Добавил:
Upload Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз: Предмет: Файл:
Color_Atlas_of_Pharmacology_3rdEd.pdf
Скачиваний:
42
Добавлен:
27.02.2016
Размер:
12.08 Mб
Скачать

188 Drugs Acting on the Motor System

Antiparkinsonian Drugs

The central nervous programming of purposive movements depends on neuronal circuits interconnecting cortical regions, the thalamus, the cerebellum, and the basal ganglia (corpus striatum; subthalamic nucleus). The basal ganglia, in particular, play an important part in the initiation and scaling of movement as well as the programming of target acquisition. A disorder primarily involving basal ganglionic motor function is known as idiopathic Parkinson disease (shaking palsy). The disease typically manifests at an advanced age and is characterized by poverty of movement (akinesia), muscle stiffness (rigidity), tremor at rest, postural instability, gait disturbance, and a progressive impairment in the quality of life. The primary cause of this disease and its syndromal forms is a degeneration of dopamine neurons in the substantia nigra that project to the corpus striatum (specifically, the caudate nucleus and putamen) and exert an inhibitory influence. Cholinergic interneurons in the striatum promote neuronal excitation.

Pharmacotherapeutic measures are aimed at compensating striatal dopamine deficiency or suppressing unopposed cholinergic activity.

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 and is likely to cause undesirable effects (vomiting; hypotension; p.116). 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. Striatal dopamine deficiency can be compensated by lysergic acid derivatives such as bromocriptine

(p.116), lisuride, cabergoline, and pergolide and by the non-ergot compounds ropinirole and pramipexole.

Inhibitors of monoamine oxidase-B (MAOB). Monoamine oxidase occurs in the form of two isozymes: MAOA and MAOB. The corpusstriatumisrichinMAOB. Thisisozyme can be inhibited by selegiline. Degradation of biogenic amines in peripheral organs is not affected because MAOA remains functional.

Inhibitor of catecholamine O-methyltrans- ferase (COMT). The CNS-impermeant entacapone inhibits peripheral degradation of L- dopa and thus enhances availability of L- dopa for the brain. Accordingly, it is suitably only for combination therapy with L-dopa.

Anticholinergics. Antagonists at muscarinic cholinoceptors such as benztropine and biperiden (p.110) can be used to suppress the sequelae of the relative predominance of cholinergic activity in the striatum (in particular, tremor). Atropine-like peripheral side effects and impairment of cognitive function limit the tolerable dosage. Complete disappearance of symptoms cannot be achieved.

Amantadine. Early or mild parkinsonian manifestations may be relieved temporarily by amantadine. The underlying mechanisms of action may involve, inter alia, blockade of ligand-gated ion channels of the glutamate/ NMDA subtype, ultimately leading to diminished release of acetylcholine.

Treatment of advanced Parkinson disease requires combined administration of the above drugs for ameliorating the symptoms of this grave condition. Commonly, additional signs of central degeneration develop as the disease progresses.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Antiepileptics 189

A. Antiparkinsonian drugs

Selegiline

CH3

N CH2 C CH

CH2 CH CH3

Inhibition of dopamine degradation by MAO-B in CNS

Dopaminergic

Cortex

Motor

control Amantadine NH2 loop

 

GABAergic

NMDA receptor:

 

 

Blockade

 

Pallidum

of ionophore:

 

attenuation of

 

 

cholinergic neurons

 

Cholinergic

 

S. nigra

Striatum

 

Degeneration in

 

Parkinson disease

 

 

 

Inhibition of cholinergic

 

 

transmission

 

 

 

 

 

rier

 

 

 

 

ainbar

 

 

 

br

 

 

 

d-

 

 

 

o

 

 

 

lo

 

 

 

 

B

 

 

 

 

 

DOPA- decarboxylase

COMT

200 mg

Carbidopa

 

 

Dopamine

 

 

HO

 

CH3

 

 

 

 

 

 

Stimulation of

mg

HO

 

CH2 C

NH NH2

 

peripheral dop-

 

 

 

COOH

2000

 

 

 

amine receptors

 

 

 

 

Inhibition of dopa-

 

 

 

decarboxylase

 

Adverse effects

 

 

 

 

 

 

 

 

 

 

Dopamine substitution

 

 

Bromo-

 

H3C H

CH3

 

L-DOPA

 

 

criptine O

 

C

OH

 

 

 

 

 

O

N

 

 

 

 

 

 

HO

 

 

H

C NH

 

 

 

N

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

N

O

H

CH2

HO

CH2 CH NH2

 

CH3

 

C

 

 

 

 

 

 

 

 

COOH

 

 

 

H3C H CH3

 

 

 

 

 

 

 

 

HN

Dopamine-receptor

 

 

 

Br

agonist

 

 

Dopamine precursor

Entacapone

 

O

 

HO

N

C2H5

 

C2H5

 

CN

 

HO

NO2

Inhibition of the peripheral catechol- O-methyltransferase

Benzatropine

H3C

N

O C H

Muscarinic acetylcholine antagonist

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

190 Drugs Acting on the Motor System

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. As both the affected brain region and the cause of abnormal excitability may differ, epileptic seizures can take on many forms. From a pharmacotherapeutic viewpoint, these may be classified as:

Generalized vs. partial (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 (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 by 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 change-over to a second-line drug or combined use (“add on”) be recommended (B), 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. The transmitters utilized by most excitatory and inhibitory neurons are glutamate and γ-aminobutyric acid (GABA), respectively (p.193A).

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+ into the cell. Valproic acid inhibits both Na+ and Ca2+ channels. The antiepileptics lamotrigine, phenytoin, and phenobarbital inhibit, among other things, the release of glutamate. Felbamate is a glutamate antagonist.

Benzodiazepines and phenobarbital augment the activation of the GABAA receptor by physiologically released amounts of GABA (B) (see pp.193, 222). Chloride influx is increased, counteracting depolarization. Progabide is a direct GABA-mimetic but not an approved drug. Tiagabine blocks removal of GABA from the synaptic cleft by decreasing its reuptake. Vigabatrin inhibits GABA catabolism. Gabapentin augments the availability of glutamate as a precursor in GABA synthesis (B).

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Antiepileptics 191

A. Epileptic attack, EEG, and antiepileptics

Drugs used in the treatment of status epilepticus:

Benzodiazepines, e.g., diazepam

Waking state

 

 

 

 

EEG

 

 

 

Epileptic attack

mV

 

 

 

 

 

 

 

 

mV

 

 

 

150

 

 

 

 

 

 

 

 

150

 

 

 

100

 

 

 

 

 

 

 

 

100

 

 

 

50

 

 

 

 

 

 

 

 

50

 

 

 

0

 

 

 

 

 

 

 

 

0

 

1 s

 

1 s

 

 

 

 

 

 

 

 

 

 

 

 

 

Drugs used in the prophylaxis of epileptic seizures

 

 

 

 

 

 

 

H

O

 

 

H

O

 

 

CH3

 

 

 

 

 

 

N

 

 

 

 

 

 

 

C

 

 

C

 

 

 

C2H5

5

 

 

N

C2H5

O

C

O

C

 

 

O

C

 

 

C

 

N

 

 

 

 

N

 

 

N

O

C

 

 

N

C

 

 

 

 

 

 

 

 

 

H

 

 

H

 

 

O

NH2

 

H

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Carbamazepine

 

Phenobarbital

 

Phenytoin

 

Ethosuximide

 

 

 

 

 

 

 

CH2

 

 

 

 

H3C

CH3

 

 

CH2

NH2

 

HC

 

 

H2C NH2

 

 

 

HC

NH2

 

H2C

CH2

 

 

 

 

 

 

CH2

 

 

 

C

 

 

CH2

 

 

H2C H

CH2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CH2

 

 

 

CH2

 

 

CH2

 

 

C

 

 

 

 

 

 

COOH

COOH

 

 

COOH

 

COOH

 

 

 

 

 

 

 

 

Valproic acid

 

Gabapentin

Vigabatrin

 

GABA

B. Indications for antiepileptics

 

 

 

Focal

 

I.

II.

III. Choice

seizures

Simple

Carbam-

Valproic acid,

Primidone,

 

 

seizures

azepine

Phenytoin

Phenobarbital

 

Complex or

+ Lamotrigine or Vigabatrin or Gabapentin

 

secondarily

 

 

 

 

generalized

 

 

 

Generalized

Tonic-clonic

Valproic acid

Carbamazepine,

Lamotrigine,

attacks

attack (grand mal)

 

Phenytoin

Primidone,

 

Tonic attack

 

 

Phenobarbital

 

 

 

 

 

Clonic attack

+ Lamotrigine or Vigabatrin or Gabapentin

 

Myoclonic attack

 

 

 

 

Absence

 

Ethosuximide

 

 

 

 

 

 

seizure

 

+ Lamotrigine or Clonazepam

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

192 Drugs Acting on the Motor System

The tricyclic carbamazepine, its analogue oxycarbazepine, 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 blocksaneuronalT-typeCa2+ channel (A); and represents a special class becauseitiseffectiveonlyinabsenceseizures.

All antiepileptics are likely, albeit in different degrees, to produce adverse effects. Sedation, dif culty concentrating, and slowing ofpsychomotordrive 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 ~ 20% of patients. Valproic acid (VPA) is less sedating than other anticonvulsants. Tremor, gastrointestinal upset, and weight gain are frequently observed; reversible hair loss is a rarer occurrence. Its hepatotoxicity should be kept in mind.

Adverse reactions to carbamazepine include nystagmus, ataxia, and 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).

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 apply the lowest dose affording safe and effective prophylaxis. Concurrent high-dose administration of folate may prevent neural tube defects.

Carbamazepine, phenytoin, phenobarbital, and other anticonvulsants induce hepatic enzymes responsible for drug biotransformation; valproate is a potent inhibitor. Combinations between anticonvulsants or with other drugs may result in clinically impor-

tant interactions (plasma level monitoring!).

Carbamazepine is also used to treat trigeminal neuralgia and neuropathic pain.

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 last 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 and generalized seizures and as add-on in Lennox–Gas- taut syndrome.

It should be noted that certain drugs (e.g., neuroleptics, isoniazid, and high-dose β-lac- tam antibiotics) lower seizure threshold and are therefore contraindicated in epileptic patients.

Outlook: Among the newer antiepileptics, gabapentin, oxycarbazepine, lamotrigine, and topiramate are now endorsed as primary monotherapeutics for both partial and generalized seizures. Their pharmacokinetic characteristics are generally more desirable than those of the older drugs.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

 

Antiepileptics

193

A. Neuronal sites of action of antiepileptics

 

 

 

Na+ Ca2+

Excitatory neuron

 

 

NMDA-

 

 

 

receptor

 

Inhibition of

 

 

 

 

 

Glutamate

glutamate

 

NMDA-receptor-

release:

 

 

 

antagonist

 

phenytoin,

 

felbamate,

 

lamotrigine

 

 

phenobarbital

 

valproic acid

 

 

Ca2+-channel

 

 

 

T-Type-

 

 

 

calcium

Voltage

 

 

channel blocker

 

 

ethosuximide,

dependent

Inhibition of

 

(valproic acid)

Na+-channel

 

action

 

 

 

 

GABAA-

 

potentials

 

 

carbamazepine

 

receptor

 

 

 

valproic acid

 

GABA

 

 

CI-

 

phenytoin

 

Gabamimetics:

 

 

 

 

 

 

benzodiazepine

 

 

 

barbiturates

 

 

Inhibitory

vigabatrin

 

 

tiagabine

 

 

neuron

 

 

gabapentin

 

 

B. Sites of action of antiepileptics in GABAergic synapse

 

Benzodiazepines

GABAA-

 

 

Tiagabine

 

 

 

 

 

Allosteric

 

β

receptor

 

 

 

α

α

 

 

 

 

Inhibition

enhance-

 

 

 

 

 

 

 

 

 

ment of

 

γ

β

α

β

α

Chloride

of GABA

GABA

 

 

 

 

γ

β

channel

reuptake

action

 

 

 

 

 

 

 

 

Barbiturates

 

 

 

 

 

 

 

 

Progabide

 

 

 

GABA-

 

GABA-

 

 

GABA

 

 

transaminase

 

mimetic

 

 

 

 

 

Vigabatrin

 

 

 

 

 

 

 

 

 

 

 

Glutamic acid

 

 

Succinic

Inhibitor

 

 

 

decarboxylase

 

 

of GABA-

 

 

 

 

 

 

semialdehyde

transaminase

 

 

 

 

 

 

Succinic acid

 

 

 

Glutamic

 

 

 

 

 

 

 

acid

 

 

 

 

 

 

 

 

 

 

Gabapentin

 

Ending of

 

 

 

 

Improved utilization

 

inhibitory

 

 

 

 

of GABA precursor:

 

neuron

 

 

 

 

glutamate

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Тут вы можете оставить комментарий к выбранному абзацу или сообщить об ошибке.

Оставленные комментарии видны всем.

Соседние файлы в предмете [НЕСОРТИРОВАННОЕ]