Barbiturates

Question 1

Adolph von Baeyer (1864)

Answer 1

-synthesized barbituates from malonic acid and urea = malonylurea but became better known as barbituric acid

Question 2

barbituric acid

Answer 2

• on its own this acid is not effective as a hypnotic sedative - it needs to be modified in the number 5 position (modified with hypnotic potency)

Question 3

the first modification of barbituric acid

Answer 3

• 1903 by Fischer and von Mering
• called “diethylbarbituric acid” to indicate 2 ethyl groups (replaced hydrogens on position 5)
• Generic name: Barbital
• Trade name: Veronal
• long onset and long duration of action

Question 4

what was one goal of early barbiturate research?

Answer 4

• have a shorter duration of action bc many of the long-acting barbiturates were unsuitable for treating insomnia since the user still woke up drowsy

Question 5

what are the classifications of barbiturates

Answer 5

• classified based on the SPEED of onset and DURATION of action
• both the speed and duration of action are influenced by the lipid solubility
• High lipid solubility = readily get in and out of the brain - useful for sleep induction or emergency management of seizures
• low lipid solubility = do not enter and leave the brain readily - they are useful in managing chronic epilepsy and anxiety
• street name: downers
• stimulant street name: uppers

Question 6

long-acting barbiturates

Answer 6

• onset in about 1hr and duration for at least 6hrs
• prototypical compound: Phenobarbital (generic) or Luminal (trade) - synthesized in 1912
• available in tablets, capsule and liquid

Question 7

intermediate-acting barbiturates

Answer 7

• the onset of 30mis and duration of 4hrs
• prototypical compound: Amobarital (generic) or Amytal (trade) - synthesized in 1923
• known as the “truth serum” but not entirely true bc while users might be talkative it doesn’t mean its the truth
• Street Names: blue angels, blue dolls, bluebirds etc. BLUE

Question 8

short-acting barbiturates

Answer 8

• the onset of 15mis and duration of 1-4hrs
• prototypical compound:
  1. Pentobarbital (generic) or Nembutal (trade) - these are YELLOW in colour
  2. Secobaritual (generic) or Seconal (trade) which are RED in colour
  3. Tuinal (generic) which is a combination of secobarbital and amobarbital - RED AND BLUE CAPSULE (multicoloured) - high abuse in the 50s and 60s

Question 9

ultra short-acting barbiturates and Propofol (Diprivan)

Answer 9

• introduced as an intravenous anaesthetic in the 30s
• not subject to much abuse bc both the method of administration and the ultra-short action
• most common are: Hexobarbital and Thiopental
  Propofol:
• not a barbiturate
• largely replaced the barbiturate iv anaesthetics and its now the most commonly used iv anaesthetic (onset is less than a minute and has a duration of 10mins)
• “milk of amnesia”
• medical professionals are among the most common to become abusers bc of the availability of access
• Michael Jackson died of this in 2009
• small therapeutic index so the risk for accidental death is high among users

Question 10

by what year did barbituates become the most widely abused drug?

Answer 10

• 1950s

- peaked 50s and 60s

Question 11

what is the charcteristics of the typical abuser?

Answer 11

• Caucasiian female
• 30-50yrs
• memeber of the middle/upper economic class

Question 12

what effects to barbituates exhibit?

Answer 12

• all the same effects the only diiference is in the time to onset and the duration of effects
• Acute effects:
  relaxation
  reduction of anxiety
  euphoria at low doses
  sedation, drowsiness, dizziness etc
  reduction of REM sleep
  coma at higher doses
  death induced by respiratory depression at higher doses
  ** there is no fast acting antidote for barbituates (ie. difficult to save someone in an overdose)

Question 13

Alcohol + barbiturates

Answer 13

• overdose often occurs with this and another depressant like alcohol
• they have similar neurochemical actions and act synergistically (ie. the combined effect is more multiplicative rather than additive)

Question 14

barbituates and pregant people

Answer 14

• substantial evidence that during early gestational periods results in abnormal neural and biochemical differentiation of the CNS, deficits in learning, retarded attainment in developmental milestones and alteration of behavioural and physiological sex differences

Question 15

male rats and barbiturate studies (3) and human study (1)

Answer 15

• a consensus that male rodents exposed to barbiturates prenatally are described as “demasculinized” or “feminized”
  Rat Studies:
  1. in unexposed rodents the activity levels are higher in females than they are in males - with male rats who were prenatally exposed to barbituates they tend to exhibit higher physical activity that is more closely related to a female rate than a male
  2. in unexposed rodents the female rat has a shorter latency period in passive avoidance than male rats who are unexposed - for male rats that have been prenatally exposed to barbituates they exhibit a shorter latency period like female rats who are unexposed
  3. barbiturate exposed male rats show sexual behaviour that more resembles an unexposed female rate - they will perform lordosis which is a sexual position the female rats take on - they also have fewer ejaculations and intromissions
  Human Study
  1. males who have been subjected to barbiturate exposure exhibit delay in puberty, undescended testes and cross-gender identities
• both males and females show lower IQ and learning disabilities in comparison to nonexposed children

Question 16

what is the main effect barbituates have on the CNS and how does this happen?

Answer 16

• the main effect is to depress neuronal activity
• barbiturates enhance the inhibitory actions of GABA - GABA keeps the ion channels open longer which reduces the excitability of the neurons - so once barbituates bind to the GABA receptor complex and increases the affinity of GABA for its receptor this prolongs the time the ion channels remain open – it is thought that the sedative-hypnotic behaviour is bc of the action on the GABAergic system
• there is also evidence that barbiturates reduce glutamate transmission - this transmission is involved in memory formation and may explain the amnesic effects of barbituates

Question 17

barbituates and the self-reinforcing paradigm

Answer 17

• they support high breakpoints in the progressive ratio procedure
• reinforcing power of barbituates is related to the speed of onset with the immediate (amobarbital) and particularly the short (secobarbital and pentobarbital) acting drugs being the most reinforcing
• seconal and tuinal are the 2 most sought after
• the exact mechanism that dopamine is released is unknown

Question 18

Barbituates + Tolerance and Physical Dependance

Answer 18

• tolerance occurs with virtually every barbiturate induced-effect including the behaviourally impairing, sleep-inducing, reinforcing and lethal effects
• tolerance occurs more rapidly to the reinforcing effects than to the lethal effects thereby increasing the chance to OD
• the tolerance that is shown has some Pavlovian conditioning involvement
• rats that received a lethal dose of the drug WITH the drug stimulating cues didn’t die but the rats that received a lethal dose WITHOUT the drug stimulating cues did die from the dose
  Physical Dependence
• there is clear evidence of physical dependence and withdrawal symptoms that result from chronic use of barbiturates (they are very similar to alcohol and symptoms of either drug may be diminished by the administration of the other drug)
• symptoms begin to appear 24-36 hours following drug termination
• without medical supervision, there is a 5% death rate of barbiturate withdrawal