Benzodiazepine
5 pharmacological effects
- anxiolytics
- sedation
- anterograde amnesia
[[cant remember anything after drug is given]] - anticonvulsant actions
- muscle relaxation
[[spinal level; not adequate for surgery muscle relaxation]]
What is the first drug you’ll give in the OR?
Benzodiazepine
-midazolam [[versed]]
- diazepam [[valium]]
- lorazepam [[ativan]]
Benzo structure
- benzene ring
- fused with 7 member diazepine ring
Benzo mechanism of action
-facilitate there action of GABA on GABAa
[[gets the membrane ready and available for GABA]]
^GABA major inhibitory NT in brain
- increases affinity of GABAa
- DOES NOT activate GABAa receptor
BRS explanation;
Benzos bind to regulatory site; benzo receptor on the GABAa receptor
- allosterically increase the affinity of GABAa receptor for GABA with an increase in the frequency of GABA- stimulated chloride conductance
- causing hyperpolarization and inhibition
***benzos have NO ACTION in the ABSENCE of GABA
Benzo general facts
-does not produce skeletal muscle relaxation ENOUGH for surgery
[[enough for back pain or neck pain]]
- it also does not alter the dose of muscle relaxant required for surgery
- less of a potential for tolerance or abuse compared to OPIOIDS and BARBS
- greater margin of safety in OD
- DO NOT induce hepatic enzymes
-Benzos have a specific antagonist
[[Flumazenil aka Romazicon]]
**BENZOS have essentially replaced BARBS for premeds and MAC sedation
[[versed is the drug of choice]]
What enhances the affinity of GABA at a GABA a receptor
Benzos
Barbs
alcohol
How does GABAa receptor work
- benzo binds to its receptor site on GABAa and facilities the opening of GABA -activated [[GABA a]] chloride channels
- GABA binds to its receptor site on GABAa and activates the channel
-channel open increased chloride conductance
[[hyperpolarize/ inhibitory]]
Benzo is a what to GABA
allosteric agonoist
Benzes allosterically increase the affinity of GABA at GABAa receptors
what kinds of NT is GABA
inhibitory
What type of channel is GABAa
inhibitory, ligand gated, cya loop; pentomer [[5 subunits]]
Differences between the types of Benzos are
potency
lipid solubility
pharmacokinetic
**generally they are all;
HIGHLY lipid soluble
HIGHLY protein bound [[albumin]]
Midazolam
[[Versed]]
**has an active metabolite
[[1 hydroxymidazolam]]
water soluble preparation
^not painful when administered
[[can mix in a saline bag]]
imidazole ring
2-3x MORE potent than diazepam [[valium]]
90-98% protein bound
[[highly protein bound]]
0.9-5.6 min to effect site
[[time it takes too hit brain depends on BBB]]
extensive Fist Pass Effect
[[PO dose larger]]
Rapid redistribution
[[highly lipid soluble; short duration]]
E 1/2 t; 1- 6.5 hours
[[slower metabolism;’ elderly and Asians]]
*Renal failure does not effect
Vd, E1/2 t or clearance
What effects BBB
AGE
older person more sensitve
ALCOHOLIC
less sensitive
Metabolism of Versed
extensive HEPATIC metabolism
hydrolysis to water soluble compound
[[1 and 4 hydroxymidazolam]]
1- hydroxymidazolam
[[active metabolite]]
conjugated and excreted by urine
Renal failure DOES NOT affect
Vd, E 1/2 t or clearance
CNS effects of Versed and Valium
- decreases cerebral blood flow (CBF)
- decreases cerebral metabolic 02 requirement (CMR02)
-DOES NOT produce isoelectric EEG
[[no flat line on EEG]]
- preserved cerebrovascular response to CO
- DOES NOT help attenuate [[reduce]] the ICP response to laryngoscope
-ANTICONVULSANT
[[antiseizure]]
-AMNESTIC
[[won’t remember anything after med is given]]
**valium has same effects
Respiratory effects of Versed and Valium
-dose dependent DECREASE in ventilation
-in the presence of opioid
INCTREASED;
HYPOXEMIA HYPOventilation
-decreased upper airway activity [[coughing, gag, swallowing]]
-depresses swallowing reflex
[[help with secretion; suction]]
**versed has same effects
CV effects of Versed
-Decreased SVR at INDUCTION dose
[[normal dose no change]]
induction dose decreases SVR; decreased BP
CO; no change in healthy heart
*does not attenuate [[reduce]] HR and BP with intubation
^just like with ICP
[[Valium has minimal CV effects]]
VERSED DOSES
ORAP Premedication and Pedi;
0.25 - 0.5mg/kg PO
[[large post; first pass effect]]
max PO dose for pedi;
20mg
IV sedation;
1 - 2.5mg
max 5mg
INDUCTION DOSE
0.1 - 0.2mg/kg over 30-60 sec
[[remember onset can be 0.9-5.6 min]]
*maintenance can be incremental or infusion
Diazepam
[[Valium]]
**Active metabolite
[[Desmethyldiazepam]]
preparation; organic solvent [[propylene glycol; benzyl alcohol]]
^PAINFUL on IV and IM injection
Viscous -pH 6.6 - 6.9
Highly Protein Bound
Highly Lipid Soluble
[[longer duration than versed; and 2-3x LESS potent]]
PO dose rapidly absorbed from GI tract
PO valium > PO versed
[[ no first pass effect ]]
Metabolism of Valium
[[versed –>hydrolysis]]
Oxidation; n-demethylation–>
desmethyldiazepam active metabolite
hepatic micro enzymes; oxazepam
temazepam
^NOT active metabolites
E1/2 t; 21-37 hours
[[increases with age]]
LONG acting >24 hrs
active metabolite
desmethyldiazepam;
48-96 hours [[not as active as valium]]
Benzos duration of action
short acting; versed
<5 hr
intermediate acting; Ativan
5-24 hrs
long acting; valium
>24 hrs
CV effects of Valium
minimal changes in SVR, BP, CO
*if HR and BP come down its r/t reduced anxiety
VALIUM DOSES
ORAL/ Premedication;
10 - 15mg
[[NO first pass effect; rapidly absorbed by GI tract]]
premedication IV; 0.2 mg/kg
INDUCTION IV;
0.5 - 1.0 mg/kg
ANTICONVULSANT;
0.1 mg/ kg
^lowest IV dose
Lorazepam
[[Ativan]]
**most potent amnesties of all the Benzos **
5- 10x potency of Diazepam
[[versed 2-3x more potent than diazepam]]
Propylene glycol as solvent
[[HURTS on injection]]
NO active metabolites
metabolism less effected by alterations in hepatic function, age and other drugs
E1/2 t;
10-20 hours
[[intermediate DOA 5-24 hrs]]
**SLOW onset; peak is 2 hrs
[[useless in OR]]
