Pharmacologic Induction Agents

Question 1

What’s behind Propofol infusion syndrome?

Answer 1

Propofol infusion syndrome is due to mitochondrial dysfunction and inability to process fatty acids, not an allergic reaction

Question 2

Propofol is made from egg yolks, but the allergy most people have to eggs is to:

Answer 2

Is to the egg whites

Question 3

Propofol and why it causes hypotension:

Answer 3

Propofol can be thought of primarily as an afterload reducer (decreased svr), but also affects preload (decreased LVEDV) and contractility (decreased SV). Propofol affects the baroreceptor response to hypotension as well. Recall that the baroreceptors decrease their rate of firing in response to hypotension, therefore decreasing sympathetic inhibition,

Question 4

Propofol and why it goes away after a bonus be infusion

Answer 4

Propofol is a potent respiratory depressant and its short clinical half-life after large bolus is (more) due to redistribution, not metabolism (although it IS quickly metabolized as well). Therefore, a preexisting infusion of propofol, even at levels where apnea is not produced, will still have a great effect on apnea time following large bolus since redistribution is limited. In other words, by occupying the tissues with a baseline infusion of propofol, redistribution of a large bolus is limited and apneic time may start to depend on metabolism

Question 5

What helps prevent etomidate induced myoclonus? Is it a seizure?

Answer 5

Pretreatment with opioids decrease etomidate associated myoclonus, which is distinctly not a seizure. Myoclonus and seizure can be difficult to distinguish when a history of epilepsy is present. Antiseizure medications (per se) are not useful in preventing myoclonus (Phenobarbital, Diazepam, & Phenytoin) as this is not a seizure. Lidocaine can decrease the burning pain associated with etomidate administration (due to the propylene glycol solvent). Both opioids and benzodiazepines have been shown to reduce the incidence of myoclonus, with probably equal efficacy.

Question 6

Why is etomidate bad? What are the good things about it?

Answer 6

Bad-adrenal suppression. Etomidate is an otherwise near ideal induction agent for ICU intubation because it has fewer cardiovascular effects than other drugs and one can maintain spontaneous ventilation in most cases to avoid muscle relaxation. As an aside, jaw clenching and myotonic movements can make intubation without muscle relaxation challenging and get the staff riled up (misinterpretation of seizure). Alternatives to etomidate for spontaneous ventilating intubation in the ICU include carefully titrated propofol, versed, and my favourite ketamine.

Question 7

After a single dose of etomidate, adrenal suppression predictably occurs in all patients (T/F)

Answer 7

True! It doesn’t decrease avr as much as Propofol though.

Question 8

Ketamine and myocardial depression:

Answer 8

Ketamine activates the sympathetic nervous system leading to increased heart rate, cardiac output, stroke volume, etc in most patients. This is because the up-regulation of the sympathetic nervous system masks the direct myocardial depression associated with large doses of ketamine. With severe CHF the sympathetic nervous system is often already nearly fully ramped up, especially with compounded stress (bowel obstruction with associated dehydration). In these cases the small increase in sympathetic activation possible is far outweighed by the direct myocardial depression, as was this case. Tachycardia is seen with ketamine, not bradycardia or heart block. Ventilatory drive is well preserved with ketamine. Also note than pretty much the only patients in heart failure that have cardiovascular collapse to ketamine exist only on the boards…so read between the lines for my opinion as far as how “dangerous” the direct myocardial depressant effects are.

Question 9

What can be administered to prevent nightmarish effects of ketamine:

Answer 9

A benzo

Question 10

11 graph

Answer 10

Efficacy and potency of drugs

Question 11

Intercompartmental clearance is a fancy word for:

What does that mean for lipophilic drugs?

Answer 11

redistribution from the central compartment to the peripheral compartments
Since peripheral compartments are less vascular (more lipid) than the central compartment, lipophilic drugs will distribute more to these compartments than a hydrophilic drug.

Question 12

Volume of distribution (Vd) is

Answer 12

drug amount (dose) divided by concentration. Memorize this (Vd = dose/ concentration)

Question 13

Hydrophilic drugs and their volume of distribution:

Answer 13

A hydrophilic drug (irrespective of whether or not its hepatically cleared) will tend to have a small peripheral volume of distribution (as compared to a less hydrophilic drug). Therefore it will have a small overall volume of distribution because the peripheral volume of distribution is small.

Question 14

Zero vs first order kinetics and what they would look like on a graph-and even a logarithmic one

Answer 14

With zero order kinetics (as related to clearance), a constant amount of drug is cleared per minute (such as ethanol). With first order kinetics a constant proportion is cleared per minute (or whatever time period you chose). Therefore a graph showing zero order kinetics will be linear and first order geometric, like this: http://curriculum.toxicology.wikispaces.net/1.1.1.5+Clearance. Note that if plotted on a logarithmic scale, the first order kinetics would appear linear (but the ABA would never do that right?..yes that was sarcasm, they very well might!).

Question 15

A drug that is highly protein-bound to alpha-1-glycoprotein is administered to a patient with greatly decreased levels of alpha-1-glycoprotein. Compared to a patient with normal levels of alpha-1-glycoprotein, the drug in this patient will:

A. Be less efficacious
B. Cleared slower
C. Have a greater ED50
D. Be more potent

Answer 15

D: Be more potent

Protein bound drugs are bound to proteins in proportion to how many binding sites are available. Therefore, with a reduction of binding sites (less alpha-1-glycoprotein), a lower proportion of the drug will be bound and a greater proportion will be free. Since a greater amount (concentration) of the unbound, free drug can go on to cause an effect, the potency will increase.

Question 16

The median effective dose (ED50) is the dose that

Answer 16

would cause a given effect in 50% of individuals.

Question 17

GABA-A vs GABA B and G protein coupled receptors

Answer 17

Midazolam is a GABA-A receptor which is a ligand gated ion channel, not a G-protein (although GABA-B is a G-protein coupled). Propofol, barbituates, etomidate, benzodiazepines, ethanol, and possibly volatile anesthetics work via this system (ions flow through and makes the membrane harder to depolarize)

So only GABA a is g coupled

Question 18

Two G protein receptor pathways:

Which drugs use them?

Answer 18

Opioids (Fentanyl), alpha and beta agonists (Epinephrine), serotonin, prostaglandins, histamine cause their effect through G-protein receptors. G-receptors go on to signal one of two pathways (as far as I think you’ll need to know for the anesthesia boards). The first is the G-protein increasing the level of cAMP, which signals protein kinase A (PKA) to cause a cellular effect. Examples of this are beta receptors. Other G-protein receptors will decrease the level of cAMP, such as with alpha-2 & opioids (although by different mechanisms.

The other G-protein mediated signal transduction system is increased activity of phospholipase C, which then cuts up membrane lipids (PIP2, for example) and makes a signal molecule such as inositlol triphosphate (IP3). The IP3 then goes on to signal different cellular processes. An example of this is the alpha-1 receptor. Serotonin and histamine receptor subsets utilize both cAMP signals as well as IP3 signals and don’t bother memorizing the subtypes. G-protein-cAMP-PKA has been often tested and with the basic exam, I think its possible they will expand to IP3 pathway too.

Question 19

Which of the following properties of propofol are false:

A. Baroreceptor reflex response is inhibited
B. It has significant antiemetic effects
C. Pain on injection can be reduced by injecting into a larger vein
D. Bolus injection will decrease preload
E. Has both strong hypnotic and analgesic properties

Answer 19

E: Has both strong hypnotic and analgesic properties

Question 20

Emergence after Propofol dose is primarily due to:
Where is the biggest extrahepatic metabolizer of Propofol?
Does skeletal muscle metabolize Propofol?

Answer 20

Emergence following a bolus dose of propofol is mostly due to redistribution from the central compartment to (vessel rich) peripheral compartments as well as a contribution of hepatic metabolism. Lung metabolism of propofol is the largest extrahepatic site of elimination. Skeletal muscle, as far as I know does not metabolize propofol, but is one of the primary vessel rich organs it will redistribute.

Question 21

As compared to propofol, fospropofol:

A. Has a slower onset
B. Has a quicker recovery
C. Does not cause apnea
D. Is less water soluble

Answer 21

A: Has a slower onset

Hopefully that was an easy one to answer. Fospropofol is a prodrug that has to be metabolized by the liver first to release propofol (and formaldehyde). Because of this extra step fospropofol has a slower onset and recovery. Like, propofol, large doses can cause significant apnea. Fospropofol is water soluble and does not require a lipid emulsion, which has decreased pain on injection.

Question 22

What happens if barbiturates are injected into an artery? What’s the tx?

Answer 22

When barbiturates are injected in an artery (at least on the boards), the artery will spasm with prolonged vasoconstriction which can ultimately lead to limb loss. The treatment is classically stellate ganglion block. There is also a component of crystallization and physical capillary obstruction with barbiturates as well. That being said, a portion of the administered drug will invariably make it to the central circulation and cause the normal effects. One effect is vasodilation (without significant baroreceptor blunting) with a decrease in blood pressure. Barbiturates cause respiratory depression and apnea as well. Neurologically, barbiturates are the gold standard for decreasing brain oxygen consumption (CMRO2), cerebral blood flow (CBF), and intracranial pressure (ICP). A classic board worthy piece of dogma is that barbiturates decrease the tolerance to pain (antianalgesic properties), which in real life is questionable.

Question 23

Which of the following do not have active metabolites:

A. Midazolam
B. Morphine
C. Meperidine
D. Ketamine
E. Propofol

Answer 23

E

Morphine is metabolized to morphine-6-gluconoride (you need to know this one) and is a major contributor to mu-receptor mediated respiratory depression (I hope your taking notes…something in this explanation is bound to be on your exam). Meperidine is metabolized to normeperidine, which in the setting of high levels (secondary to renal failure for example) can lead to seizures and CNS stimulation. Ketamine is metabolized to norketamine, which is far less potent and not very important. Propofol probably does not have active metabolites. If Fospropofol was listed, then its active metabolite would be propofol.

Question 24

Which of the following do not posses antiemetic activity:

A. Propofol
B. Midazolam
C. Etomidate
D. Droperidol

Answer 24

C: Etomidate

Propofol possesses antiemetic properties. Propofol based TIVA can decrease the incidence of post-operative nausea and vomiting (PONV) as compared to techniques utilizing high dose opioids or volatile anesthetics. Propofol can also be used to actually treat PONV as well. Droperidol is also a very effective antiemetic and its sedative and hypotensive effects are typically mild at low doses. Ondansatron and other serotonin receptor blockers as well as dexamethasone are effective drugs as well. Midazolam is a weak antiemetic, and its mechanism is likely indirect involving dopamine. Etomidate is very pro-emetic, and of the commonly used induction agents the most likely to result in PONV (far more than ketamine or barbituates).

Question 25

Which of the following is most likely to lead to a decrease in intraocular pressure:

A. 1 mg/ kg Rocuronium
B. 1 mg/ kg Succinylcholine
C. 2 mg/kg Ketamine
D. 1 MAC Desfulurane
E. 0.2 mg atropine

Answer 25

D: 1 MAC Desfulurane

Of the above choices, only volatile agents would be expected to lead to a decrease in intraocular pressure. This is likely due to decreased arterial and venous pressures (maybe especially venous?) as well as muscle relaxation (of extraocular muscles), decreased CNS outflow, and possibly decreased aqueous humor production