Introduction to CRNA School Pharmacology: Anesthesia Induction Medications

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 Introduction to CRNA School Pharmacology: Anesthesia Induction Medications

Induction Agents

Barbiturates (Derivatives of Barbituric Acid)

  • Thiopental (Pentothal)
  • Methohexital (Brevital)

 

Other Induction Agents

  • Propofol (Diprivan)
  • Etomidate (Amidate)
  • Ketamine (Ketalar)
  • Dexmedetomidine (Precedex)

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Barbiturates

  • Barbiturates are central nervous system (CNS) depressants, therefore they can produce a wide spectrum of effects, from mild sedation to general anesthesia. Two examples of barbiturates are Thiopental (Pentothal) and Methohexital (Brevital). They contain very weak analgesic properties, which makes them a poor choice for pain control.
  • Barbiturates have now largely been replaced by benzodiazepines (Midazolam, Lorazepam, Diazepam) in routine medical practice – for example in the treatment of anxiety, post traumatic stress syndrome (PTSD), and insomnia. They are still routinely used in the operating room, by CRNAs and anesthesiologist, to induce the patient and attain safe intubating conditions.

 

Chemistry

  • Barbituric acid was first created in November 27, 1864 by a German chemist named Adolf Von Baeyer. They are synthesized using urea and malonic acid. Barbituric acid does not have any sedation properties by itself. It is the side chains that give them sedative effects.

 

Uses of Barbiturates

  • Induction of anesthesia
  • Treatment of epilepsy
  • Treatment of acute migraines
  • Neurovascular anesthesia

 

CNS Effects of Barbiturates:

  • Barbiturates produce burst suppression, which reduces brain activity and metabolic needs. The decrease in the cerebral metabolic oxygen requirements (CMRO2) leads to a decreased cerebral blood flow, and thus reduces intracranial pressure. This effect on brain activity makes them “neuro-protective”, which is useful when you are intentionally interrupting circulation to the brain (i.e cerebral aneurysm clipping). Burst suppression stops 55% of the energy used by the brain during nerve to nerve communication. 40% of the brain’s metabolic activity is to maintain itself. (only hypothermia will depress this activity).

 

 Cardiovascular Effects of Barbiturates:

  • All intravenous barbiturates cause direct myocardial depression, and can also lead to a mild drop in mean arterial pressure (MAP). An exaggerated drop in blood pressure is seen with administration of barbiturates to patients with congestive heart failure (CHF), or with severe hypovolemia. This drop in blood pressure can lead to myocardial ischemia. The more antihypertensive medications a patient is taking the worse the induction hypotension will be, especially if they are on an ACE inhibitor.
  • No change in systemic vascular resistance (SVR).

 

Respiratory Effects of Barbiturates:

  • All barbiturates cause dose dependent respiratory depression. Chronic obstructive pulmonary disease (COPD) exaggerates the respiratory depressant effects of these medications. Patients receiving these medications will have a decreased responsiveness to carbon dioxide and hypoxia at medullary respiratory centers in the brain. This decreases their drive to breath resulting in decreased tidal volumes (VT) and respiratory rate. Certain barbiturates are also known to cause bronchodilation, especially in patients with reactive airway disease.

 

Metabolism:

  • Barbiturates are metabolized by “zero order metabolism”. This means a constant amount of the drug is cleared. No matter how much drug is being delivered to the liver, only the same amount will be metabolized.
  • Enzyme induction of CYP450 liver enzymes. If people are on barbituric acids for seizures they will have an increase in these liver enzymes, and will need a higher barbiturate dose in order to put them to sleep. Alcohol also induces these enzymes, so heavy drinkers such as alcoholics, will also need to have their barbiturate doses adjusted.

 

Side Effects & Contraindications:

  • Porphyrias – a group of inherited or acquired disorders of certain enzymes in the heme biosynthetic pathway (also called porphryrin pathway). They manifest with either skin problems or with neurological complications. Attacks of the disease can be triggered by drugs such as barbiturates, alcohol, sulfa drugs, hormonal contraception, sedatives and certain antibiotics. Patients with a history of porphyrias should NEVER receive barbiturates. Signs and symptoms of porphyrias include: severe abdominal pain, vomiting, seizures, mental disturbances, depression, anxiety, cardiac arrhythmias and tachycardia, skin discoloration (purple bruising), skeletal muscle weakness, and neuropathy.
  • Accidental Intra-arterial injection – Drug precipitates in the artery causing a severe arterial vasospasm, which can lead to tissue necrosis.

 CRNA School: Inhaled Anesthesia Gases

 

 

Thiopental (Pentothal)

Introduction to CRNA School Pharmacology: Anesthesia Induction Medications

Classification

  • Barbiturate

 

Chemistry

  • Acid pH
  • 9 pKa
  • 7.6
  • 85% protein bound

 

Preparation

  • 2.5% in 20 mL vial (reconstitute with 20mL NS).

 

Dosing of Thiopental

  • Induction: 3-5 mg/kg (adult)
  • Induction: 6-8mg/kg (pediatrics).

 

Mechanism of Action

  • Directly activates the neurotransmitter gamma-aminobutyric acid (GABA).
  • Antagonizes the nicotinic acetylcholine receptors (nACh).

 

Uses of Thiopental

  • Induction of anesthesia.
  • Neurovascular surgery (causes burst suppression).
  • Induction medication of choice during pregnancy.
  • Anti- seizure medication.

 

Central Nervous System Effects of Thiopental

  • Decreases cerebral metabolic oxygen requirements (CMRO2).
  • Decreases intracranial pressure (ICP).
  • Burst suppression
  • Does not effect cerebral autoregulation of blood flow.

 

Cardiovascular Effects of Thiopental

  • Decreases mean arterial pressure by 10-20 mmHg.
  • Hypotension is exacerbated with congestive heart failure (CHF) or severe hypovolemia.
  • Increased heart rate.
  • Histamine release causes vasodilation and reflex tachycardia.

 

Respiratory Effects of Thiopental

  • Histamine release (avoid in patients with reactive airway disease).
  • Bronchodilator Respiratory depression that is exacerbated with COPD.
  • Decreased carbon dioxide (CO2) responsiveness (direct medullary ventilatory depressant).

 

Side Effects & Contraindications

  • Contraindicated in patients with reactive airway disease, history of porphyrias, hypovolemia and intolerance to tachycardia.
  • Intra-arterial injection causes arterial vasopasms and intense pain. Treatment: leave needle in artery, dilute with normal saline, consider lidocaine, heparin, papaverine or phenoxybenzamine.
  • Can precipitate so avoid mixing with acidic solutions (ie Lactated Ringers).

 

 

 

 

 Methohexital (Brevital)

Introduction to CRNA School Pharmacology: Anesthesia Induction Medications

Classification

  • Barbiturate

 

Chemistry

  • Acid
  • pKa 7.9
  • 85% protein bound

 

Preparation

  • 1% (10mg/ml)
  • 2% (20mg/ml)

 

Dosing of Methohexital

  • Induction: 1.5 mg/kg

 

Mechanism of Action

  • Directly activates the neurotransmitter gamma-aminobutyric acid (GABA).

 

Uses of Methohexital

  • Seizure mapping
  • Cardioversion

 

Central Nervous System Effects of Methohexital

  • Decreases cerebral metabolic oxygen requirements (CMRO2).
  • Decreases intracranial pressure (ICP).
  • Burst suppression
  • Eliptogenic at low doses.
  • Anti-seizure at high doses.
  • Myoclonus

 

Cardiovascular Effects of Methohexital

  • Decreases mean arterial pressure by 10-20 mmHg.
  • Hypotension is exacerbated in patients with congestive heart failure (CHF) or severe hypovolemia.
  • Increased heart rate.
  • No histamine effects.

 

Respiratory Effects of Methohexital

  • Bronchodilator
  • Not as good as propofol for blunting laryngeal/tracheal reflexes.
  • Hiccups at low doses.
  • Decreased carbon dioxide (CO2) responsiveness.

 

Side Effects & Contraindications

  • Patients with a history of porphyrias.
  • Patients on Coumadin (competition for protein binding sites).
  • Intra-arterial injection causes arterial vasopasms and intense pain. Treatment: leave needle in artery, dilute with normal saline, consider lidocaine, heparin, papaverine or phenoxybenzamine.
  • May precipitate so avoid mixing with acidic solutions (ie Lactated Ringers).

 

 

 

Propofol (Diprivan)

Introduction to CRNA School Pharmacology: Anesthesia Induction Medications

 

Classification

  • Sedative/Hypnotic

 

Chemistry

  • Weak acid pKa = 11
  • 98% non-ionized at physiologic pH
  • No steroisomers (achiral)

 

Preparation

  • 10 mg/cc (20cc vial standard)
  • 1% lipid solution

 

Dosing of Propofol

  • Induction: 2 mg/kg IV (loss of consciousness in about 30 seconds).
  • Sedation: 25 – 100 mcg/kg/min.
  • TIVA (Total Intravenous Anesthesia): 100 – 300 mcg/kg/min.
  • Treatment of nausea: 1-2 mcg/kg/min.

 

Mechanism of Action

  • Primarily decreases the rate of dissociation of gamma-aminobutyric acid (GABA) away from the receptor. This increases the duration of action by holding open the chloride ion channels.

 

Uses of Propofol

  • IV induction of anesthesia, IV sedation and TIVA.
  • Treats pruritis (itching) caused by spinal opioid administration (mechanism of action is unclear).
  • Potent cerebral vasoconstrictor (used to treat intractable migraines).
  • Less postoperative nausea and vomiting than any other induction medication.
  • Causes pain with IV pushes – reduce pain by administering 1-2% lidocaine prior to giving propofol.

 

Metabolism

  • High hepatic clearance. Extra hepatic metabolism (lungs/kidneys).
  • Phase ll conjugation.

 

Kinetics

  • Elimination half-life 0.5 to 1.5 hours
  • Protein binding = 98%
  • Context Sensitive Half-Time <40 minutes with up to 8 hours of infusion.
  • Accumulates with long therapy.
  • Rapid redistribution. High liver metabolism.

 

Cardiovascular Effects of Propofol

  • Dose dependent myocardial depression.
  • Drops blood pressure more than any of our other induction agents. This is caused by its ability to relax vascular smooth muscle.
  • Negative inotrope (decreased heart contractility) – inhibits calcium influx resulting in less calcium available for muscle contraction.
  • Blunts SNS/baroreceptor reflex – When the blood pressure drops the sympathetic nervous system is unable to respond by increasing heart rate. There is an exaggerated blood pressure drop in conditions involving hypovolemia. Preloading the patient with intravenous fluids will help prevent this from happening.

 

Respiratory Effects of Propofol

  • Profoundly blunts the laryngeal reflexes (more than any other induction agent).
  • Dose dependent respiratory depression – A decrease in tidal volume and respiratory rate happens within 30-60 seconds.
  • Propofol also decreases responsiveness to hypoxemia and carbon dioxide.

 

Side Effects & Contraindications

  • “Propofol Infusion Syndrome” – propofol interferes with a transmembrane protein that takes lipids into the mitochondria. In stress states, glycogen stores are depleted and lipids are then used for energy. This originally occurred in ICUs with high doses (>4 mg/kg/hr) and prolonged infusions. Signs and symptoms include: sudden onset of bradycardia that is resistant to treatment (atropine), which can then progresses to asystole. Critically ill adults with head injuries receiving long term (> 58 hours), high dose infusions (5 mg/kg/hr) tend to develop: lipidemia, fatty infiltrates of the liver, enlarged liver, metabolic acidosis, rhabdomyolysis, myoglobinuria.

 

 

 

Etomidate (Amidate)

Introduction to CRNA School Pharmacology: Anesthesia Induction Medications

Classification

  • Carboxylated imidazole

 

Chemistry

  • Base
  • pH = 6.9
  • pKa = 4.2 D-isomer (the only pharmacologically active isomer).
  • Protein Binding 75%.

 

Preparation

  • 0.2% solution (2mg/ml)

 

Dosing of Etomidate

  • Adult dose: 0.3 mg/kg.

 

Metabolism

  • High extraction ratio.
  • Hydrolysis Prolonged in liver disease.

 

Kinetics

  • Extremely high volume of distribution (Vd).
  • Effect site equilibration (onset) = 1 minute.
  • Elimination ½ life = 2 – 5 hours.
  • High extraction ratio (cleared quick).

 

Mechanism of Action

  • Potentiates gamma-aminobutyric acid (GABA). It does not mimic GABA – has to have GABA present to work.

 

Uses of Etomidate

  • Induction of anesthesia in a hemodynamically compromised patient. (Cardiac stable – doesn’t blunt the baroreceptor reflex).
  • Used during seizure mapping.

 

Central Nervous System Effects of Etomidate

  • Dose-dependent CNS depression.
  • Decreased cerebral blood flow (CBF).
  • Decreased cerebral metabolic oxygen requirements (CMRO2).
  • Decreased intracranial pressure (ICP).
  • Uncoupling effect – etomidate can decreases cerebral blood flow more than it decreases cerebral metabolic oxygen requirements. This can lead to inadequate oxygen delivery to the brain. Etomidate is still used in neurosurgery, because it doesn’t drop the blood pressure like the other drugs. This is beneficial because it keeps the mean arterial pressure (MAP) stable, so you still have an adequate perfusion pressure (PP).

 

Cardiovascular Effects of Etomidate

  • Cardiac stable – minimal changes to heart rate, stroke volume (SV), or cardiac output (CO).
  • Small drop in blood pressure from decreased systemic vascular resistance (SVR).
  • No histamine release.

 

Respiratory Effects of Etomidate

  • Less respiratory depression than other induction medications.
  • Stimulates the medullary carbon dioxide (CO2) center in the brain causing increased tidal volume (VT) and a decreased respiratory rate.
  • Inhibits pulmonary hypoxic vasoconstriction.

 

Side Effects & Contraindications

  • Porphyria (contraindicated in patients with history of porphyrias).
  • Myoclonus (can cause sudden involuntary jerking of the muscles).
  • Adrenocortical Suppression – dose dependent inhibition of the enzyme 11-B-Hydroxylase that converts cholesterol to cortisol. Suppresses the ability of the patient to have a stress response via cortisol. This suppression lasts 4 – 8 hours, and is contraindication for use in the ICU.

 

 

 

 

Ketamine (Ketalar)

Introduction to CRNA School Pharmacology: Anesthesia Induction Medications

Classification

  • Arylcyclohexylamine

 

Chemistry

  • Base
  • Phencyclidine derivative (close cousin of PCP)
  • pH = 4.5
  • pKa = 7.5
  • Racemic mixture (S-isomer is better, however not available in the United States)
  • Protein Binding = 12% (Very lipid soluble)

 

Preparation

  • 1% (10mg/ml)
  • 5% (50mg/ml)
  • 10% (100mg/ml)  solution.

 

Dosing of Ketamine

  • Adult induction dose: 1.5 mg/kg IV (onset is about 1 minute).
  • Intense analgesia: 0.2-0.5 mg/kg.
  • Intramuscular (IM) dose: 4-8 mg/kg IM .

 

Metabolism

  • Creates an active metabolite (Nor-ketamine).
  • Autoinducer of CYP 450 liver enzymes.
  • Tachyphylaxis with routine administration.

 

Kinetics

  • High clearance (low protein bound).
  • Elimination half time 2 hours.

 

Mechanism of Action

  • N-methyl-D-aspartate receptor (NMDA) antagonist.
  • Causes dissociative anesthesia by depressing the neuronal communication between the cortex and the thalamus. At the same time it stimulates the limbic system. This results in the patient appearing to be awake while staring off into space.
  • Analgesic effects are a result of activation of opioid receptors and subcortical neurons in the spinal tract.

 

Uses of Ketamine

  • Dissociative anesthesia Ketamine is being used more and more with hip and large open spine procedures.
  • If spinal anesthesia is not strong enough, you can augment it with IV ketamine.
  • Intramuscular dose can be administered if you have a combative patient.

 

Central Nervous System Effects of Ketamine

  • Increases cerebral blood flow (CBF).
  • Increases cerebral metabolic oxygen requirements (CMRO2).
  • Increases intracranial pressure (ICP).
  • Delirium Augments neuromuscular blockade (NMB).

 

Cardiovascular Effects of Ketamine

  • Increased systemic vascular resistance (SVR).
  • Increased heart rate. Increased cardiac output (CO).
  • Increased sympathetic nervous system (SNS) outflow.
  • Myocardial depressant in patients who are catecholamine depleted (cocaine users, methamphetamine users, and people taking MAOIs).

 

Respiratory Effects of Ketamine

  • Little respiratory depression (least of all induction drugs).
  • Bronchodilaor – can treat status asthmaticus.
  • Salagog (increased salivary secretions).
  • Keeps airway tone intact (pharyngeal and Laryngeal reflexes are not effected).

 

Side Effects & Contraindications

  • Hallucinations: administer a benzodiazepines at the end of procedure. Versed helps limit the patient’s recall of the hallucinations.
  • Research has shown that ketamine causes an increase in programmed cell death. There is concern that this may cause learning disabilities in children.

 

 

 

 

Dexmedetomidine (Precedex)

Introduction to CRNA School Pharmacology: Anesthesia Induction Medications

Classification

  • Alpha-2 agonist

 

Chemistry

  • Base
  • pKa = 7.1
  • Protein Binding = 94%.

 

Preparation

  • Supplied in 2 cc vials (100mcg/cc)
  • Mix vial (200 mcg) with 48cc Normal Saline = 4 mcg/cc.

 

Dosing of Dexmedetomidine

  • Loading dose: 1 mcg/kg over 10 minutes. (If given to quickly can cause hypertension)
  • Infusion: 0.2 – 0.7 mcg/kg/hr

 

Kinetics

  • Onset: 5 min
  • Peak: 15 min

 

Mechanism of Action

  • Stimulation of alpha-2 receptors causing pre-synaptic inhibition.
  • Activation of the alpha-2 receptors results in an inhibition of cyclic adenosine monophosphate (cAMP), potassium efflux, and calcium voltage channels. This causes a hyperpolarization of the cells in the Locus Ceruleus, which is normally responsible for wake/sleep patterns in human. This results in a much more natural sleep, which is beneficial for patients in the intensive care unit (ICU).

 

Uses of Dexmedetomidine

  • Not an induction medication for general anesthesia.
  • ICU Sedation
  • Cardiovascular surgery
  • Spinal analgesia pain relief – presynaptic inhibition of substance P.

 

Central Nervous System Effects of Dexmedetomidine

  • Cerebral vasoconstrictor.
  • No change in cerebral metabolic oxygen requirements (CMRO2).
  • Doesn’t effect carbon dioxide autoregulation.
  • Sedation – more natural sleep.
  • Neuroprotective
  • No amnestic properties.

 

 

Cardiovascular Effects of Dexmedetomidine

  • Hypotension
  • Hypertension if administered too quickly (caused by alpha-2 vasoconstriction in the periphery).
  • Decreased systemic vascular resistance (SVR).
  • Decreased cardiac output (CO).
  • Bradycardia (can be severe).
  • Decreased sympathetic nervous system outflow (SNS).

 

Respiratory Effects of Dexmedetomidine

  • Minimal respiratory depression (least of all the induction drugs).
  • Initially you will see a brief decrease in tidal volume (VT) and respiratory rate.
  • Great choice for morbidly obese patients.

 

Side Effects & Contraindications

  • Antisalagogue – (dry mouth is a complaint).
  • Widens thermoregulation – (prevents shivering).
  • Not for pregnant patients – seems to cause hypoxia, hyperglycemia, bradycardia in both mothers and babies.
  • Not for spinal anesthesia.
  • Chronic pain patients can become extremely tolerant.

 

 

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