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Non-selective CNS depressants
©2010 Mark Tuttle
- Effect all CNS functions: motor, sensory,
Respiration: depress all 3 mechanisms
Tendon reflexes: Hyperreflexia-disinhibition
intellectual, autonomic, respiratory, etc.
- Neurogenic, CO2 (chemical), O2 (hypoxic)
- Disinhibition of ARAS: ↓ filter unwanted
Supplying 100% O2 may decrease hypoxic drive
- Most sensitive: Fine, learned motor skills and
stimuli
- Need high dose for effect (unless COPD)
higher integrative function
- Even high doses: still respond to stimuli
- Hyperreactivity of protective reflexis of airway
Preferential action:
o Consciousness is among most sensitive,
(laryngospasm, hiccupping, gagging) disinhibition
CNS > peripheral
reason for usage
 Overdose: respiratory death
- Least sensitive: Basic protective reflexes.
Treatment of overdose: no selective antagonists (antidote), airway, breathing, cardio, drugs (alkaline diuresis, support circulation) NO respir!!
Abuse: Used in ways that are not medically approved Tolerance: Escalation of dose to maintain effect Dependence: Drug now required for homeostasis
- Barbiturates
- Metabolic: induction of hepatic enzymes - Withdrawal syndrome
- Ethanol
o Hypnotic dose does this
o Hyperexcitability of entire CNS
- Other non-selective CNS depressants
o Relatively unique to barbiturates
o At worst: delirium, convulsions, death
- Functional: ↓ sensitivity of neurons
o Corresponds to pharmacokinetics of given drug
o Small compared to other drugs
- Requires great dose than required for hypnosis
- Cross-tolerance: to all of each other
- Psychological dependence (now called addiction)
Drug
Mechanism of action
Side effects
Pharmacokinetics
BARBITURATES
- ↑postsynaptic GABAA Receptors (inhibitory) Metabolism + excretion
- pKa 7-8, so charged & uncharged in body
In general
o All types (unlike benzodiazepines)
- Hepatic biotransformation
- Good fat:water partition coefficient
o Directly open the Cl- channel (not benzos) - Filtered, but nearly all is reabsorbed
- Potency decreased if polar group is added to a
- ↓ response to excitatory NTs, glutamate
- Raising urine pH helps concentrate drug side chain  hepatic biotransform.
- No structural requirements, probably not a
(since it is a weak acid)
- No structural requirements, probably not a “lock
“lock & key” mechanism of action
& key” mechanism of action
Sleep
- ↑ porpharyn synthesis
- Dose-response curves for all non-selective CNS
↓ time to onset of sleep
Contraindicated w/porphyria
depressants are parallel
Prototype: barbital
Subjective feeling of having slept well
but NOT for benzodiazepines
Thiopental
- Can’t keep giving dose b/c it will build up - Very large fat: water partition coefficient
and cease to depend on re-distribution
- Hepatic biotransformation is slow
and will start to depend on metabolism
- RE-DISTRIBUTION determines duration
Pentobarbital
- Hepatic biotransformation determines duration
Secobarbital
Barbital
Phenobarbital
Long
Med
Short
Non-selective CNS
depressants
In general
Benzene ring confers some selectivity as
anticonvulsant
- Poor substrate for hepatic enzymes, 1/3 to ¼ is
excreted unchanged in urine
- Long t½: 2-5 days
Others
Drug
Propofol
Mechanism of action
- ↑postsynaptic GABAA Receptors
- Greater decrease in BP and ↓ contractility
Side effects
Pharmacokinetics
- Lipid emulsion, (Fospropofol is H2O-soluble)
- Rapid onset (like thiopental)
- Brief duration of action, from distribution/metab
- Rapid onset (like thiopental)
- Brief duration of action, from distribution/metab
-
Etomidate
- ↑postsynaptic GABAA Receptors
Ketamine
- NOT a non-selective CNS depressant
- Used to produce “dissociative anesthesia”
o Alalgesia, upresponsiveness, amnesia
o Eyes often remain open
o Involuntary limb movement
o ↑ Sympathetic activity
- Chloral hydrate (trichloroethanol active metabolite), ethchlorvynol, ethyprylon, meprobamate, methaqualone (no longer available)
Usually used w/other
drugs
Non-barbiturate
sedative hypnotics