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Drugs acting on Nervous System

by Dr.Naveen Kumar at PDM Dental College & Research Institute,

Bahadurgarh on 24th Nov 2008

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Skeletal Muscle Relaxants

• Drugs adm. systemically to cause reversible Skeletal muscle paralysis required mainly for surgical procedures.

• Two types-

1. Peripheral Skeletal muscle Relaxants

- Non-Depolarizing (Competitive blockers)

- Depolarizing

- Others- Botylinum Toxin, Dantrolene

2. Central Skeletal muscle Relaxants

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Agent Pharmacological

Properties

Onset time (min)

Duration

(min)

Elimination

D-tubocurarine

Long duration4-6 80-120

Renal and liver

Pancuronium Long duration4-6 120-180

Renal

Atracurium Intermediate duration

2-4 30-60

Hoffman degradation,Plasma AChe

Rocuronium Intermediate duration 2 30-60

Renal and liver

Mivacurium Short duration2 12-18

Plasma AChe

Classification of Non-Depolarizing (Competitive blockers)

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Other Effects of Non-Depolarizing Neuromuscular Blockers

• Action at Autonomic Ganglia - d-TC blocks (Nn) also- HR, BP- newer agents have less ganglionic effects

• Histamine Release- by d-TC- d-TC-bronchospasm, bronchial and salivary secretions- newer agents have minimal His. releasing effects

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ADR- Non-Depolarizing Neuromuscular Blockers

• Hypotension- d-TC• Flushing & Asthma- d-TC• Tachycardia• Respiratory paralysis• Apnea- ChE def.- Miva

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Type of Sk. Muscle Relaxant

Depolarizing

Drug Succinylcholine

Chemical Class Dicholine ester

Pk class Ultrashort duration

Time of onset 1-1.5 mins

Duration of action 5-8 mins

Mode of Elimination Hydrolysis by plasma cholinesterases

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Other Effects of Depolarizing Neuromuscular Blockers

• Action at Autonomic Ganglia -SCh may stimulate (Nn rec.) also- HR, +BP

• Histamine Release- by SCh.

-SCh-bronchospasm, bronchial and salivary secretions

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ADR- Depolarizing Neuromuscular Blockers(SCh)

• Hyperkalemia- Arrhythmia• Muscle pain- post-op muscle soreness• SCh apnea-

- incidence- 1:3000- atypical ChE

• Sinus bradycardia• Respiratory paralysis• Malignant hyperthermia (SCh + halothane)

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Malignant Hyperthermia- Genetically altered Pd drug responses

Drug- Succinylcholine & HalothaneFeatures-Skeletal muscle rigidity Hypercarbia, hypoxiaTemperature elevationTachypnea , Tachycardia Cardiac dysrhythmias Acidosis HyperkalemiaT/t-- Dantrolene (DOC)-IV - O2

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Drug Interactions

• ChE Inhibitors--antagonize competitive and enhance

depolarizing

• Inhalational Anesthetics (synergistic)

• Aminoglycoside Antibiotics (synergistic)

• Thiopentone & SCh

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Therapeutic Uses of Muscle Relaxants1. Adjuvant in General anesthesia2. Orthopedic procedures for alignment of fractures &

dislocations- (SCh)3. To facilitate Endotracheal intubations – use one with a

short duration of action (SCh- preferred)4. To facilitate brief surgical procedures- (SCh)

- Bronchoscopy, Esophagoscopy, Laryngoscopy- short acting preferred eg., SCh

5. In electroshock treatment (ECT) of psychiatric disorders- SCh

6. Diagnosis of Myasthenia gravis7. T/t of Laryngospasm- (SCh)8. Status Epilepticus9. Tetanus10. Euthanasia

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Comparison of d-TC & SChd-TC (Non-depol.) SCh-(depol.)

Competitive antagonists at Nm rec. Persisitant Depol.

Higher dose Dual block

ChE inhibitors reverses the block -Toxicity reversed by Neostigmine

Do not reverses the block

-Toxicity reversed by fresh blood transfusion

No initial fasciculations initial fasciculations

Elimination- Liver Renal Elimination- plasma ChEs

Slow onset / Long acting Fast onset / Short acting

Histamine release Histamine release

HR HR

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Centrally acting Skeletal Muscle Relaxants

• Act - Higher centres without any loss of consciousness• Inhibit polysynaptic reflexes- muscle tone• ADR- CNS depression- sedation• Classification-1. Mephenesin group- Mephenesin, Carisoprodol,

Chlorzoxazone2. Benzodiazepine- Diazepam

3. GABA derivative- Baclofen( GABA BRec.), Gabapentin4. Central 2-AR agonist- Tizanidine• Uses- acute muscle spasm, Lumbago, neuralgia, spastic

neurological diseases (stroke, MS, ALS etc.,), Tetanus, ECT, Orthopedic procedures

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LOCAL ANAESTHETICS

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Local Anesthetics - DefinitionLocal Anesthetics - Definition

• Drugs that are applied locally (inj, topical)

• produce transient and reversible loss of nerve conduction (mainly sensory)

• without any loss of consciousness

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Local Anesthetics Local Anesthetics (LA)- HistoryLocal Anesthetics Local

Anesthetics (LA)- History• Erythroxylum coca-Indigenous plant in South America• 1860 - Niemann isolated cocaine from E.coca• 1884 - Koller - uses cocaine for topical anesthesia-ocular use• 1885 - Halsted - developed the dental nerve block techniques

for dentistry• Sigmund Freud used the stimulant effect of cocaine to treat

the morphine addiction in patients• Freud, Halsted, and Koller became addicted to cocaine• 1898- procaine- first synthetic local anesthetic drug • 1940- the first modern local anesthetic agent - Lignocaine

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History of local anesthesia

Erythroxylon coca

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History of local anesthesia

• 1886- Coca-Cola was introduced with Cocaine as one of the ingredient.

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Esters (t1/2= secs- mins)• Cocaine• Procaine • Chloroprocaine • Tetracaine• Benzocaine- Quick degradation, short DOA- Hydrolysis- plasma and liver ChE- More H.S (PABA)

EsterAromatic Amide Amine

Am”i”des (t1/2 in hrs)• Lignocaine• Bupivacaine• Prilocaine• Ropivacaine• Mepivacaine- Long DOA- N-dealkylation or hydroxylation (CYP450)- Less H.S

Chemical Classification of LA

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• Low potency / short Duration of action-

- Procaine (t1/2= 1-2hrs)

• Intermediate potency & Duration of action-

- Lignocaine / Prilocaine

• High potency / long Duration of action-

- Bupivacaine / Ropivacaine

Pk. Classification of LA

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Local Anesthetics- MOA Voltage operated Na channels (VONa)

• 1 larger subunit has ion conducting path

• 1 or 2 smaller subunits

subunit has 4 domains with 6 membrane spanning regions

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Resting / close state

Inactivated state

Inactivation gate

Activation gate

Active / Open state

Na+

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Local Anesthetic

Local Anesthetics are VONa channel Blockers

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LA binding site on VONa+ channels

TTX- Tetrodotoxin

STX-Saxitoxin from dinoflagellates (red tides).

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Resting / close state

Inactivated state

Activation gate

Active / Open state

LA bind & block Na+ channels in active or Inactivated state