Induction Agents & Sedatives Flashcards
How is propofol excreted?
Kidneys
How is propofol biotransformed (metabolized)?
Liver conjugation into inactive metabolites
How is propofol distributed?
Highly lipid soluble
Very rapid redistribution
Very quickly goes to the VRG which includes the brain which is why pts fall asleep so quickly then in a relatively short period of time it redistributes from the VRG into the peripheral compartment which includes the muscle and fat compartments.
What is propofol’s mechanism of action?
It enhances inhibitory transmission thru GABA receptors
What does propofol contain in its vial?
Its an emulsion in intralipid (a fatty substance made out of soybean oil, glycerol, egg lecithin)
—————Lecithin is from yolk, most allergies are to egg white (protein)
—————-Patients with soy allergy or egg allergy can receive propofol without any special precautions.
The intralipid is significant bc it supports bacterial (and fungal) growth – use aseptic technique
—————–Discard contents of opened vial and propofol tubing after 12 (6?) hours
Can pts with egg allergy receive propofol?
Yes, bc most people allergic to egg are allergic to egg white while propofol’s egg content is from egg yolk.
Why is the intralipid emulsion in which propofol is stored siginificant?
The intralipid is significant bc it supports bacterial (and fungal) growth – use aseptic technique
—————–Discard contents of opened vial and propofol tubing after 12 (6?) hours
How long after opening a vial of propofol do we use it?
Discard contents of opened vial and propofol tubing after 12 (6?) hours
Are there any issues with giving propfol to pts with moderate cirrhosis?
No bc it doesnt seem to slow down or have any effect on propofol’s metabolism
Is there any issue with giving propofol to patients with chronic renal failure?
No bc propofol is metabolized into inactive metabolites and enters the kidney this way and has not problems being excreted from the body despite the chronic renal failure
Induction dose of propofol
Dose: 1.5 – 2.5 mg/kg in adults
Dose: 1 mg/kg in elderly
Propofol infusion for sedation
25-75 mcg/kg/min
Propofol infusion for general anesthesia
100-200 mcg/kg/min
– the target plasma concentration = 4-6 mcg/mL
- There is some risk of awareness when used as the sole agent
- Higher incidence of movement when used as sole agent (seems to work best when used together with an inhalant, opioid, or ketamine.)
Propofol’s effect on the CV System:
- Significant ↓↓ SVR (lots of vasodilation & hypotension)
- ↓contractility,
- ↓preload → hypotension
Decrease in BP is mosre pronounces with rapid injection, old age, LV failure
Potential for bradycardia, but often tachycardia with induction
Propofol’s effect on the Respiratory System:
- Profound respiratory depression & apnea
- depresses hypoxic/hypercapnic drives
- Profound depression of upper airway reflexes
Acceptable to use with Asthmatics – less wheezing using propofol than with thiopental
Propofol’s effect on the Neuro system:
↓ CBF (cerebral blood flow) ↓ ICP (intracranial pressure) ↓ CMRO2 (cerebral metabolic rate) - Anti-emetic (useful for pts with N&V) - Anti-epileptic - On induction -> may see myoclonic twitches, hiccupping - On emergence -> may experience euphoria, intense dreaming, amorous behavior - Potential for abuse and addiction --------Little evidence of tolerance
Why does propofol burn when you inject it into a peripheral IV?
—– Most people think the burning is caused by the intralipid solvent (and propofol itself) –> produces bradykinin —-> which vasodilates, increases contact between the aqueous phase of propofol (phenol is irritating) and the free nerve endings.
How can you minimize the burning caused by propofol injection?
- Lidocaine + tourniquet (Bier block)
- Pre-treat with IV opioid
- Mixing propofol with lidocaine (to acidify the propofol emulsion and make it less likely to cause burning)
- Lidocaine also inhibits bradykinin - since bradykinin causes the burning this may be the mechanism for reducing burning sensation but unclear
Acute Hypertriglyceridemia =
An effect caused by the high-fat content of propofol and propofol’s inhibition of fatty acid oxidation
When prolonged high dose propofol infusions make the blood super fatty
Treatment:
- stop propofol infusion,
- give insulin/dextrose to promote lipoprotein lipase activity
Propofol infusion syndrome
- Presents as:
Hyperlipidemia, rhabdomyolysis, metabolic acidosis, refractory bradycardia, progresses to circulatory collapse, death - Typically occurs as an “all or none” syndrome with sudden onset and high incidence of death
- Typically seen in ICU pts who have been on prolonged high-dose infusions
Ex: ( >75 mcg/kg/min, for more than 24 hours) - Usually seen in critically ill patients, especially on vasopressors
- May reflect a genetic susceptibility
- Both the intralipid lipid solvent and propofol itself contribute to the development of hyperlipidemia and hypertriglyceridemia, but the pathogenesis is not well understood
Barbiturates include drugs like…
Phenobarbital, methohexital, thiopental, thiamylal, secobarbital
Barbiturate mechanism of action =
They depress the brain stem’s Reticular Activating System (consciousness center)
They suppress certain excitatory neurotransmitters = Acetylcholine
They enhance certain inhibitory neurotransmitters = γ-aminobutyric acid, GABA
Barbiturate solubility
Water-soluble
but the preparation is very alkaline (pH >10) and unstable (which makes is last only 2-6 weeks in refrigerator)
Barbiturate acidity
- Weak acid with pKa close to 7.4
- Pain with extravasation, but usually painless on injection
What happens if you inject a barbiturate into an a-line?
- Intra-arterial injection of thiobarbiturate → SEVERE damage → crystal formation → thrombosis, necrosis
- —————» Treat with papaverine (for vasodilation), lidocaine, stellate ganglion block (to prevent long term pain syndromes), heparin (for coagulation)
Barbituates can be divided into two general classes:
1) Thiobarbiturates (thiopental, thioamylal)
- Higher lipid solubility = greater potency, rapid onset, shorter duration
- Thiopental (pentothal) used by many states for lethal injection, and not
currently available in the U.S. due to manufacturer objections
2) Oxybarbiturates (phenobarbital, methohexital)
- Lower lipid solubility = less potency, slower onset, longer duration
BUT Methohexital is an exception = more potent and shorter duration of
action than thiopental
Benzodiazepine distribution:
- Lipid soluble drug => fast onset (30 sec) and rapid redistribution (10-20 min) after single dose
- Higher plasma levels in hypovolemia, hypoalbuminemia, acidosis, elderly
- Like other lipophilic drugs we know that multiple doses saturate peripheral compartments and slows down the redistribution process
- Poor choice for the maintenance of anesthesia bc of this phenomenon of saturation of peripheral compartments
Are barbiturates a good or bad choice for the maintenance of anesthesia?
Poor choice for the maintenance of anesthesia bc of this phenomenon of saturation of peripheral compartments
Where are barbiturates metabolized (biotransformed)?
almost completely in the liver via hepatic oxidation
How are barbiturates excreted?
By the kidneys, only after undergoing biotransformation in the liver bc they are typically protein-bound and lipid-soluble (the kidneys prefer to excrete only water-soluble and non-protein-bound drugs)
Elimination half-life of barbiturates?
Range between 3-12 hrs
The usual dose of Methohexital =
Methohexital: 1-1.5 mg/kg
Barbiturate effect on the cardiovascular system:
- ↓BP
- ↑HR (central vagolytic effect causes them to become tachy)
- venous pooling
- CO maintained except in hypovolemia, CHF, beta-blockade where CO and BP
can drop
Barbiturate effect on the Respiratory system:
- ↓hypoxic/hypercapnic drive
- experience airway obstruction
- INCREASED risk of bronchospasm/laryngospasm
Barbiturate effect on the Neuro system:
↓CBF,
↓ICP
↓↓ CMRO2 to the point where you can achieve burst suppression on EEG
(protective against hypoxia and ischemia?);
- DEFINITELY Anti-epileptic
- Can develop tolerance/dependence on them
- Maybe Anti-analgesic?
- With Methohexital we see neuro excitation symptoms (myoclonus, hiccoughs, seizures?)
- ———> Common drug of choice for electroconvulsive therapy (ECT)
Barbiturate effect on the Renal system:
Decrease renal blood flow (RBF) due to hypotension
Barbiturate effect on the Hepatic system:
↓Hepatic blood flow (HBF);
- Lead to induction of enzymes Cytochrome P450 (CYP)
- Can cause porphyrin formation which causes PORPHYRIA
Disorder of enzyme in the heme bio-synthetic pathway
Acute porphyria: overproduction and accumulation
Neuro: Abd pain, vomiting, neuropathy, weakness, seizures, hallucinations, depression, anxiety,
paranoia
Cardiac arrhythmias, pain, constipation /diarrhea
Barbiturate effect on the Hepatic system:
↓Hepatic blood flow (HBF);
- Lead to induction of enzymes Cytochrome P450 (CYP)
- Can cause porphyrin formation which causes PORPHYRIA
Disorder of enzyme in the heme bio-synthetic pathway
Acute porphyria: overproduction and accumulation
Pts may present with Neuro: Abd pain, vomiting, neuropathy, weakness,
seizures, hallucinations, depression, anxiety,
paranoia
Cardiac arrhythmias, pain, constipation /diarrhea
Is it ok to give barbiturates to pts with porphyria?
NO.
Porphyria is a rare disorder of enzyme in the heme bio-synthetic pathway
Acute porphyria: overproduction and accumulation
Pts may present with Neuro: Abd pain, vomiting, neuropathy, weakness,
seizures, hallucinations, depression, anxiety,
paranoia
Cardiac arrhythmias, pain, constipation /diarrhea
Sulfur-containing (thio-) barbiturates may evoke ________ release.
histamine
Etomidate mechanism of action
It depresses the brain stem’s Reticular activating system (consciousness center) & mimics GABA
Etomidate side effects
Myoclonus -> but it can be attenuated with some premedication of
benzodiazepines or opioids
Burning on injection -> bc its dissolved in propylene glycol
Etomidate solubility
Highly lipid soluble -> rapid redistribution
Highly protein bound
Where does Etomidate undergo biotransformation (metabolism)?
Liver via
1) hepatic hydrolysis
2) plasma esterases in blood
Biotransformation is impaired in severe liver disease pts of the decreased hepatic activity but also the decreased hepatic generation of the plasma esterases
Where is Etomidate excreted?
Kidney
Etomidate induction dose
0.2-0.3 mg/kg
Etomidate CV effects
- minimal effects
- first-line induction agent in unstable patients, trauma cases
Remember: nothing is “safe” in critically ill patients!
Effects of Etomidate on the Respiratory System:
minimal effect
Effects of Etomidate on the Neuro System:
- ↓CMRO2
- ↓CBF
- ↓ ICP
- myoclonus;
- enhances SSEP amplitude
- Anti-epileptic, but seizure-like EEG signals in epileptic patients seen (no motor
activity though) - May increase incidence of PONV
Effect of Etomidate on adrenals
- INHIBITS cortisol & aldosterone synthesis -> causing adrenal insufficiency
Can occur even after single dose
Shown to be associated with prolonged hospital stay, ICU stay, or on
ventilator
Subject of ongoing debate
Notable Etomidate drug interactions
Etomidate + fentanyl can increase Etomidate levels and prolong its action
Ketamine mechanism of action
Inhibitory + excitatory action
NMDA antagonist
Induces a form of dissociative amnesia
Dissociates the thalamus from limbic cortex =» “cataleptic state”
Pts experience profound amnesia / analgesia despite maintaining consciousness and protective reflexes
Related to Phencyclidine (PCP) ===> so it causes hallucinations
Ketamine solubility
Water-soluble preparation
Ketamine administration is via
IV
IM
Ketamine Distribution
= Rapid uptake and redistribution
Ketamine Biotransformation:
liver metabolism
high hepatic extraction (hepatic blood flow dependent)
some active metabolites
Ketamine Excretion:
Kidney
Ketamine Dose for Analgesia
Analgesia: 0.1 – 0.5 mg/kg IV
Ketamine dose for Induction
IV = 1-2 mg/kg
IM = 4-8 mg/kg
Ketamine infusion
Mixed with Propofol infusion –
Ex: 1 mg ketamine per 10 mg propofol
Ketamine Effects on CV:
↑ HR
↑ BP
↑ CO (partially by inhibiting NorEpi reuptake)
Ketamine effect on respiratory system
- bronchodilator
- ↑ salivation
- minimal effect on ventilation
Ketamine effect on Neuro system
↑CMRO2
↑ CBF
↑ ICP (at high doses)
- enhances SSEP amplitude (like etomidate)
- Hallucinations and nightmares (minimized with benzodiazepine premedication)
- Analgesia (for both acute & chronic pain)
- Amnesia
- May cause myoclonus (but probably anti-epileptic)
- Infusions have been used for the treatment of chronic pain syndromes and some psychiatric disorders like refractory depression
Name some common Benzodiazepines:
- Lorazepam (Ativan)
- Diazepam (Valium)
- Midazolam (Versed)
- Flumazenil (Romazicon)
Benzodiazepine mechanism of action
Enhance (GABA) inhibitory neurotransmitters in the cerebral cortex
Benzodiazepine absorption
IV/IM, PO, nasally, SL; IV required for GA induction (poor choice)
Distribution of benzodiazepine
moderately lipid soluble (except diazepam),
rapid redistribution
protein bound
Clinical onset of Midazolam
Onset in 30-60 seconds, but peak effect ~5 minutes – space doses appropriately when trying to sedate a pt
Duration of Midazolam effect
15-80 minutes
Benzodiazepam biotransformation occurs where?
Liver via (CYP3A4)
Dose (Midazolam):
o Premedication: 0.04 – 0.08 mg/kg IV/IM; 0.4-0.8 mg/kg PO
o Induction: 0.1-0.3 mg/kg IV (slow recovery! (not done routinely)
o Infusion: 0.02 – 0.1 mg/kg/hr
Use LESS (or AVOID) in elderly patients
Benzodiazepine effect on CV system
minimal depression
Benzodiazepine effect on Respiratory system
small decrease in hypercapnic drive esp. w/ other meds
Benzodiazepine effect on Neuro system
↓CMRO2
↓ CBF
↓ ICP but less than barbiturates;
- No burst suppression
Anterograde amnesia,
****anxiolysis;
****anti-seizure
- muscle relaxation (not to the point of paralysis but maybe useful for muscle
spasm
**Synergy with volatiles, opioids, ethanol, barbiturates, CNS depressants
- Dependence: onset of physical or psychological symptoms after reduction in dose
- Withdrawal symptoms: irritability, tremulousness, insomnia, HTN, tachycardia
**———Withdrawal can even be fatal if the dependence is high enough and the withdrawal fast enough
Can one become dependent on Benzodiazepines?
Yes.
If you’re dependent and you start decreasing the dose, some physical or psychological symptoms start occuring
- Withdrawal symptoms: irritability, tremulousness, insomnia, HTN, tachycardia
———Withdrawal can even be fatal if the dependence is high enough and the withdrawal fast enough
Flumazenil
Its a benzodiazepine drug that competitively antagonizes benzodiazepine agonist receptors with high affintity.
Its the reversal agent we use for benzo overdose.
Dose:
0.01 mg/kg up to 0.2 mg IV bolus, repeat q1 minute up to 5 doses (1 mg max dose)
Redose at 20 minute intervals as needed
**Can cause withdrawal symptoms in chronically dependent patients
No effect on MAC of volatile anesthetics
Dexmedetomidine (Precedex) mechanism of action
Highly selective alpha-2 receptor agonist
– similar to Clonidine but even more α2 specific
Dexmedetomidine (Precedex) use
sedation of ventilated ICU patients
OR: anxiolysis, MAC, anesthesia adjuvant, awake intubations
Dexmedetomidine (Precedex) dose
0.2 – 0.7 mcg/kg/hr
