2.3 barbiturates Flashcards
barbiturates
derivatives of barbituric acid
(condensed product of malonic acid and urea)
– replaced by benzos for sedative action
thiobarbiturates
barbiturates in which oxygen is replaced by sulphur
–more lipid soluble,
shortened duration of action,
increased hypnotic potency
barbiturates as a CNS depressant
barbiturates increase the duration of the GABA mediated chloride channel openings at multiple sites in the CNS and prolong GABA activity
barbiturates at high concentration
barbiturates may also be gabamimetic,
directly activating chloride channels
– can act at GABA -A receptors without GABA
barbs bind
to another side on the gaba chloride channel to exert the gaba-facilitatory action
barbs also inhibit
complex 1 of ETC and hence no ATP synthesis in neurons
(itself CNS depressant action)
(very different form bzd)
barbs increase
duration of opening not frequency like benzos
AMPA (glutamate) receptors
also blocked by barbiturates
high dose barbs can block
Na channel
ultrashort barb
20 min – thiopental
short acting barb
3-10hrs –
Pento barbital,
seco barbital,
amo barbital
long acting
1-2 days– phenobarbital
barbs on cns
produce dose dependent effects:
sedation–>sleep/hypnosis –>anesthesia–> coma
barbs reversibly depress
activity of all excitable tissues
–> mild sedation to general anesthesia to coma
TI of barbs
low
barbs and pain
increase the reaction to painful stimuli (hyperanlgesic action) hence not relied to produce sedation in pain
barbs and sleep
in low dose can produce drowsiness, reduction in excitability (sedative actions), dec sleep latency, inc total duration of sleep (inc st2), dec REM and SWS (St 3 and 4), dec night awakenings
effect of REM-NREM disruption
the subject may feel confused and unsteady if wakened early –
hangover (dizziness, distortions of mood, irritability and lethargy)
may occur in the morning after a night dose.
tolerance to sleep effect of barbs
tolerance to the effects on sleep occur w/in a few days –total sleep time may be reduced as much as 50% after 2 w/ of use
barb for anticonvulsant
phenobarbital
- -high-anticonvulsant:sedative ratio
- it has specific anticonvulsant action independent of general CNS depression
- -ok during prg
barb for respiration
depress respiration in higher doses
– neurologic, hypercapnic (chemoreceptor) and hypoxic drives to respiratory centres are depressed in succession,
overdosage causes severe reps depression and death
barb on CVS hypnotic dose
light dec in BP and HR (same as during sleep)
barb on CVS toxic dose
marked fall in BP (due to ganglionic blockade, vasomotor center depression and direct decrease in cardiac contracility)
barb on skeltal musl
anesthetic dose decreases muslce contraction by deressing transmission in autonomic ganglia
barb on liver
induce cyp450 thus increases metabolism of many lipid soluble drugs and vitamins D/K,
induce the enzyme glucuronyl transferase,
increase ALA synthetase – dangerous exacerbationof prophyria
barb on kidney
dec urine flow (due to decreased BP and increased ADH release),
severe oliguria/anuria in acute barbiturate poisoning
(due to marked hypotension)
barb on GIT
dec the tone and rhythmic contractions
barb pharmacokinetics
orally well absorbed,
distributed widely and cross placenta,
oxidation is the important biotransformation reaction,
duration of the action is dependent on the redistribution
theraputic uses of barbs is very limited bc of
lack of specificty of effect in the CNS,
lower TI than bzds,
tolerance occurs more rapidly than bzds,
liability for abuse is great,
considerabul drug interactions
barbs as anticonvulsant
phenobarbital --used in tonic-clonic seizures, status epilepticus, eclampsia, tetanus, poisoning by convulsant drugs
barbs as anesthetics
thiopental, methohexital – ultrashort acting admin by IV
barbs in hyperbilirubinemia, congenital non-hemolytic jaundice and kernicterus
phenobarbital
barbs in psych
thiopental sodium, amobarbital –
diagnosis and treatment of narcoanalysis and carcotherapy
barb on anti-anxiety and hypnotic
pentobarbital – however not used noadays
barbiturates adverse effects
hangover effect,
impairment of finemotor skills,
idiosyncrasy (paradoxical excitement in geriatric and debilitated pts),
behavioural disturbances after long term treatment,
hypersensitivity,
drug automation,
tolerance (both PK and PD) and dependance
(physical and psychological)
barb drug interactiosn w/ other CNS depressants
additive response with another CNS depressants (possible life-thratening respiratory depression) such as
anesthetics,
antihistamines,
opiates
barbs induce metabolism of
most lipid soluble drugs such as oral contraceptives, warfarin, carbamezepine, phenytoin, etc
and also increases the metabolism of vit K/D
barbs and calcium
dec calcium abs leading to coagulation defects
barbs and porphyrin syn
inc porphyrin synthesis and hence contraindi
chronic use of barbs leads to
tolerance
cross tolerance occurs btw
benzos,
barbiturates, and
ethanol
barbs vs benzos
greater abuse liability than benzos
withdrawal of barbs
abrubt withdrawal leads to the same symptosm as benzos but more intense nature, life threatening seizures can occur
acute barbiturate poisoning
respiratory depression,
marked hypotention
barb management
maintanance of ABC,
gastric lavage,
force alkaline diuresis (mannitol and NaHCO3),
hemodialysis
contraindications of barbs
kidney and liver disorders,
acute intermittent porphyria,
severe pulmonary insufficiency (asthma, COPD, Emphysema),
obstructive Sleep apnea (OSA)
novel benzodiazepine receptor agonists
zolpidem, zaleplon, eszopiclone, sopiclone -- they do not have anticonvulsant and muscle relaxant properties
zolpidem
non-benzodiazepine,
acts on a subset of bzd receptors (bz1),
less tolerance abuse liability,
used in sleep disorders
(esp to shorten sleep-latency and prolong total sleep time),
no muscle relaxation and anti-convulsant action,
duration of action 6-8hrs,
overdose reversed by flumazenil
zaleplon acts on
bz1
one of the best choices for inducing sleep
zaleplon
plasmal level of zaleplon
increases when combined with cimetidien and
decreases when given with rifampin
ezopiclone
rapid onset, effective in sleep-onset insomnia and also reduces number of awakenings and increases total sleep time and sleep quality
ezopiclone duration of action
6 hrs
ezopiclone overdoes can be reversed by
flumazenil
drug for long term use up to 6 monts
eszopiclone
buspirone
5HT1a partial agonist
– at the presynaptic receptors by interfering with the firing of 5HT neurons,
no effect on GABA,
relieves anxiety without producing marked sedative hypnotic effects
how buspirone works
initially binding decreases release of 5HT creating anxiety
BUT the receptors get desensitized and then release 5HT reducing anxiety
buspirone used for
generalized anxiety disorder and chronic anxiety
– effects seen after 1-2 weeks
(unsuitable for management of acute anxiety state)
buspirone dependence liability
none
buspirone impairment of psychomotor skills
less impairment than bzds and does not affect driving skills
buspirone abs
orrally effective and undergoes extensive first pass metabolism
buspirone does not
do muscle relaxaiton or anticonvulsant activity,
no rebound-anxiety or withdrawla signs on abrupt discontinuation
histamine H1
invovled in wakefulness
H1 antagonists
diphenhydramine,
doxylamine,
hydroxyzinej
other sleep promoting drugs
choral hydrate/trichlorofos,
melatonin (jet lag),
ramelteon (melatonin agonsit)
valerian (herbal sleep rememdy)
