1. CLINICAL PHARMACOLOGY OF DRUGS AFFECTING THE NERVOUS SYSTEM

3. Central Nervous System Stimulants
Stimulants are drugs that exert their action through excitation of the central nervous system. Psychic stimulants include caffeine, cocaine, and various amphetamines. These drugs are used to enhance mental alertness and reduce drowsiness and fatigue.
Stimulants increase alertness, attention, and energy, which are accompanied by increases in blood pressure, heart rate, and respiration.

5. Amphetamine Levoamphetamine (Benzedrine), dextroamphetamine (Dexedrine), and methamphetamine (Methedrine)
These agents produce a feeling of well being and euphoria. Cocaine and amphetamine have a significant abuse potential because of these mood enhancing effects. Tachyphylaxis or tolerance to the stimulating actions of these agents can develop. These agents produce an increase in systemic arterial blood pressure. Heart rate can either decrease or increase depending on the levels of the drug. Drug toxicity effects multiple organ systems and can result in arrhythmias, hypertension, psychosis and convulsions. The local anesthetic activity of cocaine can also contribute to rhythm disturbances.
Clinical Therapeutics of CNS Stimulants
1) Because of its local anesthetic activity, cocaine has some limited uses as a oral, nasal and ophthalmic local anesthetic.
2) Appetite suppression - amphetamine and analogs
3) Narcolepsy - methylphenidate, amphetamine analogs
4) Attention deficient disorder with hyperactivity (ADHD) - methylphenidate, amphetamine and analogs

6. Tolerance and Dependence
Regular use of amphetamines induces tolerance to some effects, which means that more and more of the drug is required to produce the desired effects. Tolerance does not develop to all effects at the same rate, however; indeed, there may be increased sensitivity to some of them.
Chronic users may also become psychologically dependent on amphetamines. Psychological dependence exists when a drug is so central to a person's thoughts, emotions, and activities that the need to continue its use becomes a craving or compulsion. Experiments have shown that animals, when given a free choice, will readily operate pumps that inject them with cocaine or amphetamine. Animals dependent on amphetamines will work hard to get more of the drug.
Physical dependence occurs when the body has adapted to the presence of the drug, and withdrawal symptoms occur if its use is stopped abruptly. The most common symptoms of withdrawal among heavy amphetamine users are fatigue, long but troubled sleep, irritability, intense hunger, and moderate to severe depression, which may lead to suicidal behavior. Fits of violence may also occur. These disturbances can be temporarily reversed if the drug is taken again.

8. Antidepressant Drugs
• All are effective in relieving depression, but they differ in their adverse effects.
• All must be taken for 2 to 4 weeks before depressive symptoms improve.
• They are given orally, absorbed from the small bowel, enter the portal circulation, and circulate through the liver, where they undergo extensive first-pass metabolism before reaching the systemic circulation.
• They are metabolized by the cytochrome P450 enzymes in the liver. Many antidepressants and other drugs are metabolized by the 2D6 or 3A4 subgroup of the enzymes.

9. Antidepressant Drugs indications for use
Antidepressant drug therapy may be indicated if depressive symptoms persist at least 2 weeks, impair social relationships or work performance, and occur independently of life events. In addition, antidepressants are increasingly being used for treatment of anxiety disorders. TCAs may be used in children and adolescents in the management of enuresis (bedwetting or involuntary urination resulting from a physical or psychological disorder). In this setting, a TCA may be given after physical causes (eg, urethral irritation, excessive intake of fluids) have been ruled out. TCAs are also commonly used in the treatment of neuropathic pain. MAOIs are considered third-line drugs, largely because of their potential for serious interactions with certain foods and other drugs.

11. Tranquilizers
Tranquilizers are divided into a Major Tranquilizer and Minor Tranquilizer group.
Major Tranquilizers include phenothiazines, indoles, thioxanthenes, butyrophenones, piperazine compounds, and piperidine compounds. Trade names include drugs such as Thorazine, Haldol, Clozaril and Risperdal. These drugs are referred to as Neuroleptics and are most commonly prescribed as anti-psychotics. This type of tranquilizer is not widely abused.
Minor Tranquiliers are the more common of the tranquilizers. These include the Benzodiazepines, known by trade names such as Valium, Xanax, Serax, Ativan, Klonopin, Librium and Tranxene. There are also combination drugs such as Librax. These drugs are very commonly prescribed as anti-anxiety drugs, or anxiolytics. They are often referred to as Sedative/Hypnotics. They are central nervous system depressants with specific sites of action. Slang references to these drugs include Libs, Tranks, Benzos, and Vees.
The primary route of administration for these medications is oral, swallowed as a tablet, capsule, or liquid. They are also available in solution form for intravenous use.

12. Effects
The minor tranquilizers induce a feeling of calm and relaxation. Depending on the medication and dosage this can range from feelings of mild euphoria to states of drowsiness, confusion, and lightheadedness. Effects can include hostility, blurred vision, hallucinations, lethargy, headaches, memory loss, disorganized thinking, and irritability. Other common effects include impaired motor function, dry mouth, nausea, vomiting, and sweating. Certain Benzodiazepines, including Valium, can produce toxic reactions when combined with alcohol.
The Benzodiazepines (Minor Tranquilizers) can be addictive even at prescribed dosages if the medication is administered for long periods of time. The withdrawal process can be painful and even life-threatening with some of the Benzodiazepines. Physical withdrawal symptoms can include general pain, stomach cramps, diarrhea, flu-like symptoms, and heart palpitations. There is also the possibility of seizure with certain medications. The withdrawal can also produce psychosis, hallucinations, delusions, paranoia, and depression.

13. SEDATIVE - HYPNOTIC AGENTS
Drug Classes of Sedative-Hypnotics
Barbiturates
Benzodiazepines
Alcohols/Imidazopyridine
Barbiturates:
Duration of Action Onset
- Phenobarbital Long (6-12 h) min
- Pentobarbital Intermediate (4-6 h) 3 min
- Secobarbital Short-Intermediate (3-6 h) 2 min
- Thiopental/ Short ( min) few seconds
Methohexital
[All are derivatives of barbituric acid]

14. 1. Sites of Action:
Barbiturates act at multiple levels of the CNS. Sedative-Hypnotic effect involves, in particular, the reticular activating system.
2. Mechanism of Action:
- facilitate the action of GABA at GABAA receptors by increasing the duration of channel openings (bind at a distinct site from that bound by benzodiazepines)
- reduce glutamate-induced depolarization via inhibitory action on AMPA-type glutamate receptors
- at high doses, reduce the responsiveness of voltage-dependent Na+ channels and directly active GABAA receptors

15. 3. CNS effects:
Dose-dependent progression: (lower margin of safety)
Sedation → ‘Hypnosis’ → Anesthesia → Coma → Death*
Anticonvulsant/antiepileptic
- all barbiturates stop convulsions in progress if given IV at high enough dosage
- some can prevent seizures (eg. phenobarbital), but are not drugs of first choice owing to sedative effect (except for children); used to maintain control of status epilepticus
For animal surgery, methohexital may be used as an induction agent only. Pentobarbital (Nembutal®) used, but has a very low margin of safety in rodents and guinea pigs (consequently, often agent of choice for rapid, humane euthanasia)

16. Adverse effects:
- *respiratory depression via action on respiratory center in the medulla is the usual cause of death with overdose; depression occurs at supra-hypnotic doses
- generalized CNS depression: impaired motor and cognitive skills
- uncommon: rash, dermatitis, decreased red blood cells and platelet
- physiological and psychological dependency: significant incidence of abuse

17. Benzodiazepines: Duration of Action
- Flurazepam Long (30-100h) [pro-drug]
- Diazepam “ [active metabolites]
- Temazepam Intermediate (10-40h)
- Triazolam Short (1-3h)

19. Effects and uses:
- drugs of choice for sedation and ‘hypnosis’ (higher margin of safety)
flurazepam: long-acting pro-drug
temazepam: slowly absorbed, intermediate acting drug with no active metabolites; most highly prescribed hypnotic
triazolam: rapid but short-acting drug
diazepam (Valium®): long-acting drug; may be useful as adjunct in animal surgery
- at sedative doses may cause euphoria and ‘disinhibition’
- anticonvulsant (primary drug for initial treatment of status epilepticus)
- anxiolytic
- muscle relaxation (used in spasticity; largely via effect in spinal cord)
- ethanol withdrawal

20. Adverse reactions:
- ‘hangover’ (esp. with benzodiazepines with long half-lives: diazepam)
- early morning awakening for benzodiazepines with short half-lives: triazolam
- impaired motor and cognitive skills
- anterograde amnesia
- chronic use/dependence: more intense withdrawal symptoms with benzodiazepines having short half-lives ‘rebound’ insomnia (and/or anxiety), restlessness and even seizures (severity and frequency of dependence less than that found for barbiturates)

21. Alcohols/Imidazopyridine:
Duration of Action
- Chloral Hydrate Long (6-10h) [pro-drug]
- Zolpidem Short (several hours)
- Zaleplon Short (1-3h)

22. 1. Chloral hydrate rapidly metabolized in liver to triethanolamine - pharmacologically active (also metabolized to trichloroacetic acid, which is toxic and may accumulate); mechanism of action is not known
- oft-used sedative-hypnotic for animals undergoing surgery
- institutional use
2. Zolpidem: non-benzodiazepine that acts via subtype of GABAA receptor
- an effective, short-acting hypnotic agent (most highly prescribed hypnotic)
- much lower risk of tolerance and dependency; but some mild cognitive impairment during onset
- little anticonvulsant or muscle relaxant effects
3. Zaleplon: an alternative non-benzodiazepine that also acts via the GABAA receptor
- similar to Zolpidem, but without effects on cognitive function

23. Narcotic Analgesic Drugs