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Learning Objectives
Understand the role of GABA in the CNS List drugs that aect the GABA system and their physiologic and clinical eects Dierentiate muscle relaxants that work on the motor end plate vs. centrally-acting agents Understand the common side-eects of drugs in the sedative-hypnotic and skeletal muscle relaxant class Dene the terms tolerance, dependence, and addiction

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Sedative-hypnotics
Alcohol
Ethanol

Benzodiazepines
Alprazolam, clonazepam, diazepam, lorazepam, temazepam

Barbiturates
Phenobarbital, secobarbital

Newer hypnotics
Zolpidem, zaleplon, eszopliclone

Melatonin receptor agonist

Ramelteon

5-HT receptor agonist

Buspirone

Skeletal muscle relaxants

Depolarizing neuromuscular blocking agents
Succinylcholine

Non-depolarizing neuromuscular blocking agents

d-tubocurarine, cistracurium, rocuronium

Centrally-acting spasmolytics
Baclofen, cyclobenzaprine, carisoprodol, metaxalone, methocarbamol, tizanidine

Direct-acting muscle relaxant

Dantrolene

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Recommended Reading
Katzung BG, et al. (eds) Basic and Clinical Pharmacology, 11th edition
Chapter 22: Sedative-hypnotic drugs Chapter 23: The alcohols Chapter 27: Skeletal muscle relaxants

Lehne RA. Pharmacology for Nursing Care, 7th edition

Chapters 25, 34, & 38

Sedative-Hypnotics

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Classication
Sedative-hypnotics are so named because they reduce anxiety and cause drowsiness
Sedatives or anxiolytics exert a calming eect Hypnotics produce drowsiness and encourage onset and maintenance of sleep Sometimes referred to as central nervous system (CNS) depressants
Depressant activity is graded and dose-dependent (see graphic next slide)

Most exert their pharmacologic eect via action on gamma-amino butyric acid (GABA) receptors in the CNS

Drug A: Ethanol or barbiturates; Drug B: Benzodiazepines

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GABA
Major inhibitory neurotransmitter
GABA-releasing neurons found throughout the CNS

Two main types of receptors

GABAA & GABAB

Many dierent subunits, mediating dierent responses

Sedation, amnesia, anesthesia, anticonvulsant, anti-anxiety, muscle relaxation
Chemical structure of GABA

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Drugs that aect GABA

Ethanol Benzodiazepines Barbiturates Non-BZ sedative-hypnotics

Alcohol
Ethyl alcohol (ethanol) is rapidly absorbed from the GI tract
Other forms of alcohol:
Methanol Isopropryl alcohol

Has a marked eect on the CNS:

Sedation Euphoria, loss of inhibition Slowed reaction time, impaired motor function Slurred speech, ataxia Emesis, stupor Coma Respiratory depression, death

Chemical structure of ethanol

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Ethanol
Two major pharmacologic eects in the CNS:
Enhances the action of GABA at GABAA receptors Inhibits the ability of glutamate to open cation channels associated with NMDA receptors

Other eects:
Heart depression of myocardial contractility Smooth muscle vasodilation in the periphery

Clinical uses:
Self-treatment of anxiety, depression, essential tremor

Benzodiazepines
Group of chemically-similar compounds used as anxiolytics and hypnotics Bind with GABAA receptors to enhance GABA-ergic activity Undergo hepatic metabolism
Phase I (oxidation)
Some have active metabolites with long half-lives

Phase II (conjugation)

Duration of activity based on kinetics:

Short-acting
Alprazolam, triazolam

Intermediate-acting
Clorazepam, lorazepam

Long-acting
Diazepam, urazepam

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Barbiturates
Older agents, no longer commonly used as sedative-hypnotics Long half-lives can lead to accumulation

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Non-BZ Hypnotics
A group of newer agents introduced in the past decade Bind to GABAA receptor at dierent site than BZs Rapidly absorbed, few metabolites, short-half lives Heavily marketed, commonly prescribed sleep aids (Ambien, Sonata, Lunesta)

Flumazenil
Antagonist of benzodiazepines, eszopiclone, zaleplon, zolpidem Doesnt block actions of ethanol or barbiturates May be used in overdose management

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Organ Level Eects

Sedative-hypnotics have varying levels of activity and clinical utility for the following:
Sedation Hypnosis Anesthesia Anticonvulsant eects Muscle relaxation Eects on respiratory and cardiac function

Physiologic Eects
Sedation
Most agents reduce anxiety at low doses
Beyond simply causing drowsiness

Hypnosis
Will induce sleep at higher doses
Decrease sleep latency Increase stage 2 NREM Decrease REM sleep Decrease stage 4 NREM

Depressant eects on cognitive functions Anterograde amnesia

Signicance of eects on REM still unclear

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Physiologic Eects
Anesthesia
High doses of sedative- hypnotics can depress the CNS to the point of general anesthesia Barbiturates have favorable characteristics BZs are used IV in combo with other agents

Anticonvulsant
Both BZs and barbiturates inhibit the spread of epileptiform electrical activity Agents used:
Phenobarbital Clonazepam Diazepam Lorazepam

Physiologic Eects
Muscle Relaxation
BZs and meprobamate have inhibitory eects on polysynaptic reexes May also depress transmission at skeletal neuromuscular junctions Agents:
Clonazepam Diazepam

At hypnotic doses, these agents produce eects on respiration similar to natural sleep At higher doses or in respiratory/cardiac compromised patients may induce:
Respiratory depression Circulatory collapse

Respiratory/Cardiac Eects

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Abuse Potential
Most sedative-hypnotics can be misused and may be compulsively abused Important denitions:
Tolerance: the need for higher doses to produce response Physical dependence: withdrawal symptoms elicited upon discontinuation Addiction: use despite harm; psychological craving and display of addictive behaviors

The BZs, barbiturates, and non-BZ agents (i.e. zolpidem) are Schedule IV Controlled Substances in the US

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Other Agents
Ramelteon (Rozerem)
Agonist at MT1 and MT2 (melatonin receptors) No direct eects on GABA Reduces sleep latency, but does not appear to aect other aspects of sleep architecture May decrease testosterone and increase prolactin levels Not a controlled substance

Buspirone (Buspar)
Reduces anxiety without causing marked sedation or euphoria Acts via serotonin and dopamine receptors; no direct GABA activity Not appropriate for acute anxiety states Does not potentiate impairment caused by other sedative-hypnotics

Other Classes (non-GABA)

Antihistamines
Diphenhydramine (Benadryl) Hydroxyzine (Atarax) Promethazine (Phenergan)

Antidepressants
Tricyclic antidepressants: amitriptyline (Elavil) Trazodone (Desyrel) SSRIs: uoxetine (Prozac), sertraline (Zoloft)

Antipsychotics
Quetiapine

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Skeletal Muscle Relaxants

Drugs that aect skeletal muscle may act via local or central means Heterogeneous group of drugs
Neuromuscular blocking agents
Non-depolarizing: pancuronium Depolarizing: succinylcholine

Centrally-acting relaxants
Benzodiazepines Baclofen, Cyclobenzaprine, Carisoprodol, Methocarbamol

Direct-acting skeletal muscle relaxant

Dantrolene

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Neuromuscular Blocking Agents

History
Curare is a poison derived from South American plants Natives used it as arrow poison in hunting
Produces skeletal and respiratory muscle paralysis Active compound is d- tubocurarine
Helped in our understanding of neuromuscular function

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Neuromuscular Function

Blockade of End Plate

Two main mechanisms:
Non-depolarizing neuromuscular blockers:
Antagonism of acetylcholine activity by blocking ACh binding to nicotinic receptors
Prevents depolarization and propagation of the action potential

Examples: pancuronium, vecuronium, rocuronium

Depolarizing neuromuscular blocker:

Paradoxically, too much depolarizing agonist also stops the propagation of the action potential
Persistent depolarization make the muscle ber resistant to ACh

Example: succinylcholine

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Botulinum Toxin
Blockade of ACh activity at the motor end plate may also occur if ACh is not released pre- synaptically Result is paralysis
Botulism BoTox Cosmetic
Other uses

Clinical Use of Neuromuscular Blocking Drugs

Surgical relaxation
Facilitates various types of surgery

Tracheal intubation
Via relaxation of pharyngeal and laryngeal muscles allows for placement of tracheal tubes

Control of ventilation
Administered in ICU to patients with ventilatory failure Allows for adequate gas exchange

Treatment of convulsions
Occasionally used for attenuate peripheral manifestations of seizure activity

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Spasmolytic Drugs
Two major clinical classications: Drugs for the treatment of spasticity Drugs for the treatment of muscle spasms

Spasticity
Characterized by exaggerated muscle stretch reex
Abnormal reex activity is velocity dependent, with rapid lengthening of the muscle causing a strong contraction in the stretched muscle Occurs when supra-spinal control is lost because of damage to or a lesion on the spinal cord/brain Causes include:
Cerebrovascular accident (CVA), cerebral palsy (CP), multiple sclerosis (MS), or spinal/head trauma

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Spasticity
Often composed of the following triad:
Painful mass muscle spasms Rigid posturing of limbs Increased reexes

Any component of the triad can occur in varying severity

http://www.comawakening.com/spasticity.html

Muscle Spasms
Increased tension in skeletal muscle following certain musculoskeletal injuries and/or inammation, such as with muscle strains
Muscle tension is involuntary, so the patient is unable to relax the muscle A loop is created between nociceptive input from damaged tissue and motor neurons controlling the muscle
Results in painful, tonic contraction of the muscle Upper motor neurons are NOT involved May occur in patients with chronic low back pain

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Skeletal Muscle Relaxants

May be divided into two groups:
Spasticity indications Muscle spasm indications

Adverse eects in general include:

Drowsiness Dizziness Ataxia Fatigue and varying degree of muscle weakness

Most recommendations support the short-term (< 3 weeks) use of SMRs in combination with NSAIDs or APAP (not opioids) for musculoskeletal conditions

Agents for Spasticity

Agents
Baclofen (Lioresal) Dantrolene (Dantrium) Tizanidine (Zanaex)

MOA: decrease polysynaptic reex activity in the spinal cord and inhibit alpha motor neuron excitability
Baclofen blocks pre- and post-synaptic GABAB receptors Dantrolene directly inhibits skeletal muscle contraction Tizanidine agonist at central alpha-2 receptors

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Baclofen
Brand name: Lioresal
(generic available)

Structural analog of gamma-amino butyric acid (GABA) Acts via GABAB receptors
Results in hyperpolarization and reduced calcium inux
Chemical structure of baclofen

Intrathecal Baclofen
Most often dosed orally, but may be delivered directly into the subarachnoid space at dierent levels of the spinal cord
Patients with severe, intractable spasticity Catheter is usually implanted surgically and attached to a programmable pump Pump may also be implanted SQ
http://cuidatucorazon.com

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Tizanidine
Brand name: Zanaex Classied as an alpha-2 adrenergic agonist Pharmacologic studies indicate 1/10 to 1/50 the potency of clonidine in blood pressure lowering ability Use for spasticity from:
Multiple sclerosis Spinal cord lesions Post CVA

May be used for muscle spasms

Dantrolene Sodium
Brand name: Dantrium The only SMR that exerts its eects directly on the skeletal muscle cell
Impairs the release of calcium from the sarcoplasmic reticulum during excitation Attenuates muscle contraction and enhances relaxation

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Dantrolene
Used for severe spasticity resulting from:
Traumatic spinal cord injury Advanced MS Cerebral palsy Stroke

Preoperative prevention of malignant hyperthermia in susceptible patients requiring anesthesia/surgery

IV during crisis, orally afterwards to prevent recurrence

Neuroleptic Malignant Syndrome Main side eect: generalized muscle weakness

Agents for Muscle Spasms

Agents: Carisoprodol (Soma) Chlorzoxazone (Parafon Forte) Cyclobenzaprine (Flexeril) Metaxalone (Skelaxin) Methocarbamol (Robaxin) Orphenadrine (Norex) Tizanidine (Zanaex) also for spasticity Mechanism of action: probably blocks interneuronal activity in the descending reticular formation and spinal cord

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Carisoprodol Toxicity
After oral administration, carisoprodol is metabolized in the liver to several biologically active metabolites, including meprobamate
Meprobamate alone is a sedative-hypnotic formerly available under the trade names Miltown or Equanil
In the 1960s, meprobamate had a street value and was sold as Uncle Milties or Bams Pharmacologically, meprobamate is related to the barbiturates and is a schedule IV controlled substance

Abusers of carisoprodol demonstrate signs of tolerance and reportedly suer withdrawal symptoms of anxiety, tremors, and in some cases, hallucinations or seizures Acute overdose may result in CNS depression, respiratory depression, coma and death

Cyclobenzaprine
Brand name: Flexeril (generic available) Most commonly prescribed SMR with similar indications and mechanism of action as other members of its class Structurally related to tricyclic antidepressants (TCAs)

Cyclobenzaprine

Amitriptyline

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Summary
Sedative-hypnotics include medications such as benzodiazepines, barbiturates, and non-BZ GABAergic agents
Used for anxiety, sleep, convulsions, or muscle relaxants BZs dier in half-life & active metabolites Non-BZs used for sleep (zolpidem, zaleplon)

Skeletal muscle relaxants are a group of drugs that include neuromuscular blockers (act at motor end plate), centrally acting agents (work at spinal cord or brain stem), and dantrolene (directly on skeletal muscle)
Used for spasticity or muscle spasms

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