CNS DRUGS

TARGETS OF CNS DRUG ACTION

 Voltage–regulated ion channels:- Na+ and Ca2+ channels
 Neurotransmitter–regulated ion Channels:
- Cl- channel regulated by GABA A receptors
- G protein coupled ion channels: cAMP, IP3, DAG

CNS TRANSMITTERS
 Glutamic acid
 GABA
 Acetylcholine
 Dopamine
 Norepinephrine
 Serotonin
 Opioid peptides

GLUTAMIC ACID
 Excitatory
 Antagonized by ketamine, phencyclidine, & newer antiepileptics

GABA
 Inhibitory
 Sedative–hypnotics & some antiepileptic drugs facilitate GABA A receptors
 Baclofen activates GABAB receptors

ACETYLCHOLINE
 M1 & M2 receptors
 Atropine antagonizes both
 AChE inhibitors facilitate Ach

DOPAMINE
 Inhibitory
 Antagonized by older antipsychotics
 Activated by anti–parkinisonian drugs, amphetamines & cocaine

SEROTONIN
 Excitatory or inhibitory
 Amplified by MAO inhibitors, selective serotonin reuptake inhibitors, TCAs, some CNS stimulants, & hallucinogens

OPIOID PEPTIDES
 E.g. Beta – endorphin, Metenkephalin, Dyno rphin, etc
 Inhibitory
 Amplified by opioid analgesics
 Antagonized by naloxone & naltrexone

NOREPINEPHRINE
 Excitatory or inhibitory
 Amplified by MAO inhibitors, tricyclic antidepressants, amphetamines, & cocaine

CLASSIFICATION
Psychotropics
- Sedative – Hypnotics
- Antipsychotics
- Antidepressants
- Mood stabilizers
- Cognitive enhancers
- Drugs of Abuse

Other CNS Drugs

• Anticonvulsants
• Skeletal Muscle Relaxants
• Opioid Analgesics & Antagonists
• General Anaesthetics
• Drugs used in Parkinsonism
• Drug treatment for Migraine
1
DEFINITIONS
• A sedative is a drug that reduces daytime anxiety, tempers excessive excitement & generally calms the patient.
• A hypnotic produces drowsiness & facilitates the onset & the maintenance of sleep.
• An anxiolytic reduces anxiety.

Sedative – Hypnotic Drugs

Benzodiazepines
Barbiturates Miscellaneous
(buspirone, Chloral hydrate,
meprobamate, zolpidem,
Zopiclone Zaleplon,
antihistamines, Sedating
Short
Long action antidepressants)
action

Intermediate
action Ultra- short
action Long -action

Short -action

SEDATIVE - HYPNOTICS

Mechanisms of Action
• Benzodiazepines (BZs) bind to the GABAA receptor increasing its affinity for GABA.
• There are two subtypes of the BZs receptors: BZ1 (or Omega 1) & BZ2 (or Omega 2) receptors. BZ1 receptors are
involved in the mediation of sleep. BZ2 receptors are involved in cognition, memory, & motor control
• Effects of BZs can be reversed by the BZ receptor antagonist flumazenil
• Barbiturates facilitate GABA actions via binding to a separate site from the BZ receptors.
• Their actions are not reversed by flumazenil.
• Zolpidem acts via BZ1 receptors; its actions are reversed by flumazenil.
• Alcohols may facilitate GABA or block glutamate receptors.
• Buspirone is a partial agonist at 5 – HT1A receptors (anxiolytic onset may take 1 – 2 weeks).

PHARMACOKINETICS
• Lorazepam is the only BZ with good absorption after IM administration.
• Most BZs have active metabolites after metabolism except lorazepam, oxazepam & temazepam
• Triazolam has the shortest t1/2.

Pharmacodynamics
• Dose – dependent CNS depression includes sedation, hypnosis, anesthesia & coma
• BZs cause anterograde amnesia & exert both muscle – relaxing & anticonvulsant actions.
• Tolerance & dependence develop with chronic use. Abrupt discontinuation may result in a withdrawal syndrome
characterized by agitation, tremors, & seizures.

Benzodiazepine Withdrawal Syndrome

• Commonly observed withdrawal symptoms:
- Irritability
- Insomnia
- Fatigue
- Headache
2
 - Tremor
- Sweating
- Concentration difficulties
- Nausea, loss of appetite
- Seizures

Drug Interactions of BZs

• Increase CNS depression
- Antihistamines
- Barbiturates
- Cyclic antidepressants
- Ethanol
• Increase BZ levels
- Cimetidine, Valproic acid
- Disulfiram, Fluoxetine,
- Erythromycin, Isoniazid

Clinical Uses
• Generalized anxiety states (buspirone)
• Panic attacks (Alprazolam,)
• Sleep disorders (Zolpidem, triazolam)
• Muscle spasticity states (diazepam)
• Seizure disorders (diazepam, lorazepam, clonazepam, phenobarbital)
• Withdrawal symptoms (diazepam)

Toxicities
• Pharmacodynamic actions include CNS depression, resulting in cognitive impairment, unwanted daytime sedation, &
decreased psychomotor skills.
• Overdose causes depression of respiratory and vasomotor drive.
• Drug interactions include additive CNS depression.

ANTIPSYCHOTICS

CONCEPTS
• The dopamine hypothesis: Schizophrenia (or psychosis) may result from a “functional excess” of dopamine in the CNS.
• Drugs that block dopamine receptors reduce psychosis while drugs that activate dopamine receptors exacerbate
symptoms or cause psychosis.
• Older antipsychotics antagonize D2 receptors. Blockade of D2 receptors in the basal ganglia result in extrapyramidal
symptoms (EPSE).
• Newer antipsychotics have a low affinity for D2 receptors and a high affinity for serotonin 5 –HT2A receptors. EPSEs are
reduced and –ve symptoms of schizophrenia improve.

Classification of Antipsychotics
Older (conventional or typical)
- Chlorpromazine, haloperidol, pimozide, fluphenazine, trifluoperazine

Newer (nonconventional or atypical)

- Clozapine, olanzapine, risperidone, quetiapine

Low – potency antipsychotics

- Chlorpromazine, clozapine, quetiapine
- Commonly cause peripheral adverse effects

High – potency antipsychotics

- Haloperidol, fluphenazine, risperidone
- Commonly cause extrapyramidal adverse effects.

Pharmacological Effects
• Dopamine receptor antagonism is the basis for the antipsychotic actions of older drugs and their efficacy as antiemetics
& also causes EPSEs & hyperprolactinemia.
• Muscarinic receptor antagonism causes atropine – like side effects especially with chlorpromazine & clozapine.
• α – Adrenoceptor antagonism causes the hypotensive actions of the phenothiazines (chlorpromazine) and clozapine.
• Sedation (an antihistamine effect) is marked with the phenothiazines

3
Clinical Uses
• Schizophrenia
- +ve symptoms (older & newer drugs)
- - ve symptoms (newer drugs)
• Other uses
- Mania
- Maintenance in bipolar disorder (newer drugs)
- Huntington’s chorea (haloperidol)
- Drug – induced psychosis

Antipsychotic Toxicities
• Extrapyramidal dysfunction:
- Acute dystonias
- Drug – induced Parkinsonism
- Akathisias
- Tardive dyskinesia
Mainly caused by the older antipsychotics.
Treatment includes lowering the dose, using anticholinergics, or changing to a newer antipsychotic drug.
• Endocrine & metabolic effects
- Amenorrhea – galactorrhea & gynecomastia (older drugs)
- Weight gain (olanzapine, chlorpromazine etc)
- Hyperglycemia (olanzapine)
• Reduction of the seizure threshold
- Phenothiazines, clozapine
• Specific toxicities
- Cardiotoxicity (phenothiazines)
- Agranulocytosis (clozapine)

MOOD STABILISERS

Subclasses
• Lithium
• Anticonvulsants
- Valproic acid
- Carbamazepine
- Lamotrigine
- Gabapentin
- Topiramate
• Others : Olanzapine

Lithium
• Li is excreted by the kidneys unchanged; therefore adequate renal function is essential to prevent Li accumulation and
intoxication.
• Li is excreted in breast milk.
• The dose of Li is usually guided by the blood level. The therapeutic blood levels are
- 0.8- 1.5 mmol/ L for the acutely manic patient
- 0.6 – 1.2 in the stabilised patient

Adverse Effects
• GI: nausea, vomiting, diarrhoea.
• Weight gain
• Tremor
• CV effects: ECG changes – T – wave inversion, hypotension, arrhythmias.
• Dermatitis
• Hypothyroidism
• Renal effects: diabetes insipidus, nephritis

ANTIDEPRESSANTS

CONCEPTS
• The amine hypothesis of depression : decrease in brain NE and/ or serotonin is responsible for the disorder.
• Most drugs effective in major depression appear to facilitate the activity of brain amines.

4
Classification
• Monoamine oxidase inhibitors (MAOIs)
- Irreversible inhibitors (e.g. Phenelzine)
- Reversible inhibitors (e.g. Moclobemide)
- Inhibit MAO type A, which results in an increase in presynaptic levels of NE and 5– HT.

• Tricyclics (TCAs)
- Amitriptyline, imipramine, clomipramine: block neuronal reuptake of NE and 5- HT increasing their postsynaptic actions.

• Selective serotonin reuptake inhibitors (SSRIs)

- Fluoxetine, citalopram, paroxetine, sertraline

• Heterocyclics:
(1) 2nd Generation:
- Amoxapine & maprotiline block NE reuptake
- Trazodone blocks serotonin reuptake
- Bupropion : NE & DA reuptake blocker

(2) 3rd Generation:

- Venlafaxine blocks reuptake of NE & 5- HT
- Mirtazapine antagonizes presynaptic α2 – receptors increasing NE release.

Pharmacological Effects
• CNS actions:
-TCAs & most heterocyclics (especially mirtazapine & trazodone) cause sedation, additive with other CNS depressants.
- SSRIs, bupropion, & venlafaxine may cause insomnia & jitteriness.

• Peripheral actions:
- Weight gain (TCAs, MAOIs)
- Weigh loss (SSRIs)

• Drug interactions from inhibition of Cytochrome P- 450 isoenzymes by nefazodone, SSRIs & venlafaxine

Clinical Uses
• Major depression
- SSRIs and newer heterocyclics are used most because they cause fewer side effects & are safe in overdose.
• Other uses:
- TCAs & SSRIs: bipolar, panic, phobia
- TCAs: neuropathic pain & enuresis
- SSRIs: bulimia, obsessive – compulsive disorder, pathological obesity, premature ejaculation.
- Bupropion: withdrawal from nicotine dependence

Adverse Effects
• MAOIs: Hypertensive reactions following ingestion of tyramine – containing foods.
• TCAs : Anticholinergic effects, hypotension, cardiac arrhythmias, convulsions
• SSRIs: Headache, insomnia, nausea, diarrhoea

Cognitive Enhancers
• Enhancement of attention
- Methylphenidate
- D- amphetamine
- Pemoline
• Enhancement of Memory
- Cholinesterase inhibitors : tacrine, donepezil, rivastigmine, metrifonate

DRUGS OF ABUSE

DEFINITIONS
• Abuse: Self – administration of any drug in a culturally disapproved manner that causes adverse consequences.
• Dependence: The physiological state produced by repeated administration of a drug, necessitating continued
administration to prevent the appearance of the withdrawal syndrome.
• Tolerance: Tolerance has developed when after repeated administration, a given dose of a drug produces a decreased
effect.

5
• Withdrawal: The psychologic & physiological reactions to abrupt cessation of dependence – producing drug.
• Addiction: A behavioral pattern of drug abuse characterized by compulsive use, the securing of its supply, and a high
tendency to relapse after discontinuation.

DRUGS OF ABUSE
• CNS Stimulants :Cocaine, amphetamine
• Sedative –hypnotics : alcohol, BZs,barbiturates
• Opioid analgesics e.g heroin,
• Marijuana (cannabis)
• Hallucinogens e.g LSD, mescaline
• Phencyclidine
• Inhalants (solvents, nitrous oxide)

Overdose Toxicities
• CNS Stimulants: hypertension, agitation,mydriasis,arrhythmias, seizureso
• Sedative – hypnotics :slurred speech, respiratory depression, mydriasis, coma
• Opioid analgesics: miosis, respiratory depression, coma.
• Hallucinogens: weakness, paresthesias, perceptual disturbances.

ANTIEPILEPTIC DRUGS

Mechanisms of Action

GABA potentiation Benzodiazepines, barbiturates, gabapentin, tiagabine, vigabatrin

Na ion channel block Carbamazepine, Phenytoin, Barbiturates, valproic acid

Ca ion channel block Ethosuximide, valproic acid

Glutamic acid antagonism Felbamate, lamotrigine, Topiramate

Clinical Uses
- Generalized tonic – clonic & partial seizures: phenytoin, carbamazepine, valproic acid.
- Absence seizures: ethosuximide, & valproic acid
- Myoclonic syndromes: valproic acid, clonazepam
- Status epilepticus: diazepam, phenytoin, lorazepam, phenobarbital

Characteristics of older antiepileptics:

Drug Indications Toxicities

Carbamazepine Used in partial & T-C CNS depression,

seizures, trigeminal hematotoxicity, liver
neuralgia & bipolar enzyme inducer,
disorder teratogenic
Clonazepam
Myoclonic seizures, Sedation is dose-limiting;
Ethosuximide anxiety,bipolar disorder Dependence liability

Phenobarbital Absence seizures GI distress, headache

2nd line drug in T-C & CNS depression,

partial seizures dependence, liver enzyme
inducer

6
Drug Indications Toxicities

Phenytoin Partial & T- C seizures Hirsutism, gingival

hyperplasia, osteomalacia,
teratogenic (craniofacial
anomalies)
Pharmacokinetic features
include variable oral
absorption, competition for
plasma protein binding and
liver enzyme induction
Valproic acid “Broadest spectrum” AED:
Absences, myoclonic, GI distress, hepatotoxicity,
partial & T- C seizures, Liver enzyme – inducer,
migraine, bipolar disorder. Teratogenic (spina bifida)

Newer Antiepileptic Drugs

Drug Clinical uses / Toxicities

Felbamate, Tiagabine, Vigabatrin Back – up in partial seizures

Gabapentin Partial seizures, bipolar disorder. Neuropathic pain, migraine. Sedation, dyskinesias,
Leukopenia

Lamotrigine Generalized & parial T-C, Myoclonic & Absences. Sedation, hematotoxicity, Skin
reactions

General Principles of Epilepsy Treatment

• Use a single drug whenever possible and increase its dose to either seizure control or toxicity.
• If a drug fails to control seizures without toxicity, switch to another appropriate drug used alone and again increase the
dose until seizure control occurs or toxicity intervenes.
• Use two drugs only when monotherapy has failed. Some patients may have more seizures when taking two drugs,
compared with one drug, because of drug interactions.

GENERAL ANAESTHETICS

Concepts
• An Ideal Anaesthetic should cause unconsciousness, analgesia, amnesia, muscle relaxation and loss of reflexes.

• Anesthesia protocols involve use of Inhaled and / or intravenous anesthetics, often with skeletal muscle relaxants.

Inhaled Anaesthetics
• Nitrous oxide
• Desflurane
• Sevoflurane
• Enflurane
• Isoflurane
• Halothane

Intravenous Anaesthetics
• Thiopental (barbiturate) has a rapid onset but short duration due to redistribution from the brain to other tissues.
• Midazolam is a BZ with amnestic effects.
• Fentanyl and related opioids have less CV actions than inhaled anesthetics. Recovery can be facilitated by naloxone.
• Propofol also has antiemetic actions.
• Ketamine causes “dissociative anesthesia.”

7
DRUGS FOR PARKISONISM AND OTHER MOVEMENT DISORDERS

Concepts
• Parkinson’s disease involves loss of dopaminergic activity in the basal ganglia (striatum), resulting in excessive
actions of Ach. Drugs that enhance dopaminergic activity and / or decrease cholinergic activity are used.

• In Huntington’s disease GABA functions are decreased and dopaminergic functions are enhanced. Drugs that block
dopamine receptors are ameliorative.

Levodopa (L – Dopa)
• Mechanism of action: L – dopa is actively accumulated in the CNS where it’s converted by dopa decarboxylase to
dopamine.
• It’s used with carbidopa, an inhibitor of peripheral decarboxylase.
• Toxicities include dyskinesias, hypotension, GI distress, psychosis.

Other Antiparkinsonian Drugs

• Bromocriptine & Pergolide: They activate striatal dopamine (DA) receptors.
• Pramipexole & Ropinirole: Activate striatal DA receptors. 1st line drugs in early treatment.
• Antimuscarinics: include benztropine, bipiriden, benzhexol. Used as adjunctive treatments for tremor & rigidity.
• Selegiline: Inhibits MAO type B.
• Entacapone & Tolcapone are COMT inhibitors: They block conversion of L-dopa to 3 – O – methyldopa which may
compete with L – dopa for uptake into the CNS.
• Amantadine: enhances dopaminergic functions and /or blocks muscarinic receptors.

Drugs for other Movement Disorders

• Huntington’s disease: Haloperidol
• Tourette’s syndrome: Pimozide, haloperidol
• Tremor : Propranolol
• Wilson’s disease : penicillamine
• Drug – induced dyskinesias: anticholinergics

OPIOD ANALGESICS

CONCEPTS

1. Opioid receptors include mu (μ), kappa (κ), & delta (δ) and are targets for opioid analgesic drugs.
2. Opioids are classified as strong, partial, or weak agonists based on analgesic efficacy
3. Naloxone & naltrexone block mu receptors
4. Mixed agonist – antagonists (nalbuphine& pentazocine) activate kappa receptors but block mu receptors

Selected opioid analgesics & their Characteristics

Strong μ agonists Morphine, meperidine (pethidine), methadone

Moderate μ agonists Oxycodone, codeine

Weak μ agonist Propoxyphene

Mixed agonist (κ) / antagonist (μ) Nalbuphine, pentazocine

Pharmacological Effects
• Analgesia – efficacy variable depending on the drug
• Sedation
• Respiratory depression
• GIT: - constipation 20 to decreased peristalsis
• Pupils – miosis
• Cough suppressants
• Emesis

Clinical Uses
• Analgesia – drug choice depends on need
• Cough suppressants : codeine, dextromethorphan
• Diarrhoea : loperamide, diphenoxylate

8
 • Anesthesia : fentanyl, morphine
GABA
• Withdrawal states:
- Methadone is used to suppress symptoms of opioid withdrawal
- Naltrexone is used to decrease craving in alcoholism