CNS Central Nervous System Stimulants

CNS Stimulants Types and Definitions

Psychomotor stimulants - Amphetamines, Methylxantines, how they work, pharmacological effects, adverse effects, therapeutic uses

Convulsant & Respiratory Stimulants - how they work, agent/drugs

Psychotomimetic drugs - General, LSD, PCP, MDMA

Central Nervous System Stimulants

CNS stimulants can be categorised in 2 distinct categories, which are:

1. Psychomotor stimulants:

            these agents cause excitement & euphoria, relieve fatigue and increase motor activity

            - convulsants & respiratory stimulants (analeptics)

            - psychomotor stimulants

2. Psychotomimetic drugs (hallucinogens):

            produce profound changes in though patterns and mood

As a group, CNS stimulants have a few clinical uses, but they are important as drugs of abuse.

Definitions

Psychostimulant - drugs which produce a transient effect in psychomotor activity

Analeptics - drugs which acts as a restorative

Anorexiants - drugs which are anorexigenic

Psychotomimetic - drugs which produce manifestations resembling those of psychosis eg. visual hallucinations, distortion of perceptions and schizophrenic-like behaviour

Convulsants & Respiratory Stimulants

Doxapram, Strychnine, Bicuculline, Picrotoxin, Pentylenetetrazol

How/Where do they work

Little effect on mental function

Act mainly on the brain stem and spinal cord

Produce - exaggerated reflex excitability

Increase in activity of the respiratory & vasomotor centres

Higher dose - would result in convulsions

Analeptics Mechanism of action

Strychnine - blockade of inhibition - post-synaptic - blocks postsynaptic NT, glycine

Picrotoxin - blockade of inhibition - pre-synaptic - blocks presynaptic NT, GABA

Doxapram - facilitating excitation - direct - stimulate respiratory center

Nikethamide - facilitating excitation - reflex - stimulate via chemoreceptors

(diagram 8)

Strychnine

Strychnine is an alkaloid and has been used for centuries as poison

It is a powerful convulsant and cause violent extensor spasms

It works by blocking receptor for glycine which is the main inhibitory transmitter acting on motor neurons)

The sequence of strychnine effects are

§  tightness of neck and jaw muscles

§  hyper-reflexia

§  tonic extension

§  tetanic symmetrical convulsions (opisthotonos)

Bicuculine

BIcuculine is a plant alkaloids which resemble strychnine but it acts by blocking receptors for GABA instead of glycine (confines to GABAa-antagonist). Its main effect is on brain rather than spinal cord

Picrotoxin

Picrotoxin is obtained from fishberry which also block the action of GABA on chloride channel (block the ion channel). It can cause convulsion.

Doxapram

Doxapram has bigger margin of safety between respiratory stimulation and convulsion

It is occasionally used as IV infusion in patients with acute respiratory failure.

Psychomotor Stimulants

Amphetamine & related drugs

Amphetamine

Metamphetamine

Methylphenidate

Fenfluramine

Methylenedioxy-metamphetamine

How do they work / Mechanism of action

Pyschostimulant drugs have impose marked effect on mental function & behaviour. They can stimulate specific area of the brain, eg. for amphetamine acts on cerebral cortex while anorexiants act on hypothalamus and limbic region.

They act by releasing monoamines from nerve terminals.

They are also substrate for neuronal uptake transporters especially for nordarenaline and dopamine. However, fenfluramine and dexfenfluramine preferentially affect 5-HT (serotonin) release by disrupting vesicular storage and reverse 5-HT transporter function.

At lose dose, amphemtamine-related drugs only affect neuronal tranporters while at high dose, MAO inhibitors are inhibited as well promoting increase level of noradrenaline and dopamine.

Pharmacological effect of Amphetamines

The main central effects are:

Locomotor stimulation (increased motor activity)

Euphoria (intense) and excitement

Subject become confident, hyperactive, talkative, and sex drive is enhanced (overall mental and physical performance is boosted)

Fatigue of both mental and physical is reduced

Mental performance is improved for simple task much more than difficult tasks

Stereotyped behaviours which consists repeated actions that are generally inappropriate to the environment

Anorexia due to feeling of fullness and loss of appetite

Therapeutic Uses of Amphetamines

They have limited use due to physical and psychological dependence. However, the most commonly used legally today are to treat:

Narcolepsy - This rare sleep disorder involves overwhelming, irresistible urges to sleep during the day despite adequate night time sleep. Amphetamine, modafinil (non-amphetamine stimulant) is used as treatment.

Attention deficit-hyperactivity disorders (ADHD) in children. Drugs used are methylphenidate and amphetamine

They may be used as appetite suppressants such as phentermine (Duromine) and sibutramien (Reductil)

Adverse effecs of Amphetamines

For short term use, amphetamine may cause the side effects as belowed:

·         dilated pupils

·         increased blood pressure

·         increased heart rate

·         decreased appetite

·         dry mouth

·         tremors

·         dizziness / nausea

·         irregular heartbeat

·         loss of coordination

·         sudden collapse

·         loss of consciousness

Amphetamine can induce a condition resembling heatstroke which is associated with muscle damage, renal failure, inappropriate secretion of ADH leading to thirst, over hydration and hyponatraemia (also known as water intoxication).

For long term use, amphetamines may cause

·         malnutrition - since amphetamines reduce the users appetite, they are less likely to eat properly and due to this they are less resistant to infections

·         chronic anxiety - to combat this users often turn to alcohol and barbiturates for help. Chronic anxiety may also lead to violent behavior.

·         chronic psychosis - symptoms may include paranoia, delusions, and bizarre behavior. This can be seen as early as 1 week after the user has stopped using. (withdrawal symptoms)

·         brain damage - long term use of amphetamines can cause damage to the brain, specifically areas that deal with memory and everyday thinking.

Researchers have mapped brain decay caused by methamphetamine use. It is found that the damage affected memory, emotion and reward systems. Areas of greatest loss (damage) are limbic system which control emotion and reward and hippocampus which deal with memory.