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 programs,
the brain sends impulses to the
spinal cord. These converge on !-motoneurons
in the anterior horn of the spinal
medulla. Efferent axons course, bundled
in motor nerves, to skeletal muscles.
Simple reflex contractions to sensory
stimuli, conveyed via the dorsal
roots to the motoneurons, occur without
participation of the brain. Neural
circuits that propagate afferent impulses
into the spinal cord contain inhibitory
interneurons. These serve to prevent
a possible overexcitation of motoneurons
(or excessive muscle contractions)
due to the constant barrage of
sensory stimuli.
Neuromuscular transmission of
motor nerve impulses to the striated
muscle fiber takes place at the motor
endplate. The nerve impulse liberates
acetylcholine (ACh) from the axon terminal.
ACh binds to nicotinic cholinoceptors
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 triggers
a release of Ca2+ from its storage organelles,
the sarcoplasmic reticulum
(SR), within the muscle fiber; the rise in
Ca2+ concentration induces a contraction
of the myofilaments (electromechanical
coupling). Meanwhile, ACh is
hydrolyzed by acetylcholinesterase
(p. 100); excitation of the endplate subsides.
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 interfere
with neural control of the muscle
cell Centrally acting muscle relaxants
lower muscle tone by augmenting
the activity of intraspinal inhibitory
interneurons. They are used in the treatment
of painful muscle spasms, e.g., in
spinal disorders. Benzodiazepines enhance
the effectiveness of the inhibitory
transmitter GABA at GABAA receptors.
Baclofen stimulates GABAB receptors.
2-Adrenoceptor agonists such
as clonidine and tizanidine probably act
presynaptically to inhibit release of excitatory
amino acid transmitters.
The convulsant toxins, tetanus toxin
(cause of wound tetanus) and strychnine
diminish the efficacy of interneuronal
synaptic inhibition mediated by
the amino acid glycine. As a consequence
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.
10–6 mg. The toxin blocks exocytosis
of ACh in motor (and also parasympathetic)
nerve endings. Death is
caused by paralysis of respiratory muscles.
Injected intramuscularly at minuscule
dosage, botulinum toxin type A is
used to treat blepharospasm, strabismus,
achalasia of the lower esophageal
sphincter, and spastic aphonia.
A pathological rise in serum Mg2+
levels also causes inhibition of ACh release,
hence inhibition of neuromuscular
transmission.
Dantrolene interferes with electromechanical
coupling in the muscle cell
by inhibiting Ca2+ 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 hyperthermia).
Muscle Relaxants
Muscle relaxants cause a flaccid paralysis
of skeletal musculature by binding to
motor endplate cholinoceptors, thus
blocking neuromuscular transmission.
According to whether receptor occupancy
leads to a blockade or an excitation
of the endplate, one distinguishes
nondepolarizing from depolarizing
muscle relaxants. As adjuncts to
general anesthetics, muscle relaxants
help to ensure that surgical procedures
are not disturbed by muscle contractions
of the patient.
Nondepolarizing muscle relaxants
Curare is the term for plant-derived arrow
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 muscles
fail (respiratory paralysis). Killed
game can be eaten without risk because
absorption of the poison from the gastrointestinal
tract is virtually nil. The curare
ingredient of greatest medicinal
importance is d-tubocurarine. This
compound contains a quaternary nitrogen
atom (N) and, at the opposite end of
the molecule, a tertiary N that is protonated
at physiological pH. These two
positively charged N atoms are common
to all other muscle relaxants. The fixed
positive charge of the quaternary N accounts
for the poor enteral absorbability.
d-Tubocurarine is given by i.v. injection
(average dose approx. 10 mg). It
binds to the endplate nicotinic cholinoceptors
without exciting them, acting as
a competitive antagonist towards ACh.
By preventing the binding of released
ACh, it blocks neuromuscular transmission.
Muscular paralysis develops within
about 4 min. d-Tubocurarine does not
penetrate into the CNS. The patient
would thus experience motor paralysis
and inability to breathe, while remaining
fully conscious but incapable of expressing
anything. For this reason, care
must be taken to eliminate consciousness
by administration of an appropriate
drug (general anesthesia) before using
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 administering
an acetylcholinesterase inhibitor,
such as neostigmine. 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 nonimmunemediated
release of histamine from
mast cells, leading to bronchospasm, urticaria,
and hypotension. More commonly,
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; rocuronium,
gallamine, mivacurium, and atracurium.
The latter undergoes spontaneous
cleavage and does not depend on
hepatic or renal elimination.
Depolarizing Muscle Relaxants
In this drug class, only succinylcholine
(succinyldicholine, suxamethonium)
is of clinical importance. Structurally, it
can be described as a double ACh molecule.
Like ACh, succinylcholine acts as
agonist at endplate nicotinic cholinoceptors,
yet it produces muscle relaxation.
Unlike ACh, it is not hydrolyzed by
acetylcholinesterase. However, it is a
substrate of nonspecific plasma cholinesterase
(serum cholinesterase).
Succinylcholine is degraded more slowly
than is ACh and therefore remains in
the synaptic cleft for several minutes,
causing an endplate depolarization of
corresponding duration. This depolarization
initially triggers a propagated
action potential (AP) in the surrounding
muscle cell membrane, leading to contraction
of the muscle fiber. After its i.v.
injection, fine muscle twitches (fasciculations)
can be observed. A new AP can
be elicited near the endplate only if the
membrane has been allowed to repolarize.
The AP is due to opening of voltagegated
Na-channel proteins, allowing
Na+ ions to flow through the sarcolemma
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 incompletely
repolarized, renewed opening
of Na channels, hence a new AP, is
impossible. In the case of released ACh,
rapid breakdown by ACh esterase allows
repolarization of the endplate and
hence a return of Na channel excitability
in the adjacent sarcolemma. With
succinylcholine, however, there is a persistent
depolarization of the endplate
and adjoining membrane regions. Because
the Na channels remain inactivated,
an AP cannot be triggered in the adjacent
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 pseudocholinesterase
(= nonspecific cholinesterase), the
succinylcholine effect is significantly
prolonged.
Since persistent depolarization of
endplates is associated with an efflux of
K+ 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 motor
nerve has been severed, ACh receptors
spread in a few days over the entire
cell membrane. In this case, succinylcholine
would evoke a persistent depolarization
with contracture and hyperkalemia.
These effects are likely to occur
in polytraumatized patients undergoing
follow-up surgery.
Antiparkinsonian Drugs
Parkinson’s disease (shaking palsy) and
its syndromal forms are caused by a degeneration
of nigrostriatal dopamine
neurons. The resulting striatal dopamine
deficiency leads to overactivity of
cholinergic interneurons and imbalance
of striopallidal output pathways, manifested
by poverty of movement (akinesia),
muscle stiffness (rigidity), tremor
at rest, postural instability, and gait disturbance.
Pharmacotherapeutic measures are
aimed at restoring dopaminergic function
or suppressing cholinergic hyperactivity.
L-Dopa. Dopamine itself cannot
penetrate the blood-brain barrier; however,
its natural precursor, L-dihydroxyphenylalanine
(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 decarboxylated
by DOPA-decarboxylase, present
in striatal tissue. Decarboxylation also
takes place in peripheral organs where
dopamine is not needed, likely causing
undesirable effects (tachycardia, arrhythmias
resulting from activation of
!1-adrenoceptors, hypotension,
and vomiting). Extracerebral production
of dopamine can be prevented by
inhibitors of DOPA-decarboxylase (carbidopa,
benserazide) that do not penetrate
the blood-brain barrier, leaving
intracerebral decarboxylation unaffected.
Excessive elevation of brain dopamine
levels may lead to undesirable reactions,
such as involuntary movements
(dyskinesias) and mental disturbances.
Dopamine receptor agonists. Deficient
dopaminergic transmission in the
striatum can be compensated by ergot
derivatives (bromocriptine, lisuride,
cabergoline, and pergolide) and
nonergot compounds (ropinirole, pramipexole).
These agonists stimulate dopamine
receptors (D2, D3, and D1 subtypes),
have lower clinical efficacy than
levodopa, and share its main adverse effects.
Inhibitors of monoamine oxidase-
B (MAOB). This isoenzyme breaks
down dopamine in the corpus striatum
and can be selectively inhibited by selegiline.
Inactivation of norepinephrine,
epinephrine, and 5-HT via MAOA is unaffected.
The antiparkinsonian effects of
selegiline may result from decreased
dopamine inactivation (enhanced levodopa
response) or from neuroprotective
mechanisms (decreased oxyradical formation
or blocked bioactivation of an
unknown neurotoxin).
Inhibitors of catechol-O-methyltransferase
(COMT). L-Dopa and dopamine
become inactivated by methylation.
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,
suppress striatal cholinergic overactivity
and thereby relieve rigidity and
tremor; however, akinesia is not reversed
or is even exacerbated. Atropinelike
peripheral side effects and impairment
of cognitive function limit the tolerable
dosage.
Amantadine. Early or mild parkinsonian
manifestations may be temporarily
relieved by amantadine. The
underlying mechanism of action may
involve, inter alia, blockade of ligandgated
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 followed
by gradual loss of symptom control,
on-off fluctuations, and development
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.
Antiepileptics
Epilepsy is a chronic brain disease of diverse
etiology; it is characterized by recurrent
paroxysmal episodes of uncontrolled
excitation of brain neurons. Involving
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, psychic,
and vegetative (visceral) phenomena.
Because both the affected brain region
and the cause of abnormal excitability
may differ, epileptic seizures can
take many forms. From a pharmacotherapeutic
viewpoint, these may be
classified as:
– general vs. focal seizures;
– seizures with or without loss of consciousness;
– seizures with or without specific
modes of precipitation.
The brief duration of a single epileptic
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 depolarizing
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 carbamazepine
being preferred for partial
(focal), especially partial complex, seizures.
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, provided
that the possible risk of pharmacokinetic
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 activating
inhibitory neurons. Most excitatory
nerve cells utilize glutamate and
most inhibitory neurons utilize !-aminobutyric
acid (GABA) as their transmitter
. Various drugs can lower
seizure threshold, notably certain neuroleptics,
the tuberculostatic isoniazid,
and "-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, permits
entry of both Na+ and Ca2+ 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 . Chloride influx
is increased, counteracting depolarization.
Progabide is a direct GABA-mimetic.
Tiagabin blocks removal of GABA
from the synaptic cleft by decreasing its
re-uptake. Vigabatrin inhibits GABA catabolism.
Gabapentin may augment the
availability of glutamate as a precursor
in GABA synthesis and can also act as
a K+-channel opener.
Carbamazepine, valproate, and
phenytoin enhance inactivation of voltage-
gated sodium and calcium channels
and limit the spread of electrical excitation
by inhibiting sustained high-frequency
firing of neurons.
Ethosuximide blocks a neuronal Ttype
Ca2+ channel and represents a
special class because it is effective only
in absence seizures.
All antiepileptics are likely, albeit to
different degrees, to produce adverse
effects. Sedation, difficulty in concentrating,
and slowing of psychomotor drive
encumber practically all antiepileptic
therapy. Moreover, cutaneous, hematological,
and hepatic changes may necessitate
a change in medication. Phenobarbital,
primidone, and phenytoin may
lead to osteomalacia (vitamin D prophylaxis)
or megaloblastic anemia (folate
prophylaxis). During treatment with
phenytoin, gingival hyperplasia may develop
in ca. 20% of patients.
Valproic acid (VPA) is gaining increasing
acceptance as a first-line drug;
it is less sedating than other anticonvulsants.
Tremor, gastrointestinal upset,
and weight gain are frequently observed;
reversible hair loss is a rarer occurrence.
Hepatotoxicity may be due to
a toxic catabolite (4-en VPA).
Adverse reactions to carbamazepine
include: nystagmus, ataxia, diplopia,
particularly if the dosage is raised
too fast. Gastrointestinal problems and
skin rashes are frequent. It exerts an
antidiuretic effect (sensitization of collecting
ducts to vasopressin !water intoxication).
Carbamazepine is also used to treat
trigeminal neuralgia and neuropathic
pain.
Valproate, carbamazepine, and other
anticonvulsants pose teratogenic
risks. Despite this, treatment should
continue during pregnancy, as the potential
threat to the fetus by a seizure is
greater. However, it is mandatory to administer
the lowest dose affording safe
and effective prophylaxis. Concurrent
high-dose administration of folate may
prevent neural tube developmental defects.
Carbamazepine, phenytoin, phenobarbital,
and other anticonvulsants (except
for gabapentin) induce hepatic enzymes
responsible for drug biotransformation.
Combinations between anticonvulsants
or with other drugs may result
in clinically important interactions
(plasma level monitoring!).
For the often intractable childhood
epilepsies, various other agents are
used, including ACTH and the glucocorticoid,
dexamethasone. Multiple
(mixed) seizures associated with the
slow spike-wave (Lennox–Gastaut) syndrome
may respond to valproate, lamotrigine,
and felbamate, the latter being
restricted to drug-resistant seizures
owing to its potentially fatal liver and
bone marrow toxicity.
Benzodiazepines are the drugs of
choice for status epilepticus (see
above); however, development of tolerance
renders them less suitable for
long-term therapy. Clonazepam is used
for myoclonic and atonic seizures.
Clobazam, a 1,5-benzodiazepine exhibiting
an increased anticonvulsant/sedative
activity ratio, has a similar range of
clinical uses. Personality changes and
paradoxical excitement are potential
side effects.
Clomethiazole can also be effective
for controlling status epilepticus, but is
used mainly to treat agitated states, especially
alcoholic delirium tremens and
associated seizures.
Topiramate, derived from D-fructose,
has complex, long-lasting anticonvulsant
actions that cooperate to limit
the spread of seizure activity; it is effective
in partial seizures and as an add-on
in Lennox–Gastaut syndrome.
Drugs Acting on Motor Systems
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