Barbiturates Class (Dr. E's lecture)

Question 1

How are barbs commercially prepared?

Answer 1

as sodium salts

Question 2

How are barbs prepared with respect to pH? why?

Answer 2

HIGHLY Alkaline formulary (about pH >10)

they’re unstable

Question 3

At room temp, what is different about TPL?

Answer 3

prepared TPL is stable and sterile for at least 6 days

Question 4

What types of isomers are in the Barbs?

Answer 4

Racemic Prep, BUT levo isomer is the potent one

Question 5

What are barbiturates derived from? what constitutes this?

Answer 5

Barbituric Acid

Urea + Malonic Acid = Barbituric Acid

Question 6

What makes a barbiturate, chemically speaking with regards to structure? What effects does this cause?

Answer 6

Substitutions at Carbon 2 and 5; have sedative, hypnotic properties

Question 7

What does it mean if there is a branched chain at C # 5 for the structure of Barbs?

Answer 7

-Branched Chain at #5 increases hypnotic activity

Question 8

If there is an Oxygen at Carbon #2 what does this mean?

Answer 8

OXYbarbiturate (Phenobarbital, Pentobarbital, Methohexital)

Question 9

If there is a Sulfur at Carbon #2 what does this mean?

Answer 9

THIObarbiturate (Thiopental)

Question 10

What does it mean if there is a phenyl group at C # 5 for the structure of Barbs?

Answer 10

-Phenyl group at #5 increases ANTIconvulsant activity (phenobarbitol)

Question 11

What does it mean if there is a methyl radical imparted in the structure of Barbiturates?

Answer 11

-Methyl radical imparts CONVULSANT activity (methohexital)

Question 12

What does it mean if there is sulfuration in the structure of barbs?

Answer 12

-Sulfuration=fat soliuble, as lipid solubility increases: shorter duration, more rapid onset, increased potency

Question 13

What is different regarding the long vs straight chain w/r/t the structure/activity relnships of Barbs?

Answer 13

-long branched chain is more potent than a straight chain

Question 14

What are the relative potencies of TPL, Thiamylal, and Methohexital?

Answer 14

TPL: 1
Thiamylal: 1.1
Methohexital: 2.5

Question 15

What is the MOA of Barbiturates?

Answer 15

• decreases the rate at which GABA dissociates from its receptor->increases duration of GABA activated Cl channel opening (enhances GABA)
• Mimics GABA at the receptor
• Decreases POST-synaptic membrane sensitivity to Ach-> some muscle relaxation- NOT surgical depth
• Also Directly decreases the transmission in the sympathetic ganglia–>hypotension
• interaction with GABA receptor produces functional inhibition of the postsynaptic neuron

Question 16

What does Barbs mimic physiologically?

Answer 16

Depresses RAS-> SLEEP

Question 17

What is the onset of barbs?

Answer 17

RAPID onset of action

Question 18

What is important about the redistribution of Barbs?

Answer 18

Redistribution=Rapid termination of Effect

Question 19

Is TPL protein bound?

Answer 19

70-85% protein bound

Question 20

What is the fat: blood partition coefficient? what does this mean?

Answer 20

11= veryyyyy lipid soluble

Question 21

what should you calculate your dosage of barbs based on?

Answer 21

IBW

Question 22

If the patient is alkalotic, what does this do to the barbs?

Answer 22

alkalosis decreases the intensity of Barbs

Question 23

If the patient is acidotic, what does this do to the barbs?

Answer 23

intensifies effect

Question 24

Are barbs acids or bases?

Answer 24

WEAK acids!!!!! remember they are ACIDS, although they are prepared in >10 pH alkaline soln

Question 25

How are oxybarbiturates metabolized?

Answer 25

Hepatic ONLY

Question 26

How are thiobarbiturates metabolized?

Answer 26

Hepatic and some extra hepatic

Question 27

What terminates pharmacologic activity?

Answer 27

side chain oxidation at C#5 to Carboxylic Acid

Question 28

Generally, how are the barbs metabolized?

Answer 28

desulfuration, hydrolysis, opens ring to water soluble combounds

Question 29

How are barbs excreted?

Answer 29

renal primarily; < 1% excreted unchanged

Question 30

Do barbs have active metabolites?

Answer 30

NO active metabolites

Question 31

What is the E 1/2 time of TPL?

Answer 31

11.6 hours

Question 32

What is the E 1/2 time of Methohexital?

Answer 32

3.9 hours

Question 33

Why are the barbs prolonged in pregnancy?

Answer 33

due to increased protein binding

Question 34

Which barb has greater hepatic clearance?

Answer 34

Methohexital

Question 35

What is different between pediatric patients with TPL and the E 1/2 time

Answer 35

In pedi patients, TPL t 1/2 time is shorter than in adults, higher rate of HBF

Question 36

What are the CNS effects of Barbs?

Answer 36

- Depresses level of consciousness - Cerebrovasoconstriction, Reduced CBF, Decreased ICP and CMRO2 - Can produce isoelectric EEG (flatline the brain=cerebral protection) - Paradoxical excitement - Small doses decrease the pain threshold, "anti-analgesic" - NO skeletal muscle relaxation - Also decreases IOP - Does NOT preclude SSEP monitoring

Question 37

What is unique about Methohexital its CNS effects?

Answer 37

- excitatory skeletal muscle movements (myoclonus) and hiccups - Cerebral protection

Question 38

Do barbs produce skeletal muscle relaxation?

Answer 38

NO

Question 39

What are the cardiovascular effects of Barbs?

Answer 39

- depression of medullary vasomotor center and decreased SNS outflow from CNS->peripheral vasodilation->preload decreases->SBP decreases, Compensatory HR INCREASE in normovolemic pts (activation of SNS peripherally!!!!) - MINIMAL myocardial depression - If SNS not intact (like in elderly), OR hypovolemic OR large doses given to decrease ICP, will see significant decreases in BP and myocardial depression - Histamine release with rapid IV administration - oral barbs produce minimal CV effects

Question 40

What do barbs cause a release of ?

Answer 40

HISTAMINE release

Question 41

What are the resp effects of Barbs?

Answer 41

- Dose dependent depression of medullary and pontine ventilatory centers - Decreased ventilatory response to hypoxia and hypercapnia - Apnea - Depression of laryngeal and cough reflexes incomplete

Question 42

What is important to note about subdoses of barbs? What does this increase the risk of?

Answer 42

if dose is not large enough can actually see a "Stage 2" like response to a/w manipulation-increased risk of laryngospasm, bronchospasm

Question 43

What do barbs do to hepatic enzymes?

Answer 43

Hepatic enzyme induction with chronic use!

Question 44

Which barb is the most potent inducer of hepatic enzymes?

Answer 44

Phenobarbital

Question 45

What drugs are metabolized more quickly due to barbs?

Answer 45

``` Oral anticoags Phenytoin TCAs Corticosteroids Vit. K ```

Question 46

What pathphysiologic condition is contraindicated with barbiturates? why?

Answer 46

Porphyrias!!! | barbs accelerate the production of heme by stimulation of the enzyme: D-aminolevulinic acid synthetase!!!

Question 47

what can barbs cause vascularly?

Answer 47

venous thrombosis

Question 48

What is a side effect of barbs that is greater than Midazolam and Propfol, but lower than Etomidate, Ketamine and volatiles?

Answer 48

N/V!

Question 49

What can barbs do to metabolism?

Answer 49

can enhance their own metabolism-tolerance builds

Question 50

What can happen if there is an allergic reaction to barbiturates?

Answer 50

Allergy 1:30,000 high mortality presents as anaphylaxis Allergy usually atopic patient-multiple allergies, with prior TPL exposure

Question 51

What should you consider with dosing and age?

Answer 51

Decrease dosing in elderly | Increase dosing in peds

Question 52

What is the induction dose of TPL?

Answer 52

3 -5 mg/kg IV | increase in peds (5-6mg/kg and infants 7-8mg/kg

Question 53

What is the induction dose of Methohexital?

Answer 53

1-2 mg/kg IV or 20-30mg/kg PR in peds

Question 54

What is the duration of a single IV induction dose of barbs? Why?

Answer 54

5 - 8 minutes | b/c of redistribution!

Question 55

What medications should Not be in a mixture with barbs?

Answer 55

``` Dont mix with opioids, catechols, NMBs, midazolam, b/c they are acidic; and Pancuronium, Vecuronium, Atracurium Alfentanil, Sufentanil Midazolam LR is too acidic->precipitates ```

Question 56

What solution should you use to reconstitute powder?

Answer 56

sterile H2O or NSS

Question 57

What can occur if barbs are injected intra-arterially? What is the treatment?

Answer 57

- Immediate, intense vasoconstriction and pain - mechanism-> crystalline precipitation inarterial vessel, inflammatory response, vasoconstriction, microembolization Treatment: - dilute with NS - Phenoxybenzamine (alpha blockers!) - Prevent thrombosis: heparin, urokinase - Brachial plexus or stellate ganglion block - Papaverine 40-80mg in 10-20ml saline or 5-10ml Lidocaine 1%

Question 58

What are the S/S of a Porphyria attack?

Answer 58

- Severe abdominal pain with diarrhea and vomiting - ANS instability-tachycardia, HTN - Electrolyte disturbances - skeletal muscle weakness, respiratory failure - Seizure - Neuropsychiatric disturbances

Question 59

What specific drugs should you avoid giving with Porphyrias?

Answer 59

``` Thiopental Thamylal Methohexital Etomidate Pentazocine ```

Question 60

In general, what is characteristic of the porphyrias?

Answer 60

- accumulation of porphyrins, the heme precursors (toxic to tissue in high concentrations) - any increase in heme requirement (accumulation of the precursors immediately preceding the area of enzyme block