WELCOM

E

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

ANTIDEPRESSANT& ANTIANXIETY

GENERAL ANAESTHETICS

SEDATIVES HYPNOTICS

ANTI PARKINSONIAN

DRUGS

ANTIEPILEPTICDRUGS

ANTIPSYCHOTIC &

ANTIMANIC

CNS

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

Alcohol, opium

Nitrous oxide

Ether

Chloroform

Cyclopropane

Thiopentone

Halothane

1844

1846

1847

1929

1956

1935

19th century

MECHANISM LIPID THEORY:

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

Patients• Non irritant• Not cause nausea/vomit• No after

effects• Fast Induction

and recovery

Surgeon• Immobility

• Muscle relaxant• Non

inflammable• Non explosive

• Provide adequate analgesia

Anaesthetist• Administration

easy• Ineffective to

organs• High Potency for

low conc• Cheap, non reactive, safety

TECHNIQUES OF INHALATION OF ANAESTHETICS

Open drop method

Through anaesthetic machines

a.Open systemb.Closed systemc.Semi closed system

CLASSIFICATIONGeneral anaesthetics

Inhalation

Gases VolatileLiquid

Intra venous

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 ANAESTHETICSGASEOUS:

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 drugAdvantages:•Cheap and very commonly used• Non toxic to lever, kidney, brainUses:• 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 ------ slowMechanism: • Reduces Ach output from motor nerve endingsAdvantages:•Potent drug, produce good analgesia•Still using in developing countries because it is cheap• Can be given by open drop methodAdverse 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 AGENTSTHIOPENTONE 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 injectionPharmacology:•Produce unconsciousness in 15-20 seconds•Consciousness is regained in 6-10 min • t1/2 of distribution phase is 3minAdverse 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 surgeryAdvantages:• Post operative nausea and vomiting –low• Patient acceptability is very goodAdverse 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 DRUGSBENZODIAZEPINES: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 absenceAdverse effects:• Injected i.v produce sedation and amnesia• If large doses given recovery delays• BZD’s 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 anaesthesi

a

•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 anaesthesi

a

•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

Sedative

Hypnotic

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)

Sedatives and

Hypnotics

CLASSIFICATION

Barbiturates:

• Long acting: phenobarbitone

• Short acting: Butobarbitone, Pentobarbitone

• Ultra short acting: Thiopentone, Methohexitone

Benzodiazepines:• Hypnotic: Diazepam Flurazepam Nitrazepam Alprazolam Temazepam Triazolam

• Antianxiety: Diazepam Chlordiazepoxide Oxazepam Lorazepam Alprazolam

• Anticonvulsant: Diazepam Lorazepam Clonazepam Clobazam

BARBITURATES: PHARMACOKINETICS:

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

ANTI-EPILEPTICDRUGS

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 SEIZURESGTCS

Absence seizures

Atonic seizures

Myoclonic seizures

Infantile spasms

Generalized

seizures

SPS

CPS

SPS/CPS

Partial seizures

CLASSIFICATION•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 structure

Based on

mechanism of action

• 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 CHEMICAL NATURE:

BASED ON MECHANISM OF ACTION: Prolongation of sod channel inactivation:• Phenytoin• Carbamazepine• Valproate• Lomatrigine• Topiramate• Zonisamide Facilitation of GABA mediated chlorine channel opening:• Barbiturate• Benzodiazepine• Vigabatrin• Valproate• Gabapentine• Tiagabine Inhibition of T type calcium current:• Ethosuximide• Trimethadione• Valproate

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

Anti-parkinsonian

drugs

INTRODUCTION

DEFINITION: Parkinsonism: A group of neurological disorders marked by hypokinesia, tremor, muscular rigidity

Antiparkinsonians: Drugs that have a therapeutic effect in parkinsonismBellad

onna alkaloi

ds

Levodopa

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 – levodopaAtropine and anticholinergic – levodopa Pyridoxine - levodopa

ANTI-PSYCHOTIC

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

•Aliphatic side chain: CHLORPROMAZINE•Piperidine side chain: THIORIDAZINE•Piperazine side chain: TRIFLUOPERAZINE

Phenothiazines

•HALOPERIDOL•PENFLURIDOL

Butyrophenones

•FLUPENTHIXOLThioxanthenes

•LOXAPINE•PIMOZIDE

Other heterocyclic's

•CLOZAPINE•OLANZAPINE•ZIPRASIDONE

Atypical antipsychotics

CLASSIFICATION

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

ANTI-DEPRESSANT

DRUGS

INTRODUCTION

DEFINITION: Depression: state of low mood and aversion to activity that can have a negative effect on a person’s thought behavior, feelings, world view and physical well being

Antidepressants: drugs which have the effect on depression/ drugs for the treatment of depression

CLASSIFICATION

RIMAs •Moclobemide•Clorgyline

TCAs •NA+5-HT reuptake inhibitors: Imipramine, doxepin•Predominantly NA reuptake inhibitors: Amoxapine

SSRIs •paroxetine•Fluoxetine

Atypical •Amineptine •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 nochange 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 anxietyClassification:Benzodiazepines: Diazepam Chlordiazepoxide OxazepamAzapirones: Gepirone IspapironeSedative antihistaminic: HydroxyzineBeta blockers: Propranolol

REFERENCES Essentials of MEDICAL PHARMACOLOGY: KD Tripathi

RANG and DALE’S pharmacology

BASIC AND CLINICAL PHARMACOLOGY –LANGE

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

www.wikipedia.org

www.surgeryencyclopedia.com

THANK YOU