DRUGS ACTING ON CENTRAL NERVOUS SYSTEM

Vaheeda rehman shaik,* 129AISO605, Dept of pharmacology, Nimra college of pharmacy.

 Central nervous system : Brain Brain stem Spinal cord

GENERAL ANAESTHETICS

INTRODUCTION
DEFINITION:
General anaesthetics: These are drugs which produce reversible loss of all sensations and consciousness.
Anaesthesia means: an- without aesthesis- sensation

HISTORY
19th century

Alcohol, opium

1844

Nitrous oxide
Ether Chloroform Cyclopropane Thiopentone Halothane

1846

1847

1929

1935

1956

 LIPID THEORY:

MECHANISM

 EFFECTS ON ION CHANNELS:

STAGES OF ANAESTHESIA

stage of analgesia stage of delirium/excitement stage of surgical anaesthesia stage of medullary paralysis

PROPERTIES OF AN IDEAL ANAESTHETIC

TECHNIQUES OF INHALATION OF ANAESTHETICS

Open drop method Through anaesthetic machines

a.Open system b.Closed system c.Semi closed system

CLASSIFICATION
General anaesthetics

Inhalation

Intra venous

Gases

Volatile

Liquid

Inducing agents

Slower acting drugs

Balanced anaesthesia (both inhalational and i.v )

 GASES: Nitrous oxide VOLATILE LIQUIDS: Ether Halothane Enflurane Isoflurane Desflurane Sevoflurane INDUCING AGENTS: Thiopentone sodium Methohexitone sodium Propofol Etomidate SLOWER ACTING DRUGS: BENZODIAZEPINES: Diazepam Lorazepam Midazolam DISSOCIATIVE ANAESTHESIA: Ketamine OPIOID ANALGESIA: Fentanyl

INHALATIONAL GENERAL ANAESTHETICS

GASEOUS:
NITROUS OXIDE:
Pharmacokinetics: Onset of action ------- quick and smooth Metabolism ------ does not occur Excretion ------ quickly removed by lungs MAC ------ 105% Recovery ------- rapid Second gas effect and diffusion hypoxia occurs Dose ------- 70% Nitrous oxide, 25-30% of oxygen, 0.2-2% another potent drug Advantages: Cheap and very commonly used Non toxic to lever, kidney, brain Uses: Nitrous oxide(50%) along with oxygen can be used for obstetric and dental

VOLATILE LIQUIDS:
ETHER: (DIETHYL ETHER)
Pharmacokinetics: Induction is prolonged and unpleasant with struggling Recovery ------ slow Mechanism: Reduces Ach output from motor nerve endings Advantages: Potent drug, produce good analgesia Still using in developing countries because it is cheap Can be given by open drop method Adverse effects: Post anaesthetic vomit and nausea Breath holding, salivation and marked respiratory secretions Premedication atropine given

HALOTHANE(FLUOTHANE) :
Pharmacokinetics: Induction ------ reasonably quite and pleasant Metabolism: 20% by liver, remaining exhaled out Elimination: 24-48 hrs after prolonged administration Recovery: smooth and reasonably quick Dose :------ for induction --- 2-4% for maintenance --- 0.5-1% causes direct depression of myocardial contractility by reducing intracellular calcium concentration and sympathetic activity fails to increase Adverse effects: Malignant hyperthermia Metabolite of halothane causes chemical and immunological injury Repeated use causes hepatitis(1 in 10,000) Cardiac output is reduced with deep anaesthesia BP falls Vascular bed dilates Heart rate reduces, tachyarrhythmia occurs Greater depression of respiration, breathing shallow

INTRAVENOUS GENERAL ANAESTHETICS

INDUCING AGENTS
THIOPENTONE SODIUM:
Derivative of thiobarbiturate (ultra short acting) Pharmacokinetics: Highly soluble in water Distribution: depends on organ blood flow (brain gets large amount) Metabolism: hepatic Elimination t1/2 is 7-12 hrs Dose: injected I.V (3-5mg/kg) as 2.5%solution Must prepare freshly before injection Pharmacology: Produce unconsciousness in 15-20 seconds Consciousness is regained in 6-10 min t1/2 of distribution phase is 3min Adverse effects: laryngospasm is a main adverse effect Recovery with shivering and delirium Other uses: control of convulsions

PROPOFOL:
Pharmacokinetics: I.V given for both induction and maintenance Distribution t1/2 2-4 minutes(rapidly) Elimination t1/2 (100 min) shorter than thiopentone due to rapid metabolism Unconsciousness occurs 15-45 seconds and lasts 5-10 min Suitable for outpatient surgery Advantages: Post operative nausea and vomiting low Patient acceptability is very good Adverse effects: Excitatory effects and involuntary movements noted for some patients Fall in BP- due to vasodilation Bradicardia is frequent Dose dependent respiratory depression Pain during injection is also frequent- can be minimized by combining with lidocaine Dose: 2mg/kg i.v bolus --- for induction 9mg/kg/hr -----------for maintenance

SLOWER ACTING DRUGS

BENZODIAZEPINES:
Pharmacokinetics: Distribution: t1/2 of diazepam is 15 min This is a premedication product Now frequently using for inducing, maintenance, and supplement anaesthesia as well as conscious sedation Dose: 0.2-0.3mg/kg or equivalent diazepam Unconsciousness in 5-10 min Amnesia persists------ 2-3 hrs Sedation persists------ 6hrs or more Post operative nausea and vomiting is absence Adverse effects: Injected i.v produce sedation and amnesia If large doses given recovery delays BZDs are poor analgesics An opioid or nitrous oxide is added if produced pain Involuntary movements are not stimulated Requires neuromuscular blockers Uses: now preferred for endoscopies, angiographies, fracture setting etc

COMPLICATIONS OF GENERAL ANAESTHESIA

During anaesthesia

Respiratory depression Cardiac arrhythmias, asystole, fall in BP Aspiration of gastric contents Laryngospasm and asphyxia Fire and explosion (rare) Delirium, convulsions, excitatory effects Recall of events during surgery

After anaesthesia

Nausea and vomiting Persisting sedation Pneumonia, atelectasis Organ toxicities Nerve palsies Emergency delirium Cognitive defects

DRUG INTERACTIONS
Antihypertensive's-general anaesthetics: BP fall Corticosteroid-anaesthetics: cardiovascular collapse Treatment: give 100mg of hydrocortisone Insulin need of a diabetic is increased during general anaesthetics Neuroleptics, opioids, clonidine and monoamine oxidase inhibitors potentiate anaesthetic effect Halothane sensitizes heart to Adr

PREANAESTHETIC MEDICATION
Preanaesthesia: agents which show synergic effect on the anaesthetic drugs

Advantages of preanaesthetics:
Decrease acidity and volume of gastric juice: less damages if aspirated Anti emetic effect extending to the postoperative period Decrease secretions and vagal stimulation Supplement analgesic action of anaesthetics and potentiate them: less anaesthetic is needed Amnesia for pre and postoperative events Relief of anxiety and apprehension preoperatively and to facilitate smooth induction

 Examples:
Sedatives-anti anxiety drugs Opioids Anticholinergics Neuroleptics H2 blockers Antiemetics

SEDATIVES AND HYPNOTICS

INTRODUCTION
DEFINITION:
SEDATIVE: drug that subdues excitement and calms the subject without inducing sleep
HYPNOTIC: drug that induces and/or maintains sleep, similar to normal arousable sleep

Hypnotic Sedative

General anaesthesia

STAGES OF SLEEP
Stage 0 (awake) Stage 1 (dozing) Stage 2 (unequivocal sleep) Stage 3 (deep sleep transition) Stage 4 (cerebral sleep) REM sleep (paradoxical sleep)

CLASSIFICATION

 Benzodiazepines:
Hypnotic: Diazepam Flurazepam Nitrazepam Alprazolam Temazepam Triazolam Antianxiety: Diazepam Chlordiazepoxide Oxazepam Lorazepam Alprazolam Anticonvulsant: Diazepam Lorazepam Clonazepam Clobazam

Barbiturates:
Long acting: phenobarbitone Short acting: Butobarbitone, Pentobarbitone Ultra short acting: Thiopentone, Methohexitone

 PHARMACOKINETICS:

BARBITURATES:

Well absorbed from g.i. tract Widely distributed in body Rate of entry into CNS is dependent on lipid solubility High lipid soluble has instantaneous entry Less lipid soluble takes longer and enters very slowly REDISTRIBUTION: its imp in case of highly lipid soluble After i.v injection consciousness is regained in 6-10 min due to redistribution Ultimate disposal occurs by metabolism t1/2 of elimination phase is 9 hours METABOLISM: intermediate lipid solubility primarily metabolized in liver by oxidation, dealkylation, and conjugation plasma t1/2 12-40 hrs EXCRETION: low lipid solubility excreted unchanged in urine t1/2 of phenobarbitone is 80-120 hrs

 PHARMACOLOGY: CNS: Barbiturates produce dose dependent effects Sedation Sleep Anaesthesia Coma HYPNOTIC DOSE: (100-200mg of short acting barbiturates) Shorten time taken to fall sleep & increase sleep duration Sleep arousable, but subject may feel confused & unsteady if waken early Night awakening are reduced REM and 3,4 sleep decreased REM NREM sleep cycle disrupted Effect of sleep progressively reduces if taken every night When drug is discontinued rebound increase in REM sleep and night mares Takes several days for normal pattern restore After a night dose hang over may occur SEDATIVE: (smaller dose of long acting barbiturates) Given at day time can produce drowsiness, reduction in anxiety & excitement They have no analgesic action Smaller dose may even cause hyperalgesia Barbiturates have anticonvulsant activity Barbiturates depress all areas of CNS

 OTHER SYSTEMS: RESPIRATION: depressed by relatively higher doses Neurogenic, respiratory centers depressed Barbiturates donot have selective antitussive actions CVS: decrease in BP & heart rate Toxic doses produce marked fall in BP due to ganglionic blockade, vasomotor centre depression and direct decrease in cardiac contractility Reflex tachycardia can occur, Dose producing cardiac arrest is about 3 times larger than that causing respiratory failure SKELETAL MUSCLE: Anaesthetic doses reduce muscle contraction SMOOTH MUSCLES: Hypnotic dose- tone and motility of bowel reduced Action on bronchial, and uterine muscles is not significant KIDNEY: Reduce urine flow by decrease BP and increase ADH release

 USES: Enzyme inducing property of phenobarbitone can be utilized to clearance of congenital nonhaemolytic jaundice adjuvant in psychosomatic disorders
ADVERSE EFFECTS: SIDE EFFECTS: hang over, mental confusion, traffic accidents IDIOSYNCRASY: excitement HYPERSENSITIVITY: Rashes, Swelling of eyelids, lips TOLERENCE AND DEPENDENCE: Tolerance due to repeated use Withdrawal symptoms are excitement , hallucinations, delirium convulsions, and death ACUTE BARBITURATE POISONING: patient will be flabby, comatose with shallow and failing respiration fall in BP and cardiovascular collapse renal shut down, pulmonary complications Lethal dose depends on lipid solubility it is 2-3g for more lipid soluble agents 5-10g for less lipid soluble agents TREATMENT: gastric lavage, alkaline diuresis, haemodialysis etc

 DRUG INTERACTIONS: Barbiturates - warfarin, tolbutamide, griseofulvin etc: induce metabolism and reduce their effectiveness Sodium valproate phenobarbitone: increase plasma concentration Phenobarbitone phenytoin and imipramine: competitively inhibits and induces metabolism Phenobarbitone griseofulvin: decreases absorption from g.i.t

ANTIEPILEPTIC DRUGS

INTRODUCTION
DEFINITION:
EPILEPSY: group of disorders of CNS characterized by paroxysmal cerebral dysrhythmia, manifesting as brief episodes(seizures) of loss or disturbances of consciousness with/without characterized body movements(convulsions) sensory or psychiatric phenomena ANTIEPILEPTICS: drugs which reduces epilepsy (mainly seizures) in human body

TYPES OF SEIZURES
Generalized seizures Partial seizures

GTCS Absence seizures Atonic seizures Myoclonic seizures Infantile spasms

SPS

CPS

SPS/CPS

CLASSIFICATION
Based on chemical structure Based on mechanism of action

Barbiturates Deoxybarbiturates Hydantoin Iminostilbene Succinamides Aliphatic carboxylic acid Benzodiazepines Phenyltriazine Cyclic GABA analogue Newer drugs

Prolongation of sod channel inactivation Facilitation of GABA mediated chlorine channel opening Inhibition of T type calcium current

BASED ON CHEMICAL NATURE: Barbiturates: phenobarbitone Deoxybarbiturates: primidone Hydantoin: phenytoin, fosphenytoin Iminostilbene: carbamazepine, oxcarbazepine Succinamides: ethosuximide Aliphatic carboxylic acid: valproic acid, divalproex Benzodiazepines: clonazepam, diazepam, lorazepam Phenyl triazine: lomatrigine Cyclic GABA analogue: gabapentin Newer drugs: vigabatrin, topiramate, tiagabine, zonisamide,

BASED ON MECHANISM OF ACTION: Prolongation of sod channel inactivation:

Phenytoin Carbamazepine Valproate Lomatrigine Topiramate Zonisamide Facilitation of GABA Barbiturate Benzodiazepine Vigabatrin Valproate Gabapentine Tiagabine Ethosuximide Trimethadione Valproate

mediated chlorine channel opening:

Inhibition of T type calcium current:

PHENYTOIN
PHARMACOKINETICS: Absorption: oral route 80-90% bound to plasma protein

Metabolism: Hepatic t1/2 is 12-24 hrs

Excretion: 5% unchanged in urine

 PHARMACOLOGY: Mechanism: Therapeutic level: Prolongation of sodium channel inactivation At high concentration: Reduction in calcium influx Inhibition of glutamate and facilitation of GABA responses Action of phenytoin: On Tonic clonic epilepsy

 ADVERSE EFFECTS: At therapeutic level: Hypersensitivity Megaloblastic anemia Osteomalacia Hyperglycemia Foetal hydantoin syndrome Hirsutism Gum hypertrophy

At high plasma levels: Fall in BP, cardiac arrhythmias---when i.v injected Nausea, vomiting Drowsiness, hallucination, mental confusion

Antiparkinsonian drugs

INTRODUCTION
DEFINITION:
Parkinsonism: A group of neurological disorders marked by hypokinesia, tremor, muscular rigidity Antiparkinsonians: Drugs that have a therapeutic effect in parkinsonism

CLASSIFICATION
Drugs effecting brain dopaminergic system
Dopamine precursor: LEVODOPA Peripheral decarboxylase inhibitors: CARBIDOPA Dopaminergic: BROMOCRIPTINE MAO-B inhibitors: SELEGILINE COMT inhibitors: ENTACAPONE Dopamine facilitator: AMANTADINE

Drugs effecting brain cholinergic system

Central anticholinergics: PROCYCLIDINE Antihistamines: PROMETHAZINE

LEVODOPA
PHARMACOKINETICS: Absorption: Small intestine Bioavailability: Gastric emptying Amino acids present in food Metabolism: First pass metabolism Plasma t1/2 of levodopa is 1-2 hrs Excretion: through urine

 PHARMACOLOGY: CNS: Hypokinesia and rigidity resolved first later tremor D1 like (D1, D5): excitatory D2 like (D2, D3, D4): inhibitory CVS: Tachycardia CTZ: Nausea and vomiting ENDOCRINE: Inhibit prolactin release

 ADVERSE EFFECTS At initiation of therapy: Nausea and vomiting Postural hypotension Cardiac arrhythmias Exacerbation of angina Alteration in taste sensation After prolonged therapy: Abnormal movements Behavioral effects Fluctuation in motor performance

 INTERACTIONS: antihypertensives levodopa Non selective MAO inhibitors levodopa Atropine and anticholinergic levodopa Pyridoxine - levodopa

ANTIPSYCHOTIC DRUGS

INTRODUCTION
DEFINITION:
Psychosis: A severe mental disorder in which thought and emotions are so impaired that contact is lost with external reality

Antipsychotics: class of medicines used to treat psychosis and other mental and emotional conditions

CLASSIFICATION
Phenothiazines Butyrophenones Thioxanthenes Other heterocyclic's Atypical antipsychotics
Aliphatic side chain: CHLORPROMAZINE Piperidine side chain: THIORIDAZINE Piperazine side chain: TRIFLUOPERAZINE

HALOPERIDOL PENFLURIDOL

FLUPENTHIXOL

LOXAPINE PIMOZIDE

CLOZAPINE OLANZAPINE ZIPRASIDONE

neuroleptics

CHLORPROMAZINE
PHARMACOKINETICS: Absorption: Oral Highly bound to plasma and tissue proteins Metabolized: Liver metabolism By CYP 2D6 Elimination: t1/2 is variable and 18-30 hrs

 PHARMACOLOGY: CNS In normal individuals: Psychomotor slowing Emotional quietening

In psychotic patients: Anxiety is relieved Hyperactivity, hallucinations, and delusions are suppressed Chlorpromazine lowers seizures & can precipitates fits in untreated epilepsy

 MECHANISM OF ACTION:

 LOCAL ANAESTHETICS: Potent as procaine but not used because of irritant action
CVS: Hypotension SKELETAL MUSCLE: No effect ENDOCRINE: Increase prolactin results in gynaecomastia & galactorrhoea Reduce gonadotropin secretions Decreased in ADH release more urine

Anti manic drugs

Antimanic drugs: mood stabilizers

Example: lithium carbonate

hallucinogens
Indole amines cannabinoids

ANTIDEPRESSANT DRUGS

INTRODUCTION
DEFINITION:
Depression: state of low mood and aversion to activity that can have a negative effect on a persons thought behavior, feelings, world view and physical well being
Antidepressants: drugs which have the effect on depression/ drugs for the treatment of depression

CLASSIFICATION
Moclobemide RIMAs Clorgyline NA+5-HT reuptake inhibitors: Imipramine, doxepin Predominantly NA reuptake inhibitors: Amoxapine paroxetine Fluoxetine

TCAs

SSRIs

Amineptine Atypical Trazodone

Tricyclic antidepressants
PHARMACOKINETICS:

Absorption: Oral Highly bound to plasma and tissue proteins

Metabolism: Liver

Excretion: Through urine over 1-2 weeks

 PHARMACOLOGY:
CNS: In normal individuals: Peculiar clumsy feeling Tiredness, light headache, sleepiness, difficulty in thinking In depressed patients: Mood is gradually elevated Patient become more communicative Produce convulsions on over dose

MECHANISM OF ACTION: Inhibition of nerve terminal NE neuronal uptake system

Increase in synaptic concentrations of NE

Desensitization of nerve terminal 2-adrenoceptors Increase in neuronal NE release Further increase in synaptic concentrations of NE Desensitization of postsynaptic -adrenoceptors with no change in postsynaptic 1-adrenoceptor sensitivity

Mechanism of action

 ANS: Dry mouth, blurring of vision Constipation, urinary hesitancy CVS: Tachycardia Postural hypotension ECG changes and cardiac arrhythmias

 ADVERSE EFFECTS: Sweating and fine tremors Postural hypotension Sedation, mental confusion and weakness Increased appetite and weight gain Seizures threshold is lowered Cardiac arrhythmias especially in ischemic heart disease Rashes and jaundice due to hypersensitivity Anticholinergic: dry mouth, bad taste epigastric distress Acute poisoning

 INTERACTIONS:
Phenytoin, phenylbutazone, aspirin, and CPZ TCAs Phenobarbitone imipramine TCAs CNS depressants MAO inhibitors - TCAs

ANTIANXIETY DRUGS
Anxiety: it is an emotional state, unpleasant, uneasiness, discomfort, and concern or fear about some defined or undefined future threats

Antianxiety: drugs which are aimed to control the symptoms of anxiety Classification: Benzodiazepines: Diazepam Chlordiazepoxide Oxazepam Azapirones: Gepirone Ispapirone Sedative antihistaminic: Hydroxyzine Beta blockers: Propranolol

REFERENCES
Essentials of MEDICAL PHARMACOLOGY: KD Tripathi RANG and DALES pharmacology BASIC AND CLINICAL PHARMACOLOGY LANGE

modern pharmacology with clinical applications Lippincott www.doctors.ac.in

www.wikipedia.org www.surgeryencyclopedia.com