Benzo/Barbs Flashcards
1
Q
Benzo MOA
A
- Inc GABAa receptor affinity for GABA
- Facilitate action of GABAa at its receptor
- -> causes inc opening of Cl channels, inc Cl conductance & hyper polarizes POST SYNAPTIC membrane, increasing the resistance to excitation.
- DOES NOT activate GABAa receptor itself
2
Q
Benzo Uses (5 pharm effects)
A
- Anxiolysis
- Sedation
- Anterograde amnesia
- Anticonvulsant (inhibit activity of limbic, hippocampus)
- Muscle relaxant (@ spinal level)
3
Q
Alpha 1 Subunit
A
Sedative Effects (most abundant subunit w//60% in CNS) Cortex & thalamus
4
Q
Alpha 2 Subunit
A
Anxiety effects
Hippocampus & amygdala
5
Q
Benzo Structure
A
Benzene ring fused 7-member diazepine ring
6
Q
Do Benzos alter NMB dose?
A
NO, muscle relaxant activity not adequate for surgical effect.
7
Q
Pharmakokinetics of Benzos:
- PB & Solubility
- Met
- Elimination
A
- Highly protein bound & very lipid soluble
- Hepatic metabolism (CYP450)
- Eliminated by kidneys
8
Q
Benzos: Neuro Effects
A
- ↓CBF & CMRO2 (can be used for burst suppression) But not neuroprotective
- DOES NOT produce isoelectric EEG (bc ceiling effect)
- Preserves cerebrovascular response to CO2
- DOES NOT attenuate ICP r/t DVL (GIVE NARCOTIC in addition to benzo!)
- EEG effects resemble barbs
- Paradoxical Excitement incidence <1% = RARE
9
Q
Benzos: CV Effects
A
Relatively stable CV effects
- ↓SVR @ induction dose
- CO unchanged
- Ceiling effect on BP↓ (only about 20%)
- DOES NOT attenuate SNS response to DVL
10
Q
Benzos: Resp Effects
A
↓ventilation (dose dependent)= ↓TV & ↓RR (careful in COPD)
- Hypoxemia & hypoventilation enhanced w/ opioid (synergistic effect)
- Depress reflex deglutition/gag reflex = good for endo suite
- CO2 response curve flattens but does not shift it (↓ slope, no shift like w/opiods)
- Decreased brain response to cO2
11
Q
Which drugs use propylene glycol as solvent? What does this mean?
A
Diazepam & Lorazepam = PAINFUL injection
*Midazolam comes in water soluble prep/no pain on inj
12
Q
Differentiate GI effects of Diazepam vs Midazolam.
A
Diazepam = Rapidly absorbed form GI tract
Midazolam = Extensive 1st pass effect (give higher PO dose) & PO meals/antacids decrease absorption (take w/empty stomach)
13
Q
What does Cimetidine do? What drug does this affect most?
A
Cimetidine inhibits CYP450 = decrease clearance of Diazepam therefore prolonged E1/2t
14
Q
How are the following drugs metabolized?
- Diazepam
- Midazolam
- Lorazepam
A
Diazepam = Oxidation & demethylation
Midazolam = Hydroxylation
Lorazepam = Glucuronidation
15
Q
Which benzos have active metabolites? What are they?
A
Diazepam = Desmethyldiazepam (most potent & longer E1/2t of 48-96hrs), oxazepam & temazepam
Midazolam = 1-hydroxymidazolam
**Lorazepam does NOT have an active metabolite
16
Q
E1/2t in Diazepam, Midazolam & Lorazepam
A
Diazepam = 21-37 hrs (desmethyldiazepam = 48-96hrs) Midazolam = 1-6 hrs Lorazepam = 10-20 hrs
17
Q
Describe the potency of benzos.
A
Midazolam = 2-3x potency of diazepam Lorazepam = 5-10x potency of diazepam!!
18
Q
Which benzo has the longest E1/2t?
A
Diazepam @ 21-37 hrs BUT still has a shorter DOA compared w/lorazepam
19
Q
Which benzo has the fastest clearance & shortest E1/2t?
A
Midazolam has the shortest E1/2t (1-6hrs) due to RAPID REDISTRIBUTION/fast effect site equilibration & fastest clearance.
20
Q
Which benzo is most potent?
A
Lorazepam 5-10x that of diazepam
21
Q
Which benzo has the slowest onset of action?
A
Lorazepam takes 2 hrs – slowest onset due to lower lipid solubility & slower entrance into CNS.
Diazepam = onset 1hr Midazolam = onset 1-6min
22
Q
Which benzo’s metabolism is least influenced by hepatic function, age & other drugs? Why?
A
Lorazepam, because the metabolism is not entirely dependent on hepatic microsomal enzymes (glucuronidation)
23
Q
Diazepam Premed PO/IV & Induction Doses
A
Diazepam DOSES:
Premed PO = 10-15mg PO
Premed IV = 0.2mg/kg IV
Induction = 0.5-1mg/kg IV
24
Q
Midazolam Premed PO/IV & Induction Doses
A
Midazolam DOSES:
Premed PO = 0.5mg/kg PO (PEDS; MAX = 20mg)
Premed IV = 1-2.5 mg IV (MAX = 5mg)
Induction 0.1-0.2mg/kg IV (over 30-60 sec)
25
Lorazepam Premed PO/IV Doses
Lorazepam DOSES:
Premed PO = 50mcg/kg PO (MAX= 4mg)
Premed IV = 1-4mg IV
26
What will prolong the E1/2t of benzos?
1) Cirrhosis & ESRD due to the DEC PROTEIN BINDING (NOT due to clearance)
2) increases progressively w/age also due to inc Vd of highly lipid soluble drug (NOT due to clearance)
27
Do benzos increase N/V?
NO
28
Flumazenil (Romazicon) MOA
Benzo receptor ANTAGONIST-- Competitively inhibits action of Benzo at recognition site on GABA receptor, high affinity for receptor
(does not reverse as potently as Narcan for Narcs – smoother reversal because structure very similar to benzos)
Imidazobenzodiazepine derivative
29
Flumazenil Effects:
- Reverse resp depression & sedation
- Sweating, HA, abnormal vision, confusion, euphoria, depression
- NO inc in HR, BP, agitation/anxiety or neuroendocrine stress response (due to similar structure)
30
Flumazenil Dose (initial bolus w/ incremental dosing, differential diagnosis dosing & infusion dosing)
0.2 mg IV, wait 2 min to peak ---- 0.1mg Q 60 sec
(MAX = 3mg IV)
5mg to differentiate OD on benzo vs coma
Infusion of 0.1-0.4mg/hr (0.5-1.0mcg/kg/min) *good for ativan
31
Does renal failure effect E1/2t, clearance, or Vd in benzos?
NO--- Does not affect in midazolam due to extensive hepatic metabolism.
32
Describe Barb structure.
-Commercially prepared as sodium salts (derived from barituatic acids)
Urea + malonic Acid = Barbituric Acid
-Only available as Racemic prep but levo isomer is 2x potent than dextro-isomers
33
Describe the substitutions made to carbon atoms in barbs. What happens if you don't make any substitutions?
**Without substitutions = no CNS activity
Substitutions at Carb #2 and #5 have sedative and hypnotic properties
- #5 = + Branch chain = ↑hypnotic activity
+ Phenyl group = ↑anticonvulsant activity (phenobarb)
- #2 = + Oxygen Atom = Oxybarbituate = hepatic met ONLY
+ Sulfur Atom = Thiobarbituate = hepatic & extra hep met (GI)
** Sulfuration (Structural change = + sulfur atom) = ↑lipid solubility, greater hyponotic potency, more rapid onset but shorter DOA (Thiopental & thiamylal)
- #3 = Methyl radical = CONVULSANT activity (methohexital), also has shorter DOA
- Long branch chain is more potent than straight chain
34
Describe Barb MOA (4)
1) ↓rate at which GABA dissociates from its receptor = ↑duration of GABA activated Cl- channel opening (enhances & MIMICS GABA activity by directly activating receptors)
2) ↓transmission in sympathetic ganglia = hypotension (direct acting effect; central effect on SNS)
3) ↓postsynaptic membrane sensitivity to Ach = muscle relaxation (not enough for surgical muscular relaxation or intubation = still need NMB
4) Depresses RAS = sleep
35
CI in barbs
Crosses placenta
Porphyria
ASTHMA (releases histamine; not methohexitol)
36
Describe the relative potency of barbs
* Thiopental TPL/STP = 1 (61% non-ionized)
* Thiamylal (Surital) = 1.1
* Methohexital (brevital) = 2.5 (75% non-ionized)
37
Pharmakokinetics of Barbs:
- Solubility
- Onset of action
- Metabolism
- Lipophilic (PB parallels lipid solubility; thiopental most lipophilic)
- Rapid Onset/rapid termination of effect: Effect-cite equilibration time (redistribution) is RAPID but metabolism is SLOW = hangover effect (Fat potential reservoir for maintaining plasma conc).
38
Describe the metabolism of Barbs. Differentiate between TPL & Methohexitol
- Extensive Metabolism: Side chain Oxidation at Carbon #5 to carboxylic acid terminates pharm activity. Oxidation occurs primarily by ER of hepatocytes.
- Can ENHANCE OWN METABOLISM bc enzyme inducers (contributes to tolerance)
Oxybarbituate (methohexitol) = hepatic metabolism ONLY
Thiobarbituate (TPL) = hepatic & extra hep met (GI)
39
Do barbs have active metabolites?
NO
40
Describe renal excretion of barbs.
Renal excretion <1% unchanged (thiopental, thiamylal & methohexital) – phenobarb is only one that undergoes significant renal excretion in unchanged form (lesser PB & lipid solubility)
41
Which induce hepatic enzymes: Barbs or benzos? What does this mean?
BARBS!!
Induces hepatic enzymes (Phenobarb most potent inducer)= metabolize other drugs (oral anticoags, phenytoin, TCAs, corticosteroids, and Vit K) quickly (give more frequent large doses of other drugs metabolized by liver) Ie: when on barbs for chronic seizure prophylaxis – rapid metabolism of muscle relaxants seen
42
Barbs stimulate which enzymes?
Hepatic microsomal enzymes AND mitochondrial enzymes
Accelerated Production of Heme by stimulation of enzyme – D-aminolevulinic acid synthetase (mitochondrial enzyme)= AVOID in PORPHYRIAS! (s/sx: severe abdom pain w/diarrhea & vom, ANS instability (tachy, htn), electrolyte instability, skeletal musc weakness, resp failure, seizures, neuropsych disturbances)
43
Describe NV incidence in benzo, barbs & non-barb agents.
```
Highest = Etomidate, ketamine & volatiles
Middle = Barbs
Lowest = Benzos, Propofol
```
44
Barbs: Neuro Effects
- Depresses LOC
- Cerebrovascoconstriciton = ↓CBF, ↓ ICP and CMRO2
- Produce Isoelectric EEG
- Paradoxical excitement (esp in elderly & in presence of pain)
* *METHOHEXITAL = dose-dependent excitatory skeletal movements (myoclonus & hiccups; ↓incidence if given w/opiods)
- Does not effect SSEP monitoring
- Decreased threshold for pain = anti-analgesic effect
- No skeletal muscle relaxation/effect on NMJ
- ↓IOP
45
Barbs: CV Effects
-Depression of medullary vasomotor center = decreased SNS outflow from CNS = PERIPHERAL VASODILATION = pooling/↓VR = ↓ PRELOAD =
↓ SBP (10-20mmhg) = compensatory ↑HR (15-20bpm)
-Minimal myocardial depression (less dep than volatile anesthetics due to compensatory HR inc)
**If SNS not intact, hypovolemic, or large doses = ↓↓BP and inc myocardial depression
- Histamine release with RAPID injection (Not w/methohexitol)
- Minimal CV effects when given PO
- Venous thrombosis (barb crystals in veins; dilute to dec risk)
46
Barbs: Resp Effects
- Dose dependent depression of medullary and pontine vent centers
- Decreased vent response to hypoxia and hypercapnia
- APNEA - must ventilate
- Depression of laryngeal and cough reflexes incomplete
- Stage 2 like response to DVL if too small dose given or when given to hypersensitive like Asthma= risk broncho and laryngospasm
47
Describe pH of barbs & how it affects other drugs
-Stored at high pH = highly alkaline (bacteriostatic) BUT barbs are all weak acids. If someone is acidotic = more effective drug (acid in acid = more lipid soluble = more effect)
-Cannot mix with Acidic drugs:
Opioids, Catechols, NMBs, midazolam
*Pancuronium
*Vecuronium
*Atracurium
*Alfentanil
*Sufentanil
*Midazolam
LR – too acidic = precipitation
48
Describe intra-arterial injection, s/sx, treatment.
Immediate intense vasoconstriction and pain radiating along distribution of artery! Obscure distal pulses- blanching- cyanosis- gangrene & nerve damage can occur.
2* to crystalline precipitation in arterial vessel, inflammatory response, vasoconstriction, microembolization
Treatment = Dilute drug, prevent spasm & sustain BF
• Dilute with NS
• Phenoxybenzamine (covalently bound vasodilator)= profound effect
• Heparin or Urokinase = prevent thrombosis
• Brachial Plexus or Stellate Ganglion Block (sympathectomy of upper extremity) = vasodilation and pain relief
• Papaverine 40-80mg in 10-20mL saline or 5-10mL Lidocaine 1% in artery
49
Which benzo has a high hepatic extraction ratio? Which has a low hepatic extraction ratio?
```
Methohexitol = HIGH hepatic extraction ratio (more dependent on CO & BF for hep clearance)
TPL = LOW hepatic extraction ratio
```
50
Which barb is most avidly bound to proteins?
```
TPL = 70-85% PB
Methohexitol = 70% PB
```
51
Which barb is associated w/histamine release?
TPL (NOT methohexitol)
52
E1/2t of Barbs (TPL & Methohexitol)
```
TPL = 11.6 hrs
Methohexitol = 3.9 hrs (due to inc hepatic clearance)
```
53
TPL Doses
- Induction
- When do you decrease the dose?
3-5 mg/ kg IV (normal dose = 1st order; ↑doses = 0 order);
5-6mg/kg Peds
7-8mg/kg Infants
↓ dose 30% in first trimester pregnancy and elderly
54
Methohexitol Doses
| -Induction
1-2 mg/ kg IV or
| 20-30mg/kg PR in PEds
55
Which barb can induce seizures? Why?
Methohexitol
+ Methyl radical to #3 = CONVULSANT activity (methohexital), also has shorter DOA
56
Name the only water soluble drug out of benzo/barbs?
Midazolam
