Pharm I - Exam II

Barbiturates are weak ___ with a pKa around 7.9

Acids

Methohexital (Brevital) is used to a limited degree in the US. Both methohexital and thiopental (Pentothal) are categorized as ____ ____ acting barbiturates with a duration of action of about _-_ mins

Ultra short

39-60

Barbiturates may stimulate ____ release from ___ ___ which may affect bronchial tone as well as blood pressure

Histamine ; mast cells

Barbiturates can precipitate and attack of ___ and they are absolutely contraindicated in those identified with the condition

Porphyria

Distribution half-life (also termed …. half-life) represents the time required for half of the drug to …

Alpha

Reach the receptor AKA achieve onset of symptoms

Elimination half-life (also termed ___ half-life) refers to the time required for 50% of the drug to …

Beta

Be metabolized (cleared)

Arrange the following benzodiazepines in order from shortest to longest distribution half-life (alpha half-life): lorazepam, midazolam, diazepam

Lorazepam (Ativan): 4-5 mins*

Midazolam (Versed): 7-15 mins

Diazepam (Valium): 10-15 mins

*this is why we use Ativan for acute seizure activity

Arrange the following benzodiazepines in order from shortest to longest elimination half-life (beta half-life): lorazepam, midazolam, diazepam

Midazolam (Versed): 2-4 hrs*

Lorazepam (Ativan): 10-16 hrs

Diazepam (Valium): 20-50 hrs

*this is why we used versed during induction; it will wear off quickly after we have induced the patient

Reversal agent for benzodiazepines

Flumazenil (Romazicon)

Which FIVE of the following drugs are >90% protein bound? (Diazepam, lorazepam, midazolam, etomidate, Propofol, ketamine, dexmedetomidine, methohexital, thiopental)

Diazepam: 98%

Lorazepam: 90%

Midazolam: 94%

Propofol: 98%

Dexemedetomidine: 94%

For the average 70kg man, list the average volumes for each of the following fluid compartments: plasma, interstitial fluid (IF), ECF, ICF

Plasma: 4L

IF: 10L

ECF (plasma + IF): 14L

ICF: 28L

The extracellular fluid compartment is comprised of which two other fluid compartments? (Plasma, interstitial fluid, or intracellular fluid?)

Plasma + IF

The more lipid soluble a drug, the ___ the volume of distribution

Higher (greater propensity to enter and disperse into the tissues)

A “large” volume of distribution (Vd) is considered to be >_L/kg?

0.6 L/kg

A “small” volume of distribution (Vd) is considered to be <_L/kg?

0.4 L/kg

A drug with a large Vd (>0.6L/kg) is widely distributed in the … and is likely … soluble?

Body (tissues) ; lipid

A drug with a small Vd (<0.4L/kg) is largely contained in the … and is likely … soluble?

Plasma ; water

Formula for volume of distribution

Vd = (amount of drug in the body) / (plasma drug concentration)

Note the range of CNS effects, peak CNS effects, and especially where the Propofol begins to leave the vital organs group for the fat group. (AKA: why does the patient wake up around 8 mins after a Propofol Bolus?)

Redistribution to the fat group removes Propofol from the CNS (vessel-rich group)

The top of the therapeutic range (5mcg/mL) on this graph represents … half-life. Why?

Distribution (alpha) half-life (per Jess)

Alpha half-life = time required to reach the receptor

What patient response occurs at the two vertical lines drawn over this graph?

End LOC (patient starts to wake up)

Takeaway: a standard 2mg/kg of Propofol gives you about 7-8 minutes of unconsciousness for intubation

Protein binding >__% is considered significant?

90

Albumin has a … charge and preferentially binds to weak … drugs

Negative ; acid

Alpha 1 acid glycoprotein (AAG) preferentially binds to weak … drugs

Base

A drug that is 99% protein bound and 1% free fraction… suddenly, the drug becomes only 97% protein bound with a 3% free fraction. This increases the unbound (active) drug concentration by ___%

300

Four types of patients that are at risk for adverse effects from highly protein bound drugs

Malnourished

Severe liver disease

Severe kidney disease

3rd trimester of pregnancy

… is a very important receptor in the CNS that has inhibitory effects when agonized

GABA-A

The GABA-A receptor is comprised of which three subunits?

Alpha, beta, gamma

Which ion channel is present on GABA-A receptors and how does it affect the target cell?

Cl- ; when agonized, the Cl- channel on the GABA-A receptor opens and causes in influx of Cl- into the cell, hyperpolarizing it and preventing excitatory stimulation

… is the principal inhibitory neurotransmitter in the CNS

GABA

… is the principal excitatory neurotransmitter in the CNS

Glutamate

NMDA receptors are activated by the agonist … and co-agonist … when voltage changes displace Mg2+ from the ion channel pore

Glutamate ; glycine

Ketamine is an antagonist to which neurotransmitter?

Glutamate

Which two ion channels are present on the NMDA receptor and what effect do they have on the target cell when activated by glutamate?

Na+ and Ca2+ ; activation of the NMDA receptor by glutamate opens these ion channels, causing an influx of Na+ and Ca2+, depolarizing the cells

Ketamine acts on NMDA receptors primarily by a … … mechanism

Pore-blocking

Ketamine … the NMDA receptor

ANTAGONIZES

Benzodiazepine are … agonists that enhance the effectiveness of GABA

Allosteric

Benzos, Propofol, and etomidate are all … mimetic

GABA

Which of the following is NOT an agonist?: benzos, Propofol, etomidate, ketamine, and dexmedetomidine

Ketamine (NMDA antagonist)

Midazolam only provides … amnesia

Anterograde

Benzos have a sedative effect and an antianxiety effect. With prolonged use, tolerance decreases the patient’s sensitivity to which one of these effects?

Sedative effects (They will still get the anxiolytic property but might not feel as sleepy)

Which GABA-mimetic drug class is used for its hypnotic sleep properties and lacks several pharmacological properties of benzos. What are some examples of this drug class?

Non-benzodiazepine receptor agonists (NBRAs)

Zolpidem (Ambien), Eszopiclone (lunesta), zaleplon (sonata), zopiclone (Imovane)

Z drugs (NBRAs) are selective enough to only act on the alpha … subunit of the GABA receptor. This allows z drugs to produce sleep without relieving … or producing … …

Alpha 1

Anxiety ; muscle relaxation

Chemically, Z drugs are NOT … but they do act on benzodiazepine receptors

Benzodiazepines

GABA-A subunit alpha 1 causes

Sedation

GABA-A subunit alpha 2 and subunit alpha 3 cause

Muscle relaxation and anxiolysis

GABA-A subunit alpha 5 causes

Cognitive effects

All of the following drugs are weak bases EXCEPT…

(Valium, Ativan, versed, etomidate, Propofol, ketamine, dexmedetomidine)

Propofol (weak acid)

Which two induction anesthetics are known to cause pain on injection?

Etomidate and Propofol

Lipid-soluble drugs (Propofol) are difficult to get into IV solutions and require … that can be irritable to veins and cause pain on injection

Solvents

Propofol’s high lipid content increases the risk of … … if it is not used within a certain amount of time after being drawn up or spiked?

Bacterial contamination

(6 hours for syringe and 12 hours for bottle w/tubing)

Propofol’s lecithin content was previously believed to cause reactivity in patients with allergies to …, …, and …

Current evidence shown no contraindications to Propofol use in patients with these allergies

Egg, soy, peanut

… is the ONLY drug that is technically classified as an IV anesthetic by the FDA. Most other induction anesthetics are classified as … …

Ketamine ; sedative hypnotics

Induction dose, onset, and duration for etomidate

Induction dose: 0.2-0.3 mg/kg

Onset: <30 seconds

Duration: 5-10 mins

Induction dose, onset, and duration for Propofol

Induction dose: 1-2 or 1-3 mg/kg

Onset: <30 seconds

Duration: 3-8 mins

Induction dose, onset, and duration for Ketamine

Induction dose: 1-2 mg/kg

Onset: 45-120 seconds

Duration: 60-120 mins

Induction dose, onset, duration for dexmedetomidine

Induction dose: 0.5-1 mcg/kg over 10 mins followed by continuous infusion of 0.2-0.7 mcg/kg/hr

Onset: 2-5 mins

Duration: 10-30 mins

The brain has a high metabolic rate and receives approximately ..% of cardiac output

15

…% of the brain’s energy consumption is used to support electro physiologic functions

60

CBF is … correlated with local cerebral metabolism

Directly (“tightly coupled”)

CBF is autoregulate and held constant over a MAP range between … and … mmHg

65-150 mmHg

Beyond doses of _ MAC, direct cerebral vasodilation results in an increase in CBF and cerebral blood volume

1 MAC

Ketamine has what effect on CMR and CBF

Increases both

Barbs, Propofol, ketamine, volatiles, and xenon have neuroprotective efficacy and can reduce … … …

Ischemic cerebral injury

Which anesthetic is associated with regional reductions in blood flow and can exacerbate ischemic brain injury?

Etomidate

In patients with rapidly elevated ICP, … provides the greatest margin of safety and ability to reduce ICP. Care must be taken not to compromise CPP through …

Propofol ; hypotension

… or … … is effective for controlling raised ICP after severe head injury

Mannitol or hypertonic saline

Prophylactic long-term hyperventilation in the first 24 hrs after severe TBI should be avoided because it can compromise …

Cerebral blood flow (can be used acutely for neurological deterioration or in surgery)

WHAT IS THE PRIMARY MECHANISM BY WHICH PROPOFOL CAUSES CV DEPRESSION?

Decreased SVR (through venodilation)

Five mechanisms of anesthetics that cause a decrease in BP

CNS depression

Direct cardiac depression

Decreased SVR

Baroreceptor depression

Hormonal changes (renin?)

Which IV anesthetic has more respiratory depressive side effects, prop or etomidate?

Propofol

Which IV anesthetic maintains airway reflexes, respirations, and is a SIGNIFICANT bronchodilator?

Ketamine

Small doses of IV … at the end of a procedure can help prevent bronchospasm/larygnospasm

Ketamine (d/t bronchodilatory effects)

Overall effect of IV anesthetics on renal and GI function

Transient depression

Etomidate may cause enzyme induction of … and suppress the enzyme …

ALA synthetase (in porphyria)

11-beta hydroxylase (important in the pathway for cortisol and aldosterone production)

Which medication can cause a low APGAR score if administered too soon before delivery?

Propofol

Risk factors for Propofol infusion syndrome (PRIS):

Young age, doses >4-5 mg/kg/hr for >48 hrs, critical illness, high fat/low carb intake, inborn errors of mitochondrial fatty acid oxidation, concomitant catecholamine infusion, steroid administration

S/s of Propofol infusion syndrome (PRIS):

CV: hypotension, wide QRS, bradycardia, VT/VF/asystole

Resp: hypoxia

Renal: AKI, hyperkalemia, green pee

Musc: rhabdomyolysis

Metabolic: hyperthermia, metabolic acidosis

Hepatic: hepatomegaly, transaminitis, steatosis, hypertriglyceridemia, lipidemia

Administering Ketamine is pretty much like giving our patients which two street drugs?

PCP and LSD

Which IV anesthetic will NOT cause the patient to go through the normal stages of anesthesia?

Ketamine (d/t lack of action on the GABA receptor)

Ketamine causes an unconscious and amnestic state referred to as … …

Dissociative anesthesia

Effects of ketamine on the eyes

Nystagmus and increase IOP

Like N2O, Ketamine has an … effect

Analgesic

When giving Ketamine, consider administering a … to prevent emergence delirium, nightmares, and hallucinations

Benzodiazepine (versed)

Ketamine increases salivation and respiratory secretions and might warrant the administration of …

Glycopyrrolate (Robinul)

Ketamine should be administered with caution in patients with:

HTN, angina, CHF, increased ICP/IOP, psychiatric disorders, airway problems? (I guess with secretions? Like CF?)

What are some clinical uses of ketamine in anesthesia practice?

Shock/CV instability

Severe dehydration/hypovolemia

Bronchospasm

Supplement an inadequate block/spinal

Low dose analgesia

Induction

Which IV anesthetic causes sedation that resembles natural sleep?

Dexmedetomidine

Which two IV anesthetics act as mild antiemetics?

Propofol and dexmedetomidine

Where are alpha-2 receptors located?

Presynaptic neurons (served as negative feedback loop for NE to decrease SNS activity)

Vascular smooth muscle (cause vasoconstriction, but to a lesser degree than the sympatholytic effects in the presynaptic neuron)

Mechanism of action of dexmedetomidine

Alpha-2 agonist

Dexmedetomidine prefers … receptors over … receptors

Alpha2 over alpha1

Precedex is a highly selective alpha-2 adrenergic receptor agonist that confers sedative, anxiolytic, analgesic, and sympatholytic properties; importantly, these effects are achieved with little to no observed … …

Respiratory depression

Which has a greater affinity for the alpha-2 receptor, dexmedetomidine or clonidine?

Dexmedetomidine

Which IV anesthetic agent can be added to a nerve block to prolong its duration of efficacy?

Dexmedetomidine

Which IV anesthetic agent can be administered near the end of a case to prevent emergence delirium?

Dexmedetomidine

… can be used as an adjuvant medication in locoregional technique and has been effectively administered as part of peripheral nerve blocks, IV regional analgesia, and central neuraxial anesthesia

Dexmedetomidine

Benefits of using dexmedetomidine with locoregional techniques? (I.e. regional blocks)

Hasten block onset

Prolong block duration

Reduce pain scores

Reduce early postoperative opioid consumption either with neuraxial blocks or peripheral nerve blocks

Dexmedetomidine was shown to cause … with all types of neuraxial routes, peripheral nerve blocks, and transverse abdominis plane block

Bradycardia

Dexmedetomidine can be used to treat/prevent postop shivering, but seems to be no more effective than standard management techniques like … and …

Forced air warming blankets and opioids

(Dex increases cost of care and potentially prolongs the need for monitoring and observation)