutamate, per- mits entry of both Nat and Ca?* ions into the cell The antiepileptics lamotrigine, phenytoin, and phenobarbital inhibit, among other things, the release of glutamate Felbamate is a glutamate antagonist

Benzodiazepines and phenobarbital augment activation of the GABAA receptor by physiologically released amounts

of GABA (B) (see p 226) Chloride influx

is increased, counteracting depolarization Progabide is a direct GABA-mimet-

ic Tiagabin blocks removal of GABA from the synaptic cleft by decreasing its re-uptake Vigabatrin inhibits GABA ca- tabolism Gabapentin may augment the availability of glutamate as a precursor

in GABA synthesis (B) and can also act as

a Kt-channel opener

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Drugs used in the treatment of status epilepticus:

Benzodiazepines, ¢.g., diazepam

Waking state [EEG] Epileptic attack

Drugs used in the prophylaxis of epileptic seizures

`

OW © oe /

CHO & < `

Carbamazepine Phenytoin Phenobarbital Ethosuximide Lamotrigine

ae CHs

3

COOH

0 HạC oh, OSO¿NH; Valproic acid Vigabatrin Gabapentin Felbamate Topiramate

A Epileptic attack, EEG, and antiepileptics

Seizures Simple seizures Carbam- Valproic acid, | | Primidone,

azepine Phenytoin, Phenobar-

Clobazam bital

Complex + Lamotrigine or Vigabatrin or Gabapentin

generalized

Generalized Tonic-clonic Valproic acid Carbam- Lamotrigine, attacks attack (grand mal) azepine, Primidone,

Tonic attack

Clonic attack + Lamotrigine or Vigabatrin or Gabapentin Myoclonic attack

vn OOD alternative

seizure

+ Lamotrigine or Clonazepam_ |

B Indications for antiepileptics

Tiêu đề	Drugs Acting on Motor Systems
Trường học	Thieme
Chuyên ngành	Pharmacology
Thể loại	Sách
Năm xuất bản	2000
Thành phố	Stuttgart

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