Barbiturates Flashcards
1
Q
(Urea + Malonic acid = barbituric acid) Why is this significant?
A
Barbituric acid itself has NO CNS effects. It is the subsitiutions at Carbon #2 and #5 that give barbiturates their sedative and hypnotic properties
2
Q
What is the significance of substitutions at carbon #5
A
- Long branched chain at #5 = more potent sedative and hypnotic properties
- Straight chain at #5 = less potent sedative and hypnotic
- Phenyl group at #5 = enhanced anticonvulsant activity (phenobarbitol)
- Methyl Radical at #5 = convulsant activity that manifests as involutary muscle movement (methohexitol)
3
Q
What is the significance of subsitutions at Carbon #2?
A
- Determines if it is an OXIbrbiturate or a THIObarbiturate
- OXI = oxygen substitution at Carbon #2
- Hepatic ONLY metabolism
- phenobarbitol (longer DOA than thiopentol)
- THIO = sulfur substitution at Carbon #2
- Hepatic and extrahepatic metbolism
- IN GENERAL:
- MORE lipid soluble
- Greater hypnotic potency
- More rapid onset and shorter DOA
- thiopentol
4
Q
What is significant about the structure of Methohexitol?
A
It has a methyl group added to the nitrogen atom of the barbituric acid ring making it have a short DOA
5
Q
Barbituriates Mechanism of Action
A
-
Activate GABAA receptors on postsynaptic cell
- increase Cl- cond. (hyperpolarize the membrane)
- functional inhibition of post synaptic neurons.
-
2 ways Barbs interact with GABAA
- Decrease rate of disassociation of GABA from the receptors – increasing GABAA activation of the Cl- channels = depression of the reticular activating system
- MIMMIC GABA = directly activate GABAA receptors.
- Target other receptor types (Glutamate, Adenosine, neuronal nNAChRs)
-
Selectively depress sympathetic ganglia
- decrease blood pressure
-
Neuromuscular junction activity
- decrease sensitivity of post synaptic membranes to the depolarizing action of ACh – Muscle relaxation
6
Q
Explain the pharmacokinetics of promt awakening
A
- Due to REDISTRIBUTION of the drug from the effect site (brain) to the inactive tissues (muscles and fat)
- Elimination from the plasma however is very long and elimination depends on metabolism (<1% excreted in the urine)
- also d/t lipid solubility the drug is sequestered in the fat and skeletal muscle and must equilibrate with plasma concentration to be eliminated.
- Fat:blood coef = 11 (more in fat than blood)
7
Q
Explain the ionization of thiopental related to acidosis
A
- Tiopentol in the BODY is an ACID
- Thiopentol pKA = 7.6 (very close to physiologic pH of 7.4)
- Acidosis will favor the nonionized fraction of hte drug (acid (7.6) + acid (7.4) = more nonionized)
- Nonionized = more lipid soluble = more access to the CNS
- Acidosis causes MORE drug to be at the effect site and will increase the intensity of the barbiturate effect
8
Q
Time frame of resistribution of barbiturates
A
Time frame of redistribution
-
Brain receives 10% of total IV dose = first 30-40s
* Fast uptake d/t high tissue perfusion (VRG) - Decrease brain concentration over the next 5 min
- 2nd uptake primarily skeletal muscle (MG)
- decreased muscle mass = decreased dose (elderly, trauma)
- After 30 minutes <10% of initial TPL remains in brain
- Fat concentration rises for 30 minutes
- reservoir = distribution is dependent on blood flow (VPG)
- Because fat takes so long to fill dose is based on lean body mass to prevent an overdose
- If the amount in the fat reservoir is less than 11x what is in the blood, drug will continue to move from blood to the fat
9
Q
MOST IMPORTANT step in terminating barbiturate pharmacologic activity
A
Side chain oxidation at carbon #5 of the benzene ring yielding carboxylic acid
10
Q
What is the main difference between thiopental and methohexitol?
A
- E1/2t and clearnace d/t hepatic metabolism
- Thiopentoal
- E1/2 = 11.6 hours
- Clearnace = 3.4 ml/kg/min
- Methohexitol
- E1/2 = 3.9 hours
- Clearnace = 10.9 ml/kg/min
11
Q
Thiopentol metabolism
A
- Thiobarbiturate = liver and extra hepatic
- 99% metabolized; <1% renal excretion unchanged
-
Dependent on enzyme activity NOT hepatic blood flow
- Oxidation at carbon #5 = main site of metabolism
- Desulfurization on Carbon #2
- Hydrolytic opening of the Barbituric acid ring
12
Q
Why does cirrhosis NOT effect the metabolism of thiopental?
A
takes a HUGE decrease in liver enzymes to prolong the duration of action
13
Q
Populations with changes in E1/2 of Thiopentol
A
- Obese – E1/2 prolonged d/t increased Vd – excess fat storage sites
- OLD – slows redistribution from central to peripheral compartments
- Need a LOWER dose to reach the effect site (brain) – decrease dose by 30%
- Pediatrics – E1/2 is shorter due to rapid hepatic clearance = rapid recovery after large dose
- Pregnancy (first trimester) - E1/2 prolonged d/t increased protein binding decrease dose by 18%
14
Q
When using TPL decrease the dose of this volitile anesthetic
A
Isoflurane
15
Q
Methohexitol metabolism
A
- Methohexitol = oxibarbituate = Hepatic ONLY metabolism
- 99% metabolized; <1% renal excretion unchanged
- Side chain oxidation yeilds inactive metabolite
- (4-hydroxymethylhexol)
- Hepatic clearance is 3x faster than thiopental
16
Q
What favors urine excreation and why?
A
- For TPL and methohexitol Alkinalization of urine favors excretion becasue more of the durg is ionized
- Phenobarbitol however alkinalization does NOT favor renal excretion
17
Q
Only barbiturate that has significan exretion in the unchanged form
A
Phenobarbitol - becasue there is less protein binding
18
Q
Clinical uses of Barbiturates
A
- Induction of anesthesia
- Treatment of increased ICP
19
Q
Barbiturates effect at the NMJ
A
Decrease sensitivity of the POSTSYNAPTIC ACh receptor may have some muscle relaxation as defined my it MOA, but skeletal muscle relaxation is incomplete and a NMB is still needed
20
Q
Why does methohexitol still have a rapid early awakening when its metabolism and E1/2 are much faster than thiopentol?
A
Because early awakening is dependent on redistribution
21
Q
Barbiturate that may cause myoclonus, hiccoughs and seizures
A
Methohexatol
22
Q
Relative potencies of thiopentol, thiamylol and methohexatol
A
Drug and Potency
- Thiopentol = 1
- Thiamylal = 1.1
- Methohexitol = 2.5
No clinical differences between TPL and Thiamylol
23
Q
% nonionized at 7.4 for thiopental and methohexatol
A
- Thiopentol = 61%
- Methohexatol = 76%
24
Q
Relative dosages of methohexatol and thiopental
A
Thiopental Dose
- IV: 3-5mg/kg
- Elderly = Decrease
- Peds IV: 5-6 mg/kg
- Infants: 7-8 mg/kg
Methohexatol
- IV: 1-2 mg/kg
- Peds Rectal: 20-30 mg/kg
25
Barbiturates and treatment of ICP
1. Drug induced **cerebral vasoconstriction**
2. **Decreased** CBF, ICP and CMRO2
3. **Isoelectric EEG** reflects a **55%** decrease in CMRO2
4. Caution with **high doses** that cause systemic hypotension which may **decrease CPP** (CPP= MAP - ICP or CVP)
26
CV effects of barbiturates
1. **Vasodilation** - decreased BP
2. **Baroreceptor** increase in HR
3. **Histamine** release
4. Decreased body **temp** - d/t **cutaneous** and **skeletal** muscle vasodilation
5. Minimal CV effects with PO doses
6. **Minimal** decreases in **myocardial contractility**
27
Who should NOT get barbiturates
1. Those with impaired SNS response - wont get compensaroy increase in HR to vasodilation
2. Hypovolemia - vasodilation can lead to CV collapse and decreased ICP and CPP
3. Drugs that may influence these two things:
* ß-blockers, central antihypertensive drugs
28
Which drugs cause histamine release
1. Thopental and thiamylal CAUSE histamine release
2. Methohexitol does NOT
29
Respiratory effects of barbiturates
1. **Dose dependent** depression of the **medullary and pontine ventalitory centers**
2. Decreased ventilatory response to **hypercarbia** (and **hypoxia** - per class notes)
* **Apnea**
* Resumption of spontaneous breathing – **slow RR** with a **decreased TV**
1. Laryngeal and cough reflexes **NOT** suppressed until large doses are given
* Laryngoscopy = may **cuase** laryngospasm
* **INCOMPLETE** laryngeal muscle paralysis
30
Barbiturates and Somatosensory Evoked Responses
Even with an isoelectric EEG still sufficient SSEP responses
31
Barbiturates and enzyme induction
1. most potent inducer
2. Drugs to consiter
3. Endongenous substances to consiter
1. **Phenobarbitol** = most potent inducer
* **20-40%** increase in hepatic enzyme induction
* Metabolism of drugs can be **doubled**
* induction can last **30 days** post d/c
1. **Drugs** to consider:
* Oral anticoagualnts
* Phenytoin
* Tricyclic antidepressants
* May enhance their own metabolism which contributes to tolerance
1. **Endogenous substances** to consider
* Corticosteroids
* Bilesalts
* Vitamin K
32
D-ALA synthetase
Barbs **stimulate production** of D-ALA synthetase
* **rate limiting step** for induction of heme synthesis) (D-aminolevulinic acid synthetase)
* **Production of heme** **is accelerated**
* **PORPHYRIA EXACERBATION**
33
Effect of Barbs on kidneys
Decreased GFR and renal blood flow **likely from** vasodilation and decrease systemic BP
34
Barbiturated readily cross the placenta, why are fetal plasma concentrations less than that of the maternal plasma concentrations?
* **clearance** by the liver and **dilution** by blood from the fetal viscera and extremeties
* therefore fetus has a lower concentration to the effect site as well.
* neonates after cessarian section have variable E1/2 from **11- 42.7** hours
35
barbiturate relationship of tolerance and enxyme induction
1. **Tolerance happens quicker** than enzyme induction doses may need to be increased **six fold**.
2. Enzyme induction does causes **increased metabolism of the drug itself**
36
Intraarterial injection of barbiturates pathology
1. **Immediate** intense vasoconstriction ,excrutuiatinc pain along the distribution of the artery
2. **Precipitation** of crystals from the alkaline formula (concentration should be \<2.5% thiopental, 1% methohexitol)
3. **Inflammation, microembolism, occulsion** of distal arteries
37
Intraarterial injection of barbiturates treament
1. **Dilute** - NS injection at site
2. **Prevent arterioal spasm and vasodilation to increase blood flow**
* pappverine **40-80mg** in saline
* Lidocaine = **5ml of 1%** solution
* phynoxybenzamine (direct acting alpha blocker)
3. **Prevent thrombosis**
* Heparin or urokinase
4. **Sympathectomy**
* Stellite ganglion block (C6-C7)
* brachial plexus block
38
Venous thrombosus
Same as intraarterial injecton, BUT it is less likely to occur becasue of the ability of the veins to expand
39
Allergic Reactions to Barbiturates
1. 1/30,000
2. high mortality
3. patients with chronic atopy most likely
4. tx with epi and adequate intravascular fluid volume
40
41
Barbituate Prototype
Sodium Pentathol (Thiopentol)
42
Sodium Petnathol (thiopentol) mechanism of action
1. decreases rate at which GABA dissociates from the receptor (**Enhances GABA**)
1. increases duration of CL- channel opening
2. **Mimics** GABA at the receptor (direct activation of Cl- channels)
43
Barbituates also depress the ___________ which causes sleep.
Reticular Activating System
44
Barbituates produce a functional inhibition of \_\_\_\_\_\_\_\_\_
the post synaptic neuron
45
Barbituate Uses
1. Sedation and Hypnosis
2. Induction agents
3. Cerebral Protection
4. Anti-seizure
46
Why does thyopentol produce a hangover effect
It has a **quick redistribution from the effect site** and a **long elimination half time**, induction effect wears off quickly, but it still takes time for the body to eliminate the drug
47
Thiopentol cases depression of the _____________ center and decreases \_\_\_\_\_\_\_\_\_\_. This results in ___________ and decreased \_\_\_\_\_\_\_\_\_.
1. Medully Vasomotor Center
2. SNS outflow
3. peripheral vasodilation
4. preload
48
Thiopentol
If the \_\_\_\_\_\_\_is not intact or patient is _________ or if large doses are given to reduce \_\_\_\_\_\_\_\_\_. We will see ______________ and \_\_\_\_\_\_\_\_\_\_. Especially in the older population. Sometimes it is dosed with __________ to avoid this.
1. SNS
2. Hypovolemic
3. ICP
4. significant decrease in BP
5. myocardial depression
6. Epinepherine
49
Thiopentol and Ventilation
1. Respiratroy depression with
2. Decreased RR and Decerease TV
50
1. causes **crystalization/gangrene/nerve** dammage
2. pain that radiates along **arterial distribution**
Intra-arterial injection of thiopentol
51
Treatment:
1. NS injection, lidocaine, papaverine, phenoxybenzamine
2. sympathectomy via brachial plexus block
Intra-arterial injection of thiopentol
52
Thiopentols effect is rapidly terminated because of \_\_\_\_\_\_\_\_\_\_\_\_\_
**Redistribution**, form brain (vessel rich) tissue to inactive sites (muscle, fat)
53
What is thiopentols E1/2 time?
11.6 hours
54
thiopentol especially effects ___________ because of the excess adipose tissue for the drug to redistribut into and then be removed from
Obese patients
55
Phenobarbitol
Is the most potent CYP 450 inducer
56
Thopentol and metabolism
It is a POTENT CYP 450 inducer
57
Barbituates and metabolism
Hepatically and they **induce** the CYP 450 system
58
Barebituates produce a dose dependant depression in the _________ and \_\_\_\_\_\_\_\_\_centers. They cause decreased ventilatory response to __________ and \_\_\_\_\_\_\_\_\_\_\_. Thus cause \_\_\_\_\_\_\_\_
1. Medullary and pontine respiratory centers
2. Hypoxia and hypercapnea
3. Apnea
59
Because barbituates induce the enzyme induction systerm, they increase the metabolism of:
1. \_\_\_\_\_\_\_\_\_
2. \_\_\_\_\_\_\_\_\_
3. \_\_\_\_\_\_\_\_\_
4. \_\_\_\_\_\_\_\_\_
5. \_\_\_\_\_\_\_\_\_
1. oral anticoagulants
2. Vitamin K
3. Phenytoin
4. TCA's
5. Corticosteroids
60
Barbituates and the placenta
1. Barbituates **readily cross** the placenta
2. **levels much lower in fetal circulation** than in maternal circulation
3. Dose reduced in emergency C-section
