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Pharm Exam I > Benzo/Barbs > Flashcards

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
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2
Q

Benzo Uses (5 pharm effects)

A
  • Anxiolysis
  • Sedation
  • Anterograde amnesia
  • Anticonvulsant (inhibit activity of limbic, hippocampus)
  • Muscle relaxant (@ spinal level)
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3
Q

Alpha 1 Subunit

A 
Sedative Effects (most abundant subunit w//60% in CNS)
Cortex & thalamus
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4
Q

Alpha 2 Subunit

A

Anxiety effects

Hippocampus & amygdala

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5
Q

Benzo Structure

A

Benzene ring fused 7-member diazepine ring

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6
Q

Do Benzos alter NMB dose?

A

NO, muscle relaxant activity not adequate for surgical effect.

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7
Q

Pharmakokinetics of Benzos:

  • PB & Solubility
  • Met
  • Elimination
A
  • Highly protein bound & very lipid soluble
  • Hepatic metabolism (CYP450)
  • Eliminated by kidneys
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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
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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
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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
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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

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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)

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13
Q

What does Cimetidine do? What drug does this affect most?

A

Cimetidine inhibits CYP450 = decrease clearance of Diazepam therefore prolonged E1/2t

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14
Q

How are the following drugs metabolized?

  • Diazepam
  • Midazolam
  • Lorazepam
A

Diazepam = Oxidation & demethylation

Midazolam = Hydroxylation

Lorazepam = Glucuronidation

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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

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16
Q

E1/2t in Diazepam, Midazolam & Lorazepam

A 
Diazepam = 21-37 hrs (desmethyldiazepam = 48-96hrs)
Midazolam = 1-6 hrs
Lorazepam = 10-20 hrs
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17
Q

Describe the potency of benzos.

A 
Midazolam = 2-3x potency of diazepam 
Lorazepam = 5-10x potency of diazepam!!
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18
Q

Which benzo has the longest E1/2t?

A

Diazepam @ 21-37 hrs BUT still has a shorter DOA compared w/lorazepam

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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.

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20
Q

Which benzo is most potent?

A

Lorazepam 5-10x that of diazepam

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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
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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)

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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
Q

Lorazepam Premed PO/IV Doses

A

Lorazepam DOSES:
Premed PO = 50mcg/kg PO (MAX= 4mg)
Premed IV = 1-4mg IV

26
Q

What will prolong the E1/2t of benzos?

A

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
Q

Do benzos increase N/V?

A

NO

28
Q

Flumazenil (Romazicon) MOA

A

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
Q

Flumazenil Effects:

A
  • 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
Q

Flumazenil Dose (initial bolus w/ incremental dosing, differential diagnosis dosing & infusion dosing)

A

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
Q

Does renal failure effect E1/2t, clearance, or Vd in benzos?

A

NO— Does not affect in midazolam due to extensive hepatic metabolism.

32
Q

Describe Barb structure.

A

-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
Q

Describe the substitutions made to carbon atoms in barbs. What happens if you don’t make any substitutions?

A

**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
Q

Describe Barb MOA (4)

A

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
Q

CI in barbs

A

Crosses placenta
Porphyria
ASTHMA (releases histamine; not methohexitol)

36
Q

Describe the relative potency of barbs

A
  • Thiopental TPL/STP = 1 (61% non-ionized)
  • Thiamylal (Surital) = 1.1
  • Methohexital (brevital) = 2.5 (75% non-ionized)
37
Q

Pharmakokinetics of Barbs:

  • Solubility
  • Onset of action
  • Metabolism
A
  • 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
Q

Describe the metabolism of Barbs. Differentiate between TPL & Methohexitol

A
  • 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
Q

Do barbs have active metabolites?

A

NO

40
Q

Describe renal excretion of barbs.

A

Renal excretion <1% unchanged (thiopental, thiamylal & methohexital) – phenobarb is only one that undergoes significant renal excretion in unchanged form (lesser PB & lipid solubility)

41
Q

Which induce hepatic enzymes: Barbs or benzos? What does this mean?

A

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
Q

Barbs stimulate which enzymes?

A

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
Q

Describe NV incidence in benzo, barbs & non-barb agents.

A 
Highest = Etomidate, ketamine & volatiles 
Middle = Barbs
Lowest = Benzos, Propofol
44
Q

Barbs: Neuro Effects

A
  • 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
Q

Barbs: CV Effects

A

-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
Q

Barbs: Resp Effects

A
  • 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
Q

Describe pH of barbs & how it affects other drugs

A

-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
Q

Describe intra-arterial injection, s/sx, treatment.

A

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
Q

Which benzo has a high hepatic extraction ratio? Which has a low hepatic extraction ratio?

A 
Methohexitol = HIGH hepatic extraction ratio (more dependent on CO & BF for hep clearance)
TPL = LOW hepatic extraction ratio
50
Q

Which barb is most avidly bound to proteins?

A 
TPL = 70-85% PB
Methohexitol = 70% PB
51
Q

Which barb is associated w/histamine release?

A

TPL (NOT methohexitol)

52
Q

E1/2t of Barbs (TPL & Methohexitol)

A 
TPL = 11.6 hrs
Methohexitol = 3.9 hrs (due to inc hepatic clearance)
53
Q

TPL Doses

  • Induction
  • When do you decrease the dose?
A

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
Q

Methohexitol Doses

-Induction

A

1-2 mg/ kg IV or

20-30mg/kg PR in PEds

55
Q

Which barb can induce seizures? Why?

A

Methohexitol

+ Methyl radical to #3 = CONVULSANT activity (methohexital), also has shorter DOA

56
Q

Name the only water soluble drug out of benzo/barbs?

A

Midazolam

Pharm Exam I (4 decks)

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