PHARMACOLOGY

Antagonists cause a rightward shift in the drug dose-response curve with an increase in the ED₅₀. Maximal response can still be attained with an increase in agonist concentration.
The dose-response curve is shifted to the left when the drug’s affinity for its receptor is increased.
The ratio between the median lethal dose and the median effective dose is called the therapeutic index.

Pharmacokinetics

First order kinetics
Phase II reactions, conjugation or synthetic reactions, involve the placement of a polar “handle” to enhance water solubility and excretion. Phase I reactions include hydrolysis, oxidation, and reduction.
By definition, intravenous administration is associated with 100% bioavailability. Intramuscular and sublingual administration is associated with 60 – 100% bioavailability. Intrathecal administration circumvents the blood-brain barrier but is associated with very low overall bioavailabilit
Remember the acronym ALONE– Atropine, Lidocaine, Oxygen, Naloxone, Epinephrine (and vasopressin). These agents can be given through an endotracheal tube.

Pharmacology related mathematics

Inhalation Anesthetics

General anesthesia is an altered physiological state characterized by reversible loss of consciousness, analgesia of the entire body, amnesia, and some degree of muscle relaxation.
Pharmacokinetics- the study of the relationship between a drug’s dose, tissue concentration, and elapsed time (how a body affects a drug).
Inhalational agents work on GABA receptors.
Pharmacodynamics- the study of drug action, including toxic responses (how a drug affects a body).
Minimum alveolar concentration (MAC) of an inhalational agent is the alveolar concentration that is required to keep 50% of the patients from moving due to surgical stimulus.
MAC of anesthesia gas is similar to the ED₅₀ of an IV anesthetic.
1.3 MAC is the amount needed to keep 99% of patients from moving due to noxious stimuli.
MAC-BAR is the concentration of an inhalational agent that blocks autonomic reflexes (1.7-2 MAC)
MAC-awake is around 0.3-0.5 MAC and is the concentration that would block voluntary reflexes.
Blood: gas partition coefficient describes how soluble an anesthetic agent is in the body and yields a numerical value. So, the higher the blood: gas partition coefficient, the more soluble the agent is in the body, and the slower the induction will be.
Because anesthetic gases are delivered to the body vaporized, uptake is directly dependent on ventilation. In fact, the degree of anesthesia is directly related to alveolar ventilation.
Conversely, in low cardiac output states, uptake of the inhalational agent is increased.
Inhalational agents and succinylcholine are known triggers for malignant hyperthermia.
Factors shown to increase MAC include youth, chronic alcohol abuse, hypernatremia and acute amphetamine, cocaine, or sympathomimetic use.
The actual degree of augmentation of nondepolarizing blockade depends on both the inhalational anesthetic (desflurane > sevoflurane > isoflurane > nitrous oxide) and the muscle relaxant employed (pancuronium > vecuronium > atracurium).
The blood/gas coefficient is the ratio of the amount of the anesthetic gas in each of two phases at equilibrium. Equilibrium is defined as equal partial pressures in the two phases. Therefore, when the partial pressure of nitrous oxide in the alveoli equals the partial pressure in the blood, the amount of nitrous oxide in 1 mL of blood will be 0.47 times the amount in 1 mL of alveolar gas.
3 – 0.4 MAC is associated with awakening from anesthesia and referred to as MAC awake.
Roughly 1.3 MAC of any of the volatile anesthetics has been found to prevent movement in about 95% of patients.
Desflurane, sevoflurane, and isoflurane predominantly reduce MAP via a reduction in systemic vascular resistance (SVR), with the dose-response relationship being least with sevoflurane.

How does an inhalation anesthetic get from the vaporizer to the patient and what factors will affect this process?

One of the first concepts to understand is FGF, or fresh gas flow. The vaporizer and flowmeter settings will determine the FGF.

↑ FGF rate + ↓ breathing system volume + ↓ absorption from the circuit == inspired gas concentration and fresh gas concentration will be closer.

Inspired gas concentration (F_I) is affected by FGF, volume of the circuit, and circuit absorption.

Alveolar gas concentration (F_A) is formed from uptake, ventilation, and concentration effect.

Arterial gas concentration (F_a) results from ventilation/perfusion mismatching.

THE TAKE HOME POINT WITH INHALATIONALS AND SOLUBILITY RELATING TO BLOOD: GAS PARTITION COEFFICIENT IS THIS… THE BRAIN MIRRORS THE LUNGS. MEANING, TO RENDER A PATIENT UNCONSCIOUS REQUIRES A CERTAIN LEVEL OF ANESTHESIA. WE MONITOR THE AMOUNT OF ANESTHESIA BY END-TIDAL CONCENTRATIONS. IF A DRUG OR INHALATIONAL IS MORE SOLUBLE IN BLOOD, IT IS MORE LIKELY TO BE DISSOLVED AND LESS OF THE GAS WILL REACH THE LUNGS. THE MORE SOLUBLE A GAS IS, THE SLOWER IT BUILDS UP IN THE LUNGS AND LONGER IT TAKES TO PRODUCE ANESTHESIA.

Gases

Nitrous oxide
- Only inorganic gas
- Colorless, odorless
- Gas at room temperature, unlike the other gases
- Stimulates sympathetic nervous system
- Increases cerebral blood flow and cerebral blood volume = increased intracranial pressure.
- Increases cerebral oxygen consumption
- Does NOT produce muscle relaxation (like the other gases)
- Contraindications: air embolism, pneumothorax, acute intestinal obstruction, intracranial air, intraocular air bubbles, etc.
- Can increase the tracheal tube cuff pressure
- Avoid in pulmonary hypertension as it increases pulmonary vascular resistance and pulmonary arterial BP.
- 34-35 times more soluble than nitrogen in blood
- Equilibrates with all tissues within 6 hours
- Most likely to cause PONV
- ETCO₂ decreases when N₂O is turned off because the gas rushes into the alveoli and dilutes the CO₂ (Fick’s law)
- After 2.5 hours of steady nitrous oxide delivery, all tissues have equalized.
- Nitrous oxide increases respiratory rate and decreases tidal volume resulting in little change in minute ventilation or PaCO2. Hypoxic drive is markedly depressed by even small amounts of nitrous oxide.
- Despite a direct depressant effect on the myocardium, blood pressure and cardiac output are mildly increased by nitrous oxide administration. This is the result of an increase in circulating catecholamines, which also results in cutaneous and pulmonary vasoconstriction.
- The F_A / F_I ratio approaches 1 most rapidly with nitrous oxide, followed by desflurane, sevoflurane and isoflurane.
- Nitrous oxide activates the sympathetic nervous system and increases SVR, which can also lead to an increase in central venous pressure (CVP) and arterial pressure.
Halothane
- Halogenated
- Preservative is thymol
- Dose-dependent BP drop from direct myocardial depression
- Blunts the baroreceptor reflex- leads to junctional rhythm and/or bradycardia
- Epinephrine doses > 1.5 mcg/kg are avoided due to arrhythmias
- Halothane produces the least amount of carboxyhemoglobin.
- Halothane most depresses the baroreceptor reflex.
- Halothane, by comparison, causes less disruption in inherent vascular tone and therefore predominantly reduces MAP by direct myocardial depression versus a reduction in preload.
Isoflurane
- Pungent ethereal odor
- Dilates coronaries
- CBF and ICP increases at MAC concentrations > 1 but less than Halothane and reversed with hyperventilation.
- Along with Desflurane, these two gases decrease SVR the most. Also, these two gases depress the baroreceptor reflex the least.
Desflurane
- Requires a special vaporizer because at high altitudes, it will boil at room temperature
- Low blood: gas solubility leads to quicker alveolar ventilation levels needed for anesthesia. Meaning, this agent produces anesthesia quicker and wakeup times are shorter.
- Pungency and airway irritation leads to coughing and/or laryngospasm.
- 2^nd most likely to cause PONV
- The only gas that is completely halogenated with fluorine.
- Least degraded by soda lime.
Sevoflurane
- Excellent choice for inhalational inductions due to absence of pungent odors and rapid increases in alveolar anesthetic concentration.
- Along with Halothane, these gases depress the baroreceptor reflex the most.
- Water is added as a preservative.
- Most degraded by soda lime.

PONV

1) N₂O

2) Desflurane

3) all others equal

Neuromuscular potentiation

1)Enflurane/Isoflurane/Desflurane/Sevoflurane

2) Halothane

3) N₂O

The greater the uptake of anesthetic agent, the greater the difference between inspired and alveolar concentrations, and the slower the rate of induction.
Low-output states predispose patients to overdosage with soluble agents, as the rate of rise in alveolar concentrations will be markedly increased.
Meyer-Overton rule
- AKA critical volume theory; unitary theory of anesthesia
- Anesthesia occurs when enough anesthesia dissolves in the lipid bilayers of neurons. The membranes of the neurons will expand, keeping these channels from opening.
Prolonged exposure to anesthetic concentrations of nitrous oxide can result in bone marrow depression (megaloblastic anemia) and even neurological deficiencies (peripheral neuropathies and pernicious anemia).

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Intravenous Anesthetics and Antagonists

Barbiturates

Methohexital is used for brief and usually pain-free procedures like ECTs. Methohexital is effective in inducing seizure activity. Advantage: methohexital, compared with thiopental, is a more rapid recovery of consciousness. Disadvantage: methohexital has an associated increased incidence of excitatory phenomena but is warranted in ECTs.
An induction dose of thiopental in healthy individuals is associated with an increase in cerebral perfusion pressure (CPP).
Barbiturates constrict the cerebral vasculature causing a decrease in cerebral blood flow and intracranial pressure. The fall in intracranial pressure exceeds the decline in arterial blood pressure, so that the cerebral perfusion pressure is usually increased.

Sedative / Hypnotics

ETOMIDATE

Painful on injection
Decreases CBF, ICP, CMRO₂ (neuro)
Depresses the adrenal cortex
Can cause nausea
Hemodynamically stable (potent vasoconstrictor)
Works on GABA receptor
Cardiovascular stability is characteristic of induction of anesthesia with 0.3 mg/kg IV of etomidate. After this dose of etomidate, there are minimal changes in heart rate, stroke volume, or cardiac output, whereas mean arterial blood pressure may decrease up to 15% because of decreases in systemic vascular resistance.
Etomidate decreases cerebral blood flow (CBF) and the rate of oxygen consumption by the brain (CRMO₂).
The induction of aminolevulinic acid synthetase (etomidate) stimulates the formation of porphyrin, which may precipitate acute intermittent porphyria or variegate porphyria in susceptible individuals

KETAMINE

Works on NMDA receptor, as well as glutamate, nicotinic, muscarinic, and opioid receptors
Dissociative amnestic
Chemically related to phencyclidine (angel dust)
Produces bronchodilation
Maintains sympathetic nervous system; pharyngeal/laryngeal reflexes intact so laryngospasm is possible.
Ketamine causes dysphoria through stimulation of the sigma receptor.
Ketamine increases cerebral oxygen consumption, cerebral blood flow and intracranial pressure. These effects preclude its use in patients with space-occupying intracranial lesions.
Ketamine increases arterial blood pressure, heart rate and cardiac output in healthy patients. These indirect effects are the result of central sympathetic nervous system stimulation and the inhibition of norepinephrine reuptake peripherally. Ketamine has a direct depressant effect on the myocardium which may be unmasked in patients who have exhausted their catecholamine stores (e.g. shock).

PROPOFOL

Works on GABA receptor
Decreases SVR, preload, and contractility
Lungs metabolize 30%
Antiemetic
Anticonvulsant
Faster and more complete awakening compared to the other IV anesthetic
Most injected propofol undergoes hepatic conjugation with glucuronate and sulfate. Propofol’s high clearance rate, 10 times that of thiopental, implies some extrahepatic metabolism can take place.
Propofol infusion syndrome is a rare, sometimes lethal phenomenon. The syndrome is associated with metabolic acidosis, acute cardiomyopathy and skeletal myopathy and is associated with propofol infusions of greater than 75 mcg/kg/min for more than 48 hours.

Dexmedetomidine

Benzodiazepines

Treats anxiety
Produces amnesia
Anticonvulsant (increases seizure threshold)
Sedative/hypnotic
Works on GABA receptor
Reversal is flumazenil (Romazicon)
The insolubility of diazepam and lorazepam in water requires that parenteral preparations contain propylene glycol, which has been associated with venous irritation.
When given alone for IV induction, the benzodiazepines display minimal cardiovascular depressant effects and depression of ventilation. Benzodiazepines decrease vagal tone.

Benzodiazepine Antagonists

Flumazenil is the benzodiazepine antagonist for overdose/reversal. It is a competitive antagonist to the benzodiazepine receptors.
Benzodiazepines can cause respiratory depression, especially when used with opioids.
Dose is 0.2 mg IV and repeated doses of 0.1 mg IV, up to 1 mg.

Opioid Agonists

CARDIAC EFFECTS
- Bradycardia from vagal stimulation.
- Myocardial contractility, baroreceptor function, and autonomic responsiveness are maintained. This is generally why opioids are widely-used in cardiac.
RESPIRATORY EFFECTS
- Opioids decrease respiratory rate first and the breaths become more shallow. With increasing dosages, apnea can occur. This is due to the shift to the right in the CO₂ response curve for respiration. Opioids decrease the sensitivity of carbon dioxide in respiratory centers, thus, increasing levels are needed to maintain effective ventilation.
- Cough suppression is achieved by depressing the medulla cough center. Codeine is known for its antitussive effects.
CENTRAL NERVOUS SYSTEM EFFECTS
- Directly inhibit the ascending transmission of nociception information from the spinal cord dorsal horn
- Activate pain control pathways that descend from the midbrain, via the rostral ventromedial medulla to the spinal cord dorsal horn.
- Miosis, constriction of the pupils, is caused through parasympathetic activity of the oculomotor nerve.
- Neuraxial administration
  - Pain that does not respond to systemic opioids may respond to these same drugs given neuraxially.
  - Opioids administered directly into the CSF work on the spinal cord opiate receptors more efficiently.
- SIDE EFFECTS
  - Opioids stimulate the chemoreceptor trigger zone in the medulla which leads to nausea and vomiting. There is also a vestibular component to opioids. Meaning, when patients begin to ambulate postoperatively, there is a higher likelihood of nausea and vomiting.
  - Muscle rigidity, in a dose-dependent manner, can occur but is most likely with the phenylpiperidines (fentanyl, sufentanil, alfentanil, and remifentanil).
  - Histamine release occurs with morphine, codeine, and Demerol. This causes vasodilation and can lead to hypotension. There is also a cause of the pruritus seen with opioids, however, even those that do not release histamine can still cause pruritus through central mu stimulation (e.g. fentanyl, sufentanil, and alfentanil).
  - Opioids decrease GI motility and secretory activity throughout the GI tract which prolongs gastric emptying. This can lead to constipation and/or ileus.
  - Opioids decrease the stress response through vasopressin release and inhibiting corticotropin and gonadotropins.
  - Neuraxial administration is associated with:
    - Respiratory depression (early is similar to PO dosing; late is seen with morphine from rostral spread)
    - Pruritus (morphine is the worst)
    - Urinary retention

Endogenous opioids, or endorphins, are either
- Proenkephalin
- Pro-opiomelanocortin
- Prodynorphin

EFFECTS	Mu-1	Mu-2	Kappa	Delta
Analgesia	Supraspinal	Spinal	Both	Both
CV/Resp/CNS	CV- bradycardia CNS- euphoria, sedation, hypothermia	CV- bradycardia Resp- depress CNS- Euphoria, dopamine turnover	Resp- depression CNS- sedation, dysphoria, hallucinations	Resp- depress
Urinary	Retention	Retention	Diuresis	Retention
Physical dependence	Low abuse potential	Yes	Low abuse potential	Yes

Delta receptor activation does NOT cause miosis, all others do.
Both mu-2 and delta receptors involve pruritus.
Inhibition of peristalsis and nausea/vomiting comes from the mu-2 receptor.

Reference: Nagelhout Nurse Anesthesia 7^th edition, page 130

By activating the receptors, opioids can control the presynaptic release and response postsynaptically to the excitatory neurotransmitters.
Opioids depress ventilation and desensitize the response to CO₂. Opioids cause the blood CO₂dissociation curve to shift and down and to the right.
These medications can also cause chest wall rigidity that prevents adequate ventilation.
Most lipid-soluble:
- Sufentanil > fentanyl > alfentanil > meperidine > remifentanil > morphine
Epidural or intrathecal opioids bind to receptors in the substantia gelatinosa. Afferent pain information is processed in this area of the spinal cord and contains mu, delta, and kappa receptors.
A spinal opioid that is lipophilic crosses spinal membranes and results in a rapid onset. The more lipophilic, the more rapid the onset. Also, the more lipophilic a spinal opioid is, the shorter the duration. This is because the duration of action is dependent upon absorption systemically rather than metabolism. Therefore, the quicker an agent can become absorbed out of the spinal/epidural space, the shorter the duration. Hydrophilic opioids are limited in absorption and migrate rostrally.
Tramadol is unique in that it acts on opioids receptors (e.g. mu, delta, and kappa) but also blocks the reuptake of norepinephrine (like tricyclic antidepressants). This allows tramadol to be used for both acute and chronic situations. Tramadol does not cause respiratory depression but should be used with caution in epilepsy.
The context-sensitive half-time reflects the combined effects of distribution and elimination on drug disposition. As the infusion duration increases, the context-sensitive half-time increases; this phenomenon is not described in any way by the elimination half-life.
Supraspinal analgesia, ventilatory depression, physical dependence and muscle rigidity after opioid administration appear to be modulated through the sigma receptor. The sigma-2 receptor has been identified as modulating the ventilatory depressant effects of the opioids.
Lamina II of the spinal cord gray matter is the primary area for opioids’ pharmacological activity.

MEPERIDINE

Avoid meperidine for those patients who are taking monoamine oxidase inhibitors (MAOIs) because severe hyperthermia, hypertension, and seizures may occur.
Intravenous meperidine (25 mg) has been found to be the most effective opioid for decreasing shivering, as well as the accompanying increase in oxygen consumption.
In patients with renal failure, normeperidine can accumulate and result in stimulation of the CNS with myoclonic activity and seizures that are not reversed by naloxone.
In general, opioids do not seriously impair cardiovascular function. Meperidine tends to increase heart rate, as it has structural similarities to atropine. High doses of morphine, fentanyl, sufentanil remifentanil and alfentanil are associated with vagus-mediated bradycardia.
The use of meperidine should be avoided when patients are using monoamine oxidase inhibitors because of severe and life-threatening reactions. Phenelzine is an example.
Meperidine has anticholinergic activity. (Atropine – like)

MORPHINE

Active metabolite, morphine-6-glucuronide, prolongs the therapeutic effect.
Most hydrophilic of the opioids
Causes a nonimmunologic histamine release

FENTANYL

Short duration of action due to:
- Rapid redistribution to inactive sites, like adipose and skeletal muscle.
- 75% of the initial dose undergoes first-pass pulmonary uptake (inactive site)
- IMPORTANT DISTINCTION- A SINGLE DOSE OF FENTANYL HAS A SHORTER ACTION THAN MORPHINE BECAUSE OF THE REDISTRIBUTION TO INACTIVE SITES. HOWEVER, WITH MULTIPLE DOSES OR A CONTINUOUS INFUSION, THESE INACTIVE SITES ARE SATURATED AND DURATION OF ACTION BECOMES PROLONGED.
- TAKEHOME POINT: FENTANYL DURATION IS DUE TO REDISTRIBUTION RATHER THAN METABOLISM. A SINGLE DOSE OF FENTANYL HAS A CLINICALLY SHORTER DURATION OF ACTION BECAUSE OF REDISTRIBUTION. HOWEVER, THE ELIMINATION HALF-TIME IS LONGER THAN MORPHINE.
More lipid soluble than morphine; produces a profound analgesia, ventilatory depression, and sedation.

ALFENTANIL

Quick onset and short duration of action
Alfentanil has a more rapid onset of action than fentanyl.

REMIFENTANIL

Smallest volume of distribution and largest clearance
Rapid onset and ultrashort duration
Ester link renders it susceptible to blood and tissue esterases.
Bolus dosing is not recommended in pre- or postoperative.
Prompt offset so transition to a longer-acting opioid is imperative.

Remifentanil is the only opioid that is NOT metabolized by the liver.
- Metabolized by nonspecific esterases.

Order of potency (most to least)
1. Remifentanil
2. fentanyl
3. alfentanil
4. meperidin

HYDROMORPHONE

No active metabolites, recommended in patients with renal failure

SUFENTANIL

Most potent of the phenylpiperidines
- Used in cardiac and other major surgeries

TRAMADOL

Weak mu agonist
Also produces analgesia by inhibition of norepinephrine and serotonin reuptake and presynaptic stimulation of 5-hydroxytryptamine release.
- - Racemic mixture
    - + enantiomer binds to mu and inhibits serotonin
    - – enantiomer inhibits norepinephrine uptake and stimulates alpha-2

METHADONE

Uses:
- Chronic pain
- Opioid use disorders

Absorbed well PO
- Less euphoria
- Long half-life because of extensive protein-binding (90%)

HISTAMINE RELEASE	NO HISTAMINE RELEASE
Morphine	Fentanyl
Codeine	Sufentanil
Demerol	Alfentanil

Opioid Agonist-Antagonist

BUTORPHANOL

Butorphanol produces its therapeutic effect by working on kappa and delta receptors. Respiratory depression is minimal because mu receptor stimulation is minimal.

BUPRENORPHINE

Potent partial agonist to mu

NALBUPHINE

Can reverse opioid-induced respiratory depression while keeping the analgesic properties.

Opioid Antagonists

Opioid agonists are converted into antagonists by substituting an alkyl group for a methyl group. There are other ways but this is the most common. These antagonists competitively bind to the mu receptor sites to prevent activation.
Pure mu opioid receptor antagonists:
- Naloxone (Narcan)
  - Requires high dosage to reverse profound sedation and respiratory depression
  - Only minimal dosage is required to reverse pruritus, urinary retention, and nausea/vomiting.
- Naltrexone
- Nalmefene
Naloxone is a nonselective antagonist of kappa, delta, and mu receptors. It can be used to treat opioid-induced ventilatory depression immediately after surgery, neonatal opioid ventilation depression, and opioid overdose.

Dose is 1-4 mcg/kg IV which quickly reverses the analgesia as well as the depression of ventilation. Because of it short duration (about 30 minutes), additional doses may be necessary.

REFERENCE: Nagelhout Nurse Anesthesia 7^th edition, pages 138-150

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Depolarizing and Nondepolarizing Neuromuscular Relaxants and Antagonists

A motor nerve branches to contact with the junctional area of the muscle surface. The neurotransmitter acetylcholine (ACh) is found within vesicles near the most distal aspect of the motor neuron. The junctional cleft is the space between the terminal neuron and muscle surface and contains extracellular fluid and acetylcholinesterase, the enzyme responsible for metabolizing ACh. The postjunctional motor membrane is rich in ACh receptors.
Paralytics are medications that facilitate muscle relaxation for surgery and intubation. NMBAs act peripherally at the NMJ and muscle fibers to block neuromuscular transmission.

There are two groups of NMBAs: depolarizers and nondepolarizers.

Succinylcholine (only clinically available depolarizer)

It is 2 Ach molecules that act like Ach at the NMJ, binding to the alpha subunits of the Ach receptor.
It directly stimulates both nicotinic and muscarinic receptors, at the motor-end plates of skeletal muscle and PNS receptors respectively.
Sux can cause either an increase in HR/BP due to autonomic ganglia activation or a decrease in HR due to muscarinic effects.
Metabolism via pseudocholinesterase.
Side-effects include:
- Hyperkalemia (normally 0.5-1 mEq/L)
- Allergic reaction; malignant hyperthermia
- Bradycardia
- Tachycardia and HTN
- Skeletal muscle pain
- Masseter spasm
- Increased pressures of the eye/stomach/cranium
- Myoglobinuria
- An exaggerated hyperkalemic response may be seen in:
  - Unhealed burns
  - Stroke
  - Immobilization
  - Sepsis
  - Muscular dystrophy
  - Severe trauma

Nondepolarizers

These medications exert their effect by competitively antagonizing Ach at the receptor sites.
They work on postsynaptic nicotinic receptors of skeletal muscle motor-end plates.
Prevent channels from opening.
They are highly water-soluble due to at least one quaternary ammonium group.
Benzylisoquinoliniums
- Mivacurium
  - Short-acting and causes histamine-release
- Atracurium
  - Hoffmann elimination (pH and temperature); causes histamine-release; Laudanosine is the major metabolite
- Cisatracurium
  - Hoffmann elimination (pH and temperature); does not cause histamine-release; Laudanosine is the major metabolite
Steroid derivatives
- Pancuronium
  - Long-acting
  - Vagolytic
  - Primarily renal-excretion
- Pipecuronium
- Vecuronium
  - Primarily hepatic excretion
- Rocuronium
  - Mainly hepatic excretion
  - Short-acting
  - Alternate to succinylcholine for RSI and/or malignant hyperthermia

BENZYLISOQUINOLINIUMS

Cisatracurium is eliminated by Hofmann elimination (temperature and pH). Atracurium, cisatracurium, and mivacurium are three nondepolarizing muscle relaxants that are NOT excreted by the kidney.
Atracurium is metabolized by ester hydrolysis and Hoffman elimination (temperature and pH).

STEROID DERIVATIVES

Rocuronium is eliminated primarily by biliary excretion (50-70%) and secondarily by renal excretion (10-25%) and hepatic metabolism (10- 20%). Sugammadex, a modified γ- cyclodextrin, acts by selectively encapsulating free molecules of amino steroidal neuromuscular relaxants such as vecuronium and rocuronium forming 1:1 inclusion complex in the plasma. Rocuronium is noted for its quick onset as it is an alternative to Succinylcholine for RSI.

BLOCKADE

With a depolarizing block at the neuromuscular junction, the following occurs:
- Motor end plate contracts and remains open
- Potassium diffuses out of the cell
- Mimics acetylcholine
The chemical structure and physiological properties of neuromuscular blockers is best described as ionized quaternary ammonium compounds.
Anticholinesterase drugs, such as edrophonium, antagonize nondepolarizers at the neuromuscular junction. Chronic anticonvulsant treatment causes the block to be decreased. Neuromuscular blockade by nondepolarizers is decreased until 60 days after a thermal injury. Gentamicin is known to increase nondepolarizer blockade.
The orbicularis oculi, diaphragm, and laryngeal muscles mirror each other in onset and recovery with respect to neuromuscular blockade. The central muscles are paralyzed first and recover first. The adductor pollicis is a muscle that is innervated by the ulnar nerve and would respond later and recover slower than the other options listed than the orbicularis oculi, laryngeal muscles, and diaphragm.

There are two known triggers to MH, volatile anesthetics and succinylcholine.

Response to neuromuscular blockers in special situations:

Myasthenia Gravis -Resistance to succinylcholine but increased sensitivity to NDNMBs

Eaton-Lambert Syndrome -Increased sensitivity to both depolarizing and non-depolarizing NMBs

Duchenne’s muscular dystrophy -Succinylcholine is contraindicated. Normal response to NDNMBs

Huntington’s Chorea -Prolonged response to succinylcholine

Special characteristics of specific NMB’s

Atracurium

Succinylcholine

Rocuronium

Pancuronium

pH and temperature dependent

Two acetylcholine molecules linked

Antagonist to acetylcholine

Atropine-like at SA node

Miscellaneous Facts

Laudanosine is a metabolite of atracurium.
Cisatracurium and atracurium have the following in common: Hofmann elimination, requires no renal nor hepatic metabolism, and Laudanosine metabolite. However, atracurium is known for histamine release and cisatracurium is not.
Normal dibucaine number is 80%, meaning that pseudocholinesterase is normally inhibited 80% by dibucaine. The normal duration of an intubation dose of succinylcholine lasts up to 10 minutes. With atypical heterozygous pseudocholinesterase, the dose would last up to 30 minutes and this dibucaine number would be 50-60%. Homozygous pseudocholinesterase deficiency would cause the succinylcholine dose to last 3 hours or longer.
Each ACh receptor in the neuromuscular junction normally consists of five protein subunits, two α subunits, β, δ and ε subunits. Only the two identical α subunits are capable of binding ACh molecules and both must be bound for the channel to open.
Hypokalemia, hypermagnesemia and hypocalcemia augment a nondepolarizing block. The response of a patient with hypercalcemia is unpredictable.

Anticholinesterase Agents

Acetylcholinesterase hydrolyzes ACh rapidly, which controls the receptor activation duration. From the time ACh is released and diffuses across the synaptic cleft, half is hydrolyzed by acetylcholinesterase before Ach can reach the nicotinic cholinergic receptors (nAChRs).
Muscarinic side effects are stimulated at lower amounts of Ach than required for nicotinic effects. These muscarinic side effects include bradycardia, salivation, mioisis, and hyperperistalsis.
Anticholinergic drugs are also required for reversal of neuromuscular paralysis to limit the muscarinic side effects (which are stimulated at much less dosages).
Anticholinesterase agents
- Inhibit acetylcholinesterase, the enzyme that breaks down ACh to choline and acetic acid.
- Fasciculations of skeletal muscles from presynaptic sites
- Extremely high doses may cause neuromuscular blockade but not clinically relevant. This is a direct effect on the NMJ.
- There are 3 types of anticholinesterase drugs, divided according to their mechanism of action:
  - Acetylcholinesterase is reversibly inhibited at the anionic site; e.g. edrophonium.
  - Carbamyl ester formation produces reversible inhibition of acetylcholinesterase at the esteratic site; e.g. physostigmine, neostigmine, and pyridostigmine.
  - Echothiophate is the only clinically-used organophosphate anticholinesterase drug that irreversibly inactivates acetylcholinesterase.
- Physostigmine is a tertiary amine (as opposed to the others previously mentioned being quaternary) and crosses the blood brain barrier.
- Edrophonium is short-acting.

Selective Relaxant Binding Agents

Sugammadex is a selective relaxant binding agent. Vecuronium, a non-depolarizing neuromuscular blocking agent with a greater potency than rocuronium, has the same basic steroid nucleus structure as rocuronium.
If spontaneous recovery has reached 2/4 TOF twitches, the dose of sugammadex is 2 mg/kg and is considered a moderate block.

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Local Anesthetics

Local anesthetics bind to the receptors inside the cell of a sodium channel. This prevents action potentials from firing.
- The unionized, or base, form diffuses across the nerve sheath and membrane
- Both the base and cationic forms in the axoplasm re-equilibrate
- Na⁺ conductance is stopped because the receptor site inside the Na⁺ channel becomes bound by the cation
Voltage-gated ion channels open in response to voltage, or when the cell becomes depolarized. Ligand-gated channels, however, open in response to a ligand, or a chemical signal, that binds.
Sensitivity to local anesthesia blockade is dependent on:
- Diameter of the axon
- Degree of myelination
- Other factors, including anatomic and physiologic
Potency- lipid solubility
Onset of action- pK_a (and lipid solubility)
- pK_a is the pH where the ionized and unionized forms exit in equal concentrations.
- All local anesthetics are weak bases. Therefore, those closer to 7.4 pH will have more in the lipid-soluble form, or unionized.
Duration of action- protein binding (and lipid solubility)

DURATION OF ACTION

SPEED OF ONSET

POTENCY

PROTEIN BINDING

pK_A

LIPID SOLUBILITY

Rate of systemic absorption
- IV > tracheal > intercostal > caudal > paracervical > epidural > brachial plexus > sciatic > subcutaneous
Local anesthetics are divided into two groups according to their intermediate chains (this chain links aromatic group with the amine group): esters and amides

	ESTERS 1 ‘i’	AMIDES 2 ‘i’s’
Metabolism	Pseudocholinesterase	P-450 liver enzymes
Systemic toxicity	Uncommon	More common
Allergic reaction	PABA- possible	Rare
Onset of action	Slow	Fast
pK_a	More alkaline (> 8.5)	More physiologic (7.6 – 8.1)

Local anesthetics are weak bases.
Diffusion through lipid bilayers is quicker when the local anesthetic becomes more nonionized. Sodium bicarbonate is an alkaline solution that increases the pKa and results in quicker onset.

LOCAL ANESTHETIC	pK_a
Mepivacaine	7.6
Etidocaine	7.7
Prilocaine	7.8
Lidocaine	7.8
Bupivacaine	8.1
Ropivacaine	8.1
Tetracaine	8.2
Cocaine	8.7
Procaine	8.9
Chloroprocaine	9.0

NEED TO KNOW

Cocaine is the only local anesthetic with vasoconstrictor properties.
Bupivacaine is highly protein bound and blocks cardiac sodium channels. Accidental IV injection is extremely life-threatening, often requiring lipid emulsion infusion and/or cardiac bypass.
- Cardiac toxicity: bupivacaine > etidocaine > ropivacaine
- Protein binding from greatest to least: bupivacaine (95%) > etidocaine/ropivacaine/tetracaine (94%) > mepivacaine (77%) > lidocaine (64%) > prilocaine (6%)
Ropivacaine is very similar to bupivacaine (onset and duration) but it is much less likely to cause cardiac toxicity. It is less potent and leads to less of a motor block than bupivacaine, yielding a larger therapeutic index.
EMLA (eutectic mixture of local anesthetics)
- Lidocaine 2.5% and Prilocaine 2.5%
- Should not be used on infants less than 1 month old, mucous membranes or broken skin, or patients with a metabolic disorder that increases methemoglobinemia chances
Prilocaine and benzocaine can cause methemoglobinemia, which is the conversion of hemoglobin to methemoglobin.
- Prilocaine- EMLA cream
- Benzocaine- throat spray; hurricane spray; cetacaine
- Treatment: Methylene blue IV (1-2 mg/kg 1% over 5 minutes); methylene blue reduces Fe³⁺ to Fe²⁺
Dibucaine number
- Dibucaine depresses pseudocholinesterase activity. The normal pseudocholinesterase number is 80%.
- Heterozygous atypical plasma cholinesterase: 40-60
- Homozygous atypical plasma cholinesterase: 20

FIBER	MODALITY	SIZE (mm)	CONDUCTION (m/s)	SENSITIVITY	MYELINATION
A alpha	Motor	12-20	70-120	+	Yes
	Proprioception	12-20	70-120	++	Yes
A beta	Touch Proprioception	5-12	30-70	++	Yes
A gamma	Motor	3-6	15-30	++	Yes
A delta	Pain Cold Touch	2-5	12-30	+++	Yes
B	Pre-ganglionic autonomic fibers	< 3	3-14	++++	Some
C	Pain Warm/cold Touch	0.4-1.2	0.5-2	++++	No
C	Post-ganglionic sympathetic fibers	0.3-1.3	0.7-2.3	++++	No

Vasoconstrictors
- Most commonly epinephrine, but also phenylephrine
- Decreases absorption and increases uptake by the neurons
- Improves analgesia quality
- Increases the duration of action
- Decreases side effects
Local anesthetic toxicity presents first with CNS symptoms, specifically excitation, then followed by seizure, and loss of consciousness.
Epinephrine decreases blood flow to the site. This results in less absorption. Amide local anesthetics are metabolized by the liver which is a slower process than ester metabolism.
Ester local anesthetics are generally less toxic than amides because of pseudocholinesterase metabolism and less protein bound. Although tetracaine is an ester, it is metabolized by pseudocholinesterase slower.
Prilocaine, benzocaine, and nitroglycerin are all capable of producing methemoglobinemia.
Methemoglobinemia is a decreased oxygen-carrying complication due to the oxidation of hemoglobin to methemoglobin. Nitroglycerin, phenytoin, and benzocaine are all known oxidizers. Methylene blue is a reducer and the treatment for methemoglobinemia.
Lidocaine 5% administered for subarachnoid blockade is associated with cauda equina syndrome.
Increasing the amount of carbon atoms in local anesthetics increases the lipid solubility.

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Lipid Emulsion

LAST – Local Anesthetic Systemic Toxicity

The most frequent CNS symptoms are seizures, agitation, and loss of consciousness. In about half of these presentations, cardiovascular symptomatology presents as refractory hypotension and bradycardia. Local anesthetic systemic toxicity (LAST) can progress to supraventricular tachyarrhythmias and wide complex dysrhythmias to complete heart block or asystole.

Several practices help reduce the risk and/or severity of LAST:

- Careful aspiration before each injection
- Small, incremental administration (3-5 mL) with continuous heart rate monitoring
- Direct visualization and confirmation of local anesthetic deposit with ultrasound
- Incorporating a vasoactive agent (like epinephrine or neosynephrine)

Risk factors for LAST
- Patient attributes
  - Extremes of age
  - Low muscle mass
  - Female
  - Arrhythmias, heart failure
  - Metabolic disease, hepatic insufficiencies, CNS disease, low plasma protein binding
- Local anesthetics
  - Potent anesthetics
  - Vascularity of block
  - High dose
  - Prolonged infusion
- Practice setting
  - Non-hospital setting

Treatment of LAST

Get help at the first signs of LAST
Airway management
- Secure airway and ventilate with 100% oxygen
- Prevent further exacerbation by avoiding hypoxia, hypercapnia, and acidosis
Administer 20% LIPID EMULSION
- Bolus over 2-3 minutes 100 mL for patients over 70 kg OR 12 mL/kg for less than 70 kg
- Follow by infusion over 15-20, 200-250 mL for patients over 70 kg or 0.25 mL/kg/min for patients less than 70 kg
- Consider repeat bolus and increasing the infusion to 0.5 mL/kg/min if cardiovascular instability continuous
- Maintain infusion for at least 10 minutes after restoration of circulatory stability
- Recommend 12 mL/kg lipid emulsion as the upper limit for initial dosing
Seizure management
- Halt seizures with benzodiazepines
- Consider small dose of succinylcholine for intractable seizures to minimize acidosis and hypoxemia
Cardiovascular resuscitations with modified ACLS
- Administer small initial doses of epinephrine (less than 1µg/kg)
- Recommend amiodarone for ventricular arrhythmias
- Avoid vasopressin, calcium channel blockers, beta blockers, or local anesthetics
Alert the nearest facility having cardiopulmonary bypass capability if cardiac instability persists
Continue to monitor for at least 2-6 hours after the resolution of symptoms, especially for patients with significant cardiovascular morbidities

REFERENCE: 3^rd American Society of Regional Anesthesia and Pain Medicine practice advisory on local anesthetic systemic toxicity

REFERENCE: Barash Clinical Anesthesia 9^th edition, pages 541-545

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Regional Anesthesia Adjuncts

NEURAXIAL

Subarachnoid

Vasoconstrictors

May prolong the block by inhibiting absorption of local anesthetics or by acting directly on spinal cord alpha receptors.
Epinephrine
Phenylephrine

Alpha 2 agonists

Prolong the duration of subarachnoid anesthesia and analgesia
Clonidine
Dexmedetomidine

Lipid-soluble opioids

Enhance intraoperative anesthesia and provide a few hours of postoperative pain relief.
Fentanyl
Sufentanil

Hydrophilic opioids

Provides 12-24 hours of postoperative pain relief but leads to pruritus and nausea/vomiting.
Morphine

Baricity

The specific gravity of CSF is 1.003-1.008. If the solution is less than 1.003, it is hypobaric. If the solution is greater than 1.008, it is hyperbaric.
Sterile water makes the local anesthetic hypobaric.
Dextrose added to the local anesthetic make it hyperbaric.

Epidural

Sodium bicarbonate

Raises the pH of local anesthetics which increases the nonionized amount of the drug (active part).
Onset of action is quicker
The density is increased

Epinephrine and alpha-2 agonists

Epinephrine decreases systemic absorption
Alpha 2 agonist stimulation produces analgesia
These medications speed the onset and improve the quality.

Opioids

Speed the onset and improve the quality of the block.
Common side effects are pruritus, nausea, and vomiting (worst with morphine)
Fentanyl, sufentanil, hydromorphone, and morphine

PERIPHERAL

Epinephrine should NOT be used in blocks involving terminal vessels, like:
- Ears, nose, penis, toes (digits), and intravenous (BIER)

REFERENCE: Barash Clinical Anesthesia 9^th edition, pages, 906-909; Nagelhout Nurse Anesthesia 7^thedition, pages 1141-1175

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Anticholinergics / Cholinergic Agonists

Anticholinergic Agents

Anticholinergics antagonize the effects of ACh at muscarinic cholinergic postganglionic sites.
ACh is also the neurotransmitter at the nicotinic cholinergic postganglionic sites but requires much greater concentrations to be stimulated. Therefore, anticholinergics can also be considered antimuscarinics because of their selectivity to muscarinic receptors.

	ATROPINE	SCOPOLAMINE	GLYCOPYRROLATE
Sedation	1	3	0
Anti-sialagogue	1	3	2
Tachycardia	3	1	2
Relaxes smooth muscle	2	1	2
Mydriasis	1	3	0
Prevent nausea	1	3	0
Decrease stomach acidity	1	1	1
Fetal heart rate	0	Questionable	0

Anticholinergic effects: 0=NONE 1=MILD 2=MEDIUM 3=HIGH

Anticholinergic uses:
- Preoperative medication
- Increase heart rate
- Reverses neuromuscular blockade when combined with anticholinesterases
- Bronchodilation
- Biliary and ureteral smooth muscle relaxation
- Mydriasis
- Decreases stomach acidity
- Prevents nausea from motion
Scopolamine and atropine both cross the blood brain barrier, (scopolamine is much greater).

Cholinergic Agonists

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Non - Opioid Analgesics

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Cardiovascular Medications

Amlodipine

Terazosin

Losartan

Spironolactone

Lisinopril

Labetalol

Calcium channel blocker

Alpha blocker

Angiotensin receptor blocker

Aldosterone antagonist

Angiotensin converting enzyme inhibitor

Beta blocker

INOTROPES

Sympathomimetics activate alpha-adrenergic, beta-adrenergic, or dopaminergic receptors either directly or indirectly.
- Cyclic adenosine monophosphate (cAMP) production leads to calcium influx. Increased calcium concentrations enhance actin-myosin interaction which leads to a more forceful myocardial contraction (increased inotropy; beta 1).
- Decreased calcium influx and hyperpolarization causes bronchial, vascular, and smooth muscle relaxation. This is beta 2.
- Stimulation of alpha 1 cause increased calcium influx and release of bound calcium in the cell.
- The enzyme responsible for cAMP production is adenylate cyclase. Alpha 2 produces its effects by inhibiting this enzyme.
- Dopaminergic stimulation produce renal artery dilation. These receptors activate adenylate cyclase.
- Catecholamines are inactivated by monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT).
  - MAO catalyzes oxidative deamination.
  - COMT methylates a hydroxyl group and the metabolites are conjugated with glucuronic acid.
    - Metabolites appear in urine:
      - 3-methyoxy-4-hydroxymandelic acid
      - Metanephrine (epinephrine)
      - Normetanephrine (norepinephrine)
    - Because synthetic catecholamines are NOT inactivated by COMT, MAO is the only route for metabolism. MAOIs (antidepressants) can lead to exaggerated responses with these drugs.
  - Sympathomimetics are most often used to increase myocardial contractility or for blood pressure management.
  - Other uses for sympathomimetics:
    - Bronchospasm treatment for asthmatics
    - Anaphylaxis management
    - Adjunct to local anesthesia

CALCIUM

Positive inotropic effect

GLUCAGON

Glucagon increases myocardial contractility and heart rate. It increases intracellular levels of cAMP by mechanisms independent of beta-adrenergic receptor stimulation.
Glucagon increases myocardial contractility. The positive inotropic and chronotropic effects of glucagon increase cardiac output.
Enhances formation of cAMP
Increases myocardial contractility and heart rate in the presence of beta blockade
Evokes the release of catecholamines but not the main pharmacological mechanism

SYMPATHOMIMETIC CHART

DRUG	Alpha-1	Beta-1	Beta-2	Cardiac output	Heart rate	PVR	MAP	Airway resistance
EPINEPHRINE	+	++	++	++	++	+/-	+	– –
NOREPINEPHRINE	+++	++	0	–	–	+++	+++	0
DOPAMINE	++	++	+	+++	+	+	+	0
ISOPROTERENOL	0	+++	+++	+++	+++	—	+/-	– – –
DOBUTAMINE	0	+++	0	+++	+	0	+	0
EPHEDRINE	++	+	+	++	++	+	++	– –
MEPHENTERMINE	++	+	+	++	++	+	++	–
AMPHETAMINE	++	+	+	+	+	++	+	0
METARAMINOL	++	+	+	–	–	+++	+++	0
PHENYLEPHRINE	+++	0	0	–	–	+++	+++	0
METHOXAMINE	+++	0	0	–	–	+++	+++	0

ORANGE Natural catecholamines

GREEN Synthetic catecholamines

PINK Synthetic non-catecholamines (indirect-acting)

BLUE Synthetic non-catecholamines (direct-acting)

Epinephrine

Uses:
- Anaphylaxis
- Cardiopulmonary resuscitation
- Shock
Myocardial contractility, heart rate, vascular and bronchial smooth muscle tone, glandular secretions, and metabolism (glycogenolysis and lipolysis).
- Beta 1 increases SBP, HR, and cardiac output.
- Beta 2 slightly decreases DBP.
- Alpha 1 stimulation can produce intense vasoconstriction. Yet, beta 2 activation vasodilates skeletal muscle.
- Beta 2 receptors are responsible for bronchodilation.
- Glycogen and triglycerides are broken down into glucose and free fatty acids, respectively. This occurs due to beta 1. Alpha 1 stimulation inhibits insulin release.
Beta-2 is stimulated at small doses (1-2 µg/minute IV)
Beta-1 stimulation occurs at 4 µg/minute IV.
Stimulation of alpha and beta receptors occurs at 10-20 µg/minute IV.

Norepinephrine

Use:
- First line drug for shock, specifically for sepsis or vasodilatory shock
Endogenous neurotransmitter released from postganglionic sympathetic nerves.
Norepinephrine increases peripheral vascular resistance more than isoproterenol, dobutamine, and epinephrine.
Norepinephrine activates alpha-1, alpha-2, and beta-1 receptors.
Increases SVR and decreases venous return; stimulates vagal response
Increases SBP, DBP, and MAP.

DOPamine

Endogenous catecholamine that is the immediate precursor of norepinephrine.
Increases cardiac output with only minimal elevation in heart rate, BP, and SVR.
Rates:

LOW DOSE	1-4 mcg/kg/min	Dopaminergic stimulation
MODERATE	5-10 mcg/kg/min	Beta stimulation
HIGH	>11 mcg/kg/min	Alpha stimulation

Isoproterinol

Synthetic catecholamine and is the most potent at beta 1 and 2 receptors of all these drugs.
It is used to increase heart rate during heart bock and prior to pacemaker insertion.
Isoproterenol increases dilation of blood vessels in skeletal muscle.

DoBUTamine

Synthetic catecholamine
Beta-1 is the main receptor that dobutamine stimulates.
Dobutamine is a selective β-agonist. Heart rate increases are less marked than with other β-agonists resulting in favorable effects on myocardial oxygen balance.
Effective in heart failure patients where heart rate and SVR are increased.

Ephedrine

Indirect-acting synthetic non-catecholamine that is “weak epinephrine,” meaning it stimulates the alpha and beta receptors.

Amphetamine

Resemble ephedrine

Phenylephrine

Synthetic non-catecholamine that directly acts on alpha 1 receptors.
The infusion of phenylephrine will increase the systemic vascular resistance by stimulating the alpha-1 receptors. Phenylephrine causes greater venoconstriction than arterial.

Vasopressin

Potent vasoconstrictor but selectively dilates renal afferent, pulmonary, and cerebral arterioles.

PHOSPHODIESTERASE INHIBITORS

Competitively inhibits PDE III which decreases the hydrolysis of cAMP and cGMP. The result of these drugs increase intracellular calcium concentration and causes vascular and airway smooth muscle relaxation.
This class of drugs works independently of beta receptors.
Amrinone is a cardiac inotrope and can cause significant thrombocytopenia.
Milrinone that produces positive inotropic and vasodilating effects like amrinone. It has minimal effects on heart rate and myocardial oxygen consumption.
Nonselective phosphodiesterase inhibitors, like theophylline, inhibit all fractions of PDE isoenzymes (I-V).

CARDIAC GLYCOSIDES (E.G. DIGITALIS)

Digoxin binds to the alpha subunit of the Na⁺/K⁺/ATPase pump in cardiac cells
- Results in increased calcium intracellularly
Effects:
- Increased inotropy
- Lowers heart rate
- Decreases conduction through AV node
- Resultant effect of increased parasympathetic activity
Used for the management of supraventricular tachydysrhythmias related to rapid ventricular response.
These drugs work by slowing the conduction of cardiac impulses through the atrioventricular node. Most notably used in the treatment of chronic congestive heart failure.
Because the therapeutic window is narrow, toxicity is common. The most common cause is diuretics that deplete potassium. Levels > 3 ng/mL are toxic.
Treatment includes potassium and magnesium correction, cardiac antidysrhythmics (like phenytoin, lidocaine, and atropine), and pacemaker.

ALPHA AND BETA RECEPTOR AGONISTS/ANTAGONISTS

Sympatholytics oppose the downstream effects postganglionic nerve stimulation by the sympathetic nervous system.

ALPHA ANTAGONISTS

Uses:
- Hypertension
- Benign prostatic hyperplasia (BPH)
- Pheochromocytoma
- Raynaud phenomenon
- Ergot alkaloid toxicity
Decreased blood pressure secondary to vasodilation. There may also be reflex tachycardia.
Phenoxybenzamine is nonselective and irreversible. The effects are terminated by metabolism. It is used to treat pheochromocytoma preoperatively 1-3 weeks before surgery.
Phentolamine is competitive and nonselective. It has a shorter duration and is used for short-term control of pheochromocytoma. Also can be used to treat local infiltrations of vasoconstrictors (e.g. dopamine infused through a peripheral IV that infiltrated).
Prazosin, doxazosin, and terazosin are selective alpha-1 blockers used for chronic hypertension and BPH. There is no alpha-2 activity which means there is no effect on norepinephrine levels.
Tamsulosin, alfuzosin, and silodosin are alpha-1 selective and used to relax the bladder neck and prostate. Tamsulosin can produce floppy iris syndrome, making cataract surgery more difficult.

BETA ANTAGONISTS

Beta blockers depress the conduction through the AV node and decrease contractility. When beta 2 receptors are blocked, bronchospasm and/or airway irritability can occur.
Uses:
- Treats angina pectoris, HTN, postmyocardial infarctions, supraventricular tachyarrhythmias, like Wolff-Parkinson White, and atrial fibrillation
- Suppresses sympathetic activity for intubations
- Management of hypertrophic obstructive cardiomyopathy and CHF
- Treatment of migraines
- Preoperative preparation for hyperthyroid patients
Some beta blockers are partial agonists and possess intrinsic sympathomimetic activity (ISA). This minimizes bronchoconstriction risk.
- Examples: pindolol, acebutolol, penbutolol, and carteolol.
Some beta blockers have membrane-stabilizing activity, meaning they can diminish arrhythmogenic activity.
- Examples: propranolol and pindolol
Propranolol is a nonselective competitive antagonist. Beta 2 blockade would promote bronchospasm so not wanted in COPD.
Labetalol and carvedilol are mixed beta and alpha blockers.
- Labetalol acts on beta to alpha 7:1 ratio.
Atenolol:
- Treats hypertension.
- Long-acting (once a day) beta-1 selective blocker
- Appropriate for sensitive airways or diabetes
- Only beta blocker that is eliminated by the kidneys
Nebivolol is beta-1 specific and has nitric oxide-mediated vasodilating properties.
Caution with beta blockers
- Can result in bronchospasm and development of cardiac failure in high risk patients
- Beta-2 blockade potentiates vasoconstriction in peripheral vascular disease and Raynaud phenomenon
- Hypoglycemic effects are masked for diabetics and the ability to increase glucose levels is impaired
- Serum potassium is increased because skeletal muscle uptake is decreased.
Beta blockade use in anesthesia
- Esmolol is the drug of choice because of its rapid onset and short duration. It is metabolized by nonspecific esterases in the blood.
- Labetalol is a nonselective beta blocker. It can be given in obstetrics because uterine blood flow is not effected.
CURRENT ACC/AHA GUIDELINES
- Continue beta blockers perioperatively for those already currently prescribed these medications. HOWEVER, avoid starting beta blockers immediately before surgery and in emergency surgery settings, in those known cerebrovascular disease, or in sepsis.

Prazosin is alpha-1 specific, useful in congestive heart failure, and lowers afterload without effecting the heart rate.
Phenoxybenzamine is a nonselective alpha adrenergic receptor antagonist.
Atenolol and metoprolol are beta-1 specific.
Dobutamine is a selective β-agonist. Heart rate increases are less marked than with other β-agonists resulting in favorable effects on myocardial oxygen balance.
Norepinephrine increases peripheral vascular resistance more than isoproterenol, dobutamine, and epinephrine.
Isoproterenol and dobutamine are synthetic catecholamines.
Norepinephrine activates alpha-1, alpha-2, and beta-1 receptors.
Beta-2 effects are seen when epinephrine is infused at 1-2 µg/min IV.
Isoproterenol increases dilation of blood vessels in skeletal muscle.
The infusion of phenylephrine will increase the systemic vascular resistance by stimulating the alpha-1 receptors. Phenylephrine causes greater venoconstriction than arterial.
Beta-1 is the main receptor that dobutamine stimulates.
Dopamine infusion stimulates primarily beta-1 receptors at 3-10 mcg/kg/min.
A dopamine infusion at 3 mcg/kg/min is intended to stimulate dopaminergic receptors that promote renal vasodilation.

CENTRALLY ACTING ALPHA-2 ADRENERGIC AGONISTS

Uses:
- Treat hypertension
- Short-term sedation
- Analgesic in epidural
- Suppression of alcohol withdrawal symptoms
Stimulation of alpha 2 receptors prevents presynaptic release of norepinephrine in nerve terminals of sympathetic neurons.
Abrupt withdrawal can lead to a sudden increase in circulating catecholamines and rebound hypertension.
Clonidine treats hypertension.
Clonidine promotes perioperative hypothermia, blunts sympathetic reflex responses seen in direct laryngoscopy and surgery, and decreases anesthetic requirements.
Dexmedetomidine is an alpha 2 agonist used for short-term sedation.

Catecholamines, renin, and angiotensin are all involved in rebound hypertension after abruptly stopping clonidine.

ACE INHIBITORS

Angiotensin converting enzyme inhibitors treat:
- HTN
- Angina
- Diabetic neuropathy
- CHF
- Management of post myocardial infarction
Physiology
- Decreased blood pressure causes release of renin from kidneys
- Renin converts angiotensinogen (from liver) to angiotensin 1
- Angiotensin 1 is converted to angiotensin 2 by angiotensin-converting enzyme (ACE; from the lungs)
- Angiotensin 2 is a potent vasopressor that stimulates norepinephrine and aldosterone
- The end result is increased peripheral vasoconstriction with an increase in blood pressure and a decrease in cardiac output
- Higher aldosterone levels lead to increased sodium and water reabsorption and increased potassium secretion
- ACEIs block this process and produce vasodilation
  - Prevent angiotensin 1 to 2
- Adverse effects:
  - Dry cough (25% of patients)
    - ACE is responsible for bradykinin metabolism in the lungs
  - Angioedema
  - Renal failure
  - Hyperkalemia

ANGIOTENSIN II RECEPTOR INHIBITORS

Angiotensin II receptor blockers treat HTN and CHF
The action of ARBs is similar to ACEIs but the mechanism of action is different
- Competitive blockade of type 1 angiotensin 2 (AT₁) receptors

ANESTHESIA MANAGEMENT of ACEIs and ARBs

Vasoplegic syndrome (VS) is the unexpected refractory hypotension under general anesthesia with a MAP less 50 mm Hg, cardiac index greater than 2.5, and decreased SVR despite adrenergic vasopressor administration.
Most common in heart surgery
There is no consensus on continuing or stopping these medications before surgery.

DIRECT VASODILATORS

Mechanism of action is primarily an induced increase in nitric oxide. Both sodium nitroprusside and nitroglycerin donate nitric oxide (NO). NO then activates enzyme soluble guanylate cyclase, which, in turn, increases the production of cyclic guanosine monophosphate (cGMP). Cyclic GMP is a second messenger that relaxes vascular smooth muscle and promotes vasodilation that results in lowering the blood pressure.
Sodium nitroprusside
- Produces arterial and venous relaxation
- Used for the acute management or emergent control of HTN, controlled hypotension, and for acute cardiac disorders
- Decreases preload and afterload → decreases cardiac filling pressure and increases stroke volume and cardiac output
- Left ventricular volumes are decreased → decreases myocardial wall tension → decreases myocardial oxygen consumption
Nitroglycerin
- Has a greater effect on venous than arterial venous
  - Causes venodilation and a decrease in preload
- Used for angina pectoris and controlled hypotension
  - Chest pain relief is by decreasing preload and cardiac work
- Not as effective for controlled hypotension as sodium nitroprusside
Hydralazine
- Works primarily on arterial vessels
- Increased heart rate occurs because of a decrease in afterload
- Can be used IV but the onset is much longer
Cyanide toxicity
- Sodium nitroprusside chemically contains 5 cyanide ions that are released upon metabolism by plasma hemoglobin.
- One cyanide ion binds with methemoglobin to form cyanomethemoglobin. The other 4 are converted to thiocyanate in the liver and then eliminated by the kidneys. Important to note: the conversion to thiocyanate requires B₁₂.
- Cyanide toxicity occurs when this pathway is overwhelmed. In general, when more than 500 mcg/kg of sodium nitroprusside is infused faster than 2 mcg/kg/min, cyanide is produced faster than the patient can eliminate.
- 1^st signs are metabolic acidosis, increased mixed venous oxygen content, increased heart rate, and tachyphylaxis.
- Treatment:
  - STOP sodium nitroprusside infusion
  - Administer oxygen
  - Treat metabolic acidosis
  - Sodium nitrite 3% @ 4-6 mg/kg promotes production of methemoglobin so that excess cyanide ion can be bonded.
  - Sodium thiosulfate, vitamin B₁₂, hydroxycobalamin, and methylene blue

Nitroglycerin and sodium nitroprusside both increase cyclic guanosine monophosphate.

Nitroglycerin is a nitric oxide donor.

Acute cyanide toxicity results in base deficit.

Sodium nitroprusside contains five (5) cyanide ions.

By uncoupling oxidative phosphorylation, cyanide can prevent the formation of ATP.

Hydralazine is an antihypertensive that causes an increase in heart rate.

Sodium nitroprusside decreases both preload and afterload

NITRIC OXIDE

Nitric oxide is the result of the amino acid arginine converted by nitric oxide synthetase (NOS). The anesthetic focus of NO is vasodilation. The 3 forms of NOS:
- Constitutive form- endothelial NOS
  - Endothelial nitric oxide causes:
    - Vasodilation
    - Decreased vascular resistance
    - Decreased blood pressure
    - Inhibition of platelet aggregation and adhesion
    - Inhibition of leukocyte adhesion and transmigration
    - Reduced vascular smooth muscle proliferation
    - Acts to prevent atherosclerosis
  - Nitric oxide or nitrovasodilators activate soluble guanylyl cyclase and produce cyclic guanosine monophosphate (cGMP) from guanosine triphosphate in smooth muscle cells.
- Neuronal NOS
  - Nitric oxide plays a crucial role as a neurotransmitter from the peripheral efferent nerves in blood vessels and gastrointestinal tracts. In the brain, nitric oxide functions mainly as a neuromodulator.
- Inducible NOS
  - Under pathologic conditions (e.g. during inflammation), high levels of nitric oxide are produced after induction of the expression of iNOS, mainly in macrophages.

ANTIDYSRHYTHMICS

Cardiac dysrhythmias resulting from digoxin toxicity are best treated with phenytoin and lidocaine.
Amiodarone has the chemical structure like thyroxine. Remember that amiodarone can cause hyper- or hypothyroidism is susceptible patients.

CLASS	ELECTROPHYSIOLOGIC EFFECT	DRUG
I	Depresses phase 0 depolarization (blocks sodium channels)
IA	Moderate depression and prolonged repolarization	Quinidine, procainamide, disopyramide
IB	Weak depression and shortened repolarization	Lidocaine, mexiletine, phenytoin, tocainide
IC	Strong depression with little effect on repolarization	Flecainide, propafenone, moricizine
II	Beta-adrenergic blocking effects	Esmolol, propranolol, metoprolol, atenolol, carvedilol
III	Prolongs repolarization (blocks potassium channels)	Amiodarone, bretylium, sotalol, Ibutilide, dofetilide
IV	Calcium channel-blocking effects	Verapamil, diltiazem
OTHER		Adenosine, adenosine triphosphate, digoxin, atropine

CALCIUM CHANNEL BLOCKERS

Treats:
- Angina
- HTN
- Arrythmias
- PVD
- Esophageal spasm
- Cerebral vasospasm
- Controlled hypotension
3 classes of CCBs
- Dihydropyridines
- Benzothiazepines
- Phenylalkylamine
All CCBs have negative actions on inotropy and chronotropy
They are class 4 antiarrhythmics
- Depress electrical impulses at the SA/AV nodes
- Produce coronary and systemic vasodilation
Mechanism of action
- Depolarization of SA/AV nodes depends on influx of calcium during the depolarization phase of the cardiac action potential
- CCBs block this channel which prolongs phase 2 of the cardiac action potential and decreases chronotropy
- Because ventricular pacemaker foci are sodium-dependent, CCB are used for atrial tachyarrhythmias (like WPW) and ventricular response to atrial fibrillation/flutter
Beneficial for angina because they have negative inotropic effects
Nimodipine
- Used to treat cerebral vasospasm associated with neurologic emergencies, like ruptured aneurysms and neurosurgery.
Verapamil
- Atrial tachyarrhythmias
Nicardipine
- IV administration for perioperative HTN
Clevidipine
- IV antihypertensive
- Highly selective for vascular muscle and does not effect myocardial contractility or conduction
- Rapidly metabolized by nonspecific esterases

TYROSINE HYDROXYLASE INHIBITORS

Tyrosine hydroxylase catalyzes tyrosine to dopa, which is the rate-limiting step in catecholamine synthesis.
Add-on drug to alpha and beta blockers for control of blood pressure in pheochromocytoma

CATECHOL-O-METHYLTRANSFERASE INHIBITORS

COMTIs enhance the action of levodopa and produce less fluctuation in drug response.
Treatment of Parkinson’s

Verapamil works on cardiac nodal tissue.

Glucagon increases myocardial contractility and heart rate. It increases intracellular levels of cAMP by mechanisms independent of beta-adrenergic receptor stimulation.

Glucagon increases myocardial contractility. The positive inotropic and chronotropic effects of glucagon increase cardiac output.

Avoid trimethaphan when a patient has bronchoconstriction.

REFERENCE: Nagelhout Nurse Anesthesia 7^th edition, pages 177-203

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Bronchodilators

Short-Acting Beta-2 Agonists	Albuterol
Long-Acting Beta-2 Agonists	Salmeterol Formoterol
Corticosteroids	Beclomethasone Budesonide Ciclesonide Fluticasone Flovent HFA Mometasone
Long-Acting Corticosteroid and Beta-2 Agonist Combinations	Fluticasone/Salmeterol Budesonide/Formoterol Mometasone/Formoterol
Leukotriene Modifiers	Montelukast Zafirlukast Zileuton
Anti-IgE Antibody	Omalizumab
Theophylline	Theophylline
Anti-interleukin-5 (IL-5) Antibodies	Mepolizumab Reslizumab Benralizumab

Drugs used to treat asthma include beta-adrenergic agonists, methylxanthines, glucocorticoids, anticholinergics, leukotriene blockers, and mast cell-stabilizing agents. Montelukast is a leukotriene receptor antagonist.
Albuterol, a beta-2 agonist, relaxes smooth muscle of the bronchi by increasing the intracellular concentration of the second messenger, cyclic adenosine monophosphate (cAMP). Cyclic AMP promotes bronchodilation.
Ipratropium is a congener of atropine and a quaternary ammonium drug.

COPD management includes beta-2 agonists, corticosteroids, or anticholinergics for bronchodilation.
Ideally, anticholinergic activity would be selective for receptors M₁ and M₃ because M₂ reduces acetylcholine release and blocks some of the benefits of beta-2 agonists.
- Tiotropium is more selective for M₃ receptors than atropine and ipratropium.

Asthma therapy is more likely to involve inhaled corticosteroids and COPD is more likely to use inhaled anticholinergics.
Budesonide is the preferred inhaled corticosteroid for pregnancy.

Albuterol is the preferred inhaled short-acting beta-2 in pregnancy.

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Psychopharmacologic Therapy

ANTIDEPRESSANTS

Depression is a mood disorder characterized by sadness and pessimism. Medications treat cerebral deficiencies of dopamine, norepinephrine, and serotonin or alterations in receptor activities.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Inhibit reuptake of serotonin at the presynaptic nerve membrane
Fluoxetine, paroxetine, sertraline, and citalopram

Tricyclic Antidepressants (TCAs)

Used for treatment of depression and chronic pain syndromes
Amitriptyline, nortriptyline, and imipramine
TCAs work at nerve synapses by blocking neuronal reuptake of catecholamines, serotonin, or both.
Tricyclic antidepressants can produce:
- Anticholinergic effects (e.g. dry mouth, blurred vision, tachycardia, urinary retention, etc.)
- Orthostatic hypotension- treat with direct-acting vasopressors
- Sedation
The most important interaction between anesthetic agents and TCAs is an exaggerated response to both indirect-acting vasopressors and sympathetic stimulation. Avoid:
- Pancuronium
- Ketamine
- Meperidine
- Epinephrine containing local anesthetics

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs are effective with depression that is accompanied by panic attacks and prominent anxiety.
Phenelzine, isocarboxazid, and tranylcypromine
Two MAO isoenzymes:
- A- selective for serotonin, dopamine, and norepinephrine
- B- selective for tyramine and phenylethylamine
MAOIs increase adrenergic neurotransmitters by binding/inhibiting monoamine oxidase.
Avoid these drugs:
- TCAs
- Opioids- meperidine
- Indirect-acting sympathomimetics
- Fluoxetine
Use phenylephrine, a direct-acting sympathomimetic to treat the hypotension.

Lithium

Mania is a mood disorder characterized by elation, hyperactivity, and flight of ideas. Bipolar patients may have fluctuations between mania and depression episodes. Mania is thought to be related to excessive norepinephrine activity in the brain.
Lithium and lamotrigine are the drugs of choice for treating acute manic episodes and preventing their recurrence.
Lithium toxicity > 2 mEq/L. Mild toxicity manifests as skeletal muscle weakness, ataxia, sedation, and widening of the QRS complex. Severe toxicity may produce atrioventricular block, hypotension, and seizures.

ANTIPSYCHOTICS

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome is related to dopamine blockade in the basal ganglia and hypothalamus and impairment of thermoregulation.
Resembles malignant hyperthermia
This syndrome is a rare complication of antipsychotic therapy occurring hours or weeks after the medication is administered. Meperidine and metoclopramide can also lead to this syndrome.
Treatment includes dantrolene and bromocriptine (dopamine agonist) are effective.

Schizophrenia

The majority of patients who receive an antipsychotic such as haloperidol, fluphenazine, chlorpromazine, and risperidone for some time are susceptible to neuroleptic malignant syndrome. Schizophrenics are commonly treated with antipsychotics.
Mild alpha blockade and anticholinergic activity can occur.
Avoid ketamine because these drugs decrease the seizure threshold.

ANTIPARKINSONIANS

Mild disease:
- Anticholinergics- trihexyphenidyl, benztropine, and ethopropazine
- MAOIs: selegiline and rasagiline
- Antiviral drug- amantadine.
Moderate to severe disease
- Dopaminergic agent:
  - Levodopa is the most effective treatment
    - Levodopa is a precursor of dopamine. This drug is given with a decarboxylase inhibitor which decreases the breakdown so that the dose of Levodopa can be decreased while increasing efficiency.
  - Catechol-O-methyltransferase inhibitors (COMTIs) are also used to prevent the decarboxylation of levodopa.
  - Dopamine receptor agonists:
    - Ergot
      - Bromocriptine, cabergoline, lisuride, and apomorphine
    - Non-ergot derivatives
      - Pramipexole and ropinirole
    - Selegiline is a selective MAO type B enzyme inhibitor
    - Drugs that help with side effects:
      - Ondansetron for nausea
      - Diphenhydramine can treat acute Parkinson crisis and extrapyramidal reactions produced by droperidol
    - Avoid drugs that antagonize dopamine:
      - Droperidol, metoclopramide, prochlorperazine, and possibly alfentanil
    - Continue Parkinson’s medication perioperatively and avoid dopamine antagonists

Others

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Prostaglandins

The principal precursor of PGE₂ is arachidonic acid. Arachidonic acid is released by phospholipase C and phospholipase A₂.

- Histamine and other stimuli activate phospholipase enzymes.
- Corticosteroids inhibit phospholipase enzymes.
Arachidonic acid serves to help produce prostaglandins via the cyclooxygenase or lipoxygenase pathway.
Cyclooxygenase (COX) is necessary for the initial synthesis (oxidation) of prostaglandins. Thromboxane synthetase is required to convert PGH₂ to thromboxane (TXA₂). COX isoforms:
- COX-1: platelets and gastric mucosa
- COX-2: inflamed tissues and brain/spinal cord
Lipoxygenase enzymes can be found in platelets, vascular endothelium, the lungs, and leukocytes. The result from the lipoxygenation of arachidonic acid is leukotrienes.
- Leukotrienes increase in the following:
  - Bronchial asthma
  - Neonatal pulmonary hypertension with hypoxemia
  - Adult respiratory distress syndrome (ARDS)
- Rapidly metabolized by the lungs; the secondary breakdown occurs in the liver.

PROSTACYCLIN

Derived from arachidonic acid
Synthesized by endothelial cells
Vasodilator and most potent known inhibitor of platelet aggregation
Stimulates nitric oxide
Serves better inhaled as IV administration is not selective to the lungs

ILOPROST

Long-acting derivative of prostacyclin and also is a potent inhibitor of platelet aggregation
Produces vasodilation but less hypotension than prostacyclin

HEMATOLOGY

The COX product of arachidonic acid in platelets is thromboxane. It acts as an intense stimulus for platelet aggregation.

CARDIOVASCULAR

Prostaglandins promote vasodilation and increase sodium excretion.

PULMONARY

Pulmonary vasoconstriction may be related to increased thromboxane.
Prostaglandins may produce bronchoconstriction or bronchodilation. When there is an imbalance between prostaglandins and thromboxane, bronchial asthma can result.

RENAL

Prostaglandins are synthesized in the kidneys and help to modulate blood flow and glomerular filtration rate.
Misoprostol helps to improve renal function and lowers the risk of acute rejection in renal transplant patients treated with cyclosporine and prednisone.

UTERUS

Prostaglandins are important in the initiation and maintenance of labor.
Prostaglandins are also believed to be a cause of dysmenorrhea.
Aspirin helps to decrease pain associated with dysmenorrhea. It also increases the average length of gestation and the duration of spontaneous labor.
Carboprost is an example of a prostaglandin agent used for inducing contractions.

LEUKOTRIENE ANTAGONISTS

Zileuton inhibits leukotriene generation involved in asthma by impairing arachidonic acid to leukotriene.
Montelukast blocks leukotrienes from binding and decreases bronchospasm, vasoconstriction, and eosinophil recruitment.

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Histamine Receptor Antagonists

HISTAMINE-1

H1-receptor antagonists are highly selective for H1-receptors while sparing histamine 2 and 3 receptors

May also activate:
- muscarinic cholinergic
- 5-hydroxytryptamine (5-HT; serotonin)
- alpha-adrenergic receptors

Caution should be used with these medications when used in conjunction with other respiratory depressants as they can have an additive effect.

Causes smooth muscle contraction in the respiratory and GI tracts
Can cause sneezing and pruritus by sensory nerve stimulation

First generation antagonists
- Diphenhydramine
- promethazine
- hydroxyzine

Second generation antagonists
- Fexofenadine
- loratadine

HISTAMINE-2

Regulation of gastric acid secretion by parietal cells is through acetylcholine, gastrin, and histamine.

Histamine has paracrine-like effects on the parietal cells and plays a central role in the regulation of acid secretion by parietal cells after its release from enterochromaffin-like (ECL) cells.

Histamine-2 receptor antagonists exert their effect by raising gastric pH and decreasing gastric volume.

Examples:
- Cimetidine
- Ranitidine
- Famotidine

Cimetidine and ranitidine both alter cytochrome P-450 enzymes and can slow metabolism of other drugs that utilize this route.
- Cimetidine is most likely to inhibit this system and then to a lesser extent ranitidine. Famotidine does not effect this system.

Drugs that may be effected when a patient is taking cimetidine:
- Beta blockers- propranolol and labetalol
- Anesthetics- diazepam and halothane
- Others: lidocaine, phenytoin, coumadin, meperidine, quinidine, and tricyclic antidepressants

REFERENCE: Nagelhout Nurse Anesthesia 7^th edition, pages 786-790

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Antiemetics

Nausea/vomiting

5 neurotransmitters in the vomiting center and chemoreceptor trigger zone:
- Histamine₁
- Dopamine₂
- Serotonin (5HT₃)
- Acetylcholine (muscarinic)
- Neurokinin (substance P)

Cranial nerves involved:
- 5 (trigeminal)
- 7 (facial)
- 9 (glossopharyngeal)
- 10 (vagus)
- 12 (hypoglossal)

Vestibular apparatus in the inner ear
- Histamine₁
- Acetylcholine (muscarinic)
- Irritation or distention in the pharynx, esophagus, stomach, and upper portions of the small intestines can initiate vomiting by sending signals to the vomiting center.

Vomiting nerve impulses are transmitted by both vagal and sympathetic afferent nerve fibers to multiple sites in the brain stem. From here, the signals are transmitted to:

Upper GI tract by the cranial nerves 5, 7, 9, 10, and 12
Lower GI tract by vagal and sympathetic nerves
Diaphragm and abdominal muscles by spinal nerves

The chemoreceptor trigger zone for emesis, or AREA POSTREMA, is located in the fourth ventricle. Stimulation of this area can also result in vomiting.

Drugs, such as morphine and digitalis, can stimulate the chemoreceptor trigger zone and induce vomiting.

Sudden change of direction or movement of the body (motion sickness) can result in vomiting through stimulation of the vestibular system in the inner ear.

CHEMORECEPTOR TRIGGER ZONE

D2 receptor
NK1 receptor
5HT3 receptor

VESTIBULAR SYSTEM

Muscarinic M1 receptor

HEART

Mechanoreceptors
5HT3 receptor
Vagus nerve

STOMACH

Nausea and vomiting

VOMITING CENTER

Muscarinic M1 receptor

5-HT₃-RECEPTOR ANTAGONISTS

Serotonin is released from the enterochromaffin cells of the small intestine, stimulates the vagal afferents through 5-HT₃ receptors and initiates the vomiting reflex.
These medications are selective to the 5-HT₃ receptor with no binding to the other 5-HT receptors.

Examples:

ondansetron
Tropisetron
granisetron
dolasetron

These are not effective for motion sickness or vestibular stimulation because the areas responsible are rich in muscarinic and histamine receptors.
The most commonly reported side effect from ondansetron is headache.
Caution use with known QT elongation
Serotonin syndrome is possible when patients are taking SSRIs or SNRIs
Ondansetron is safe for use in patients with Parkinson’s.

GASTROINTESTINAL PROKINETICS

Examples:
- Metoclopramide
- cisapride
- domperidone
- erythromycin

Metoclopramide
- Dopamine antagonist that increases lower esophageal sphincter tone, stimulates motility of the upper GI tract, and relaxes the pylorus and duodenum during gastric contraction.
- Gastric ion secretion is unchanged.
- Works on postganglionic cholinergic nerves intrinsic to the GI tract walls
- Anticholinergics oppose metoclopramide in lower esophageal sphincter tone and GI motility.
- Opioid-induced GI hypomotility may not be reversible with metoclopramide
- CNS- blocks dopamine receptors; this can cause extrapyramidal symptoms (e.g. oculogyric crises, opisthotonus, trismus, torticollis)
- Akathisia can accompany IV administration. This is a feeling of unease and restlessness in the lower extremities
- Contraindicated with parkinson’s and intestinal obstruction.

REMEMBER

Metoclopramide increases lower esophageal sphincter tone and promotes gastric emptying by increasing gastric and small bowel motility.
Metoclopramide is best avoided in patients with Parkinson’s disease because of possible side effect from dopamine antagonism, like akathisia

ANTACIDS

Antacids raise gastric pH by neutralizing HCl.

Clinically useful antacids:
- aluminum salts
- calcium salts
- magnesium salts

These react with hydrochloric acid to form neutral, less acidic, or poorly soluble salts.

Cause neutralization of gastric fluid pH increases gastric motility via the action of gastrin (aluminum hydroxide is an exception) and increases lower esophageal sphincter tone by a mechanism that is independent of gastrin.
Best way to quickly increase gastric pH

Non-particulate antacids such as sodium citrate increase gastric pH at the time of administration, and hence are more effective than histamine-2 receptor antagonists in the short term.

Antacids have an immediate effect, compared to the delayed onset of effects of H2-receptor antagonists
Antacids increase gastric volume, unlike H2-receptor antagonists.

Complications:
- Acid rebound– marked increase in gastric acid hours after antacid neutralization; unique to calcium-containing antacids
- Milk-alkali syndrome- hypercalcemia, increased BUN and creatinine, and systemic alkalosis; most common with calcium carbonate
- Phosphorus depletion– aluminum salts antacids
- Drug interactions- besides the aluminum antacids, delivery of gastric contents to the small intestine is sped up by antacids

Nonparticulate antacids, like sodium citrate (Bicitra), lower the pH of gastric content reliably.

OTHERS

GLUCOCORTICOIDS

The antiemetic mechanism of action is unclear but involves decreases in serotonin and inhibition of prostaglandin synthesis.
A single dose does not increase wound complications.
Should be given during the induction of anesthesia to aid in prophylaxis of PONV because the onset is 1 hour.
Can raise blood glucose levels by 40 mg/dL in type 2 diabetics
Dexamethasone and methylprednisolone are most common.
Similar efficacy= dexamethasone 4 mg IV – ondansetron 4 mg IV – droperidol 1.25 mg IV.
Caution in diabetes.

BUTYROPHENONES (ANTIPSYCHOTICS)

First-generation antipsychotics that block dopamine receptors in the basal ganglia and limbic portions of the forebrain.
Haloperidol and droperidol are examples.
FDA Black box warning: Can cause prolongation of QT interval and extrapyramidal symptoms.
Contraindicated in parkinson’s….

NEUROKININ 1 RECEPTOR ANTAGONISTS

Aprepitant (Emend), fosaprepitant (Emend- IV), netupitant/palonosetron (Akynzeo), and rolapitant (Varubi) are examples.
Neurokinin receptors are in the nucleus of the solitary tract (NST), involved in central regulation of visceral function.
Caution: decreases oral contraceptives effectiveness.

ANTICHOLINERGIC

Blocks transmission of cholinergic impulses to prevent nausea and vomiting.
Transdermal scopolamine should be applied the evening before surgery.
Onset is 4 hours and duration of at least 24 hours.
Most effective when PCA is used for pain.
Caution with elderly and contraindicated in closed-angle glaucoma

BENZODIAZEPINES

- Decreases dopamine in CTZ and decreases serotonin by binding to GABA

REFERENCE: Nagelhout Nurse Anesthesia 7^th edition, pages 208-211, 215

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Insulin

It is synthesized in the beta cells of the pancreas.
Total daily insulin secretion is 60 units but only 30 units are delivered peripherally because the liver removes half when passed through hepatic circulation.
Insulin is cleared within 10-15 minutes, primarily by the liver and, to a lesser extent, the kidneys.
It promotes storage of:
- Carbohydrates
- Fat
- Protein
Insulin also serves to move electrolytes into the cell, like:
- Potassium
- Phosphate
- Magnesium
Major insulin sites of action:
- Liver
- Muscle
- Adipose tissue
Stimulation of insulin secretion is by plasma glucose levels. Both the sympathetic and parasympathetic systems innervate the islets. Beta stimulation and vagal activity increases insulin.
Incretin hormones help to lower blood glucose levels by potentiating insulin production and decreasing glucagon secretion from the pancreas. These GI hormones are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).

INSULIN TYPE	ONSET	PEAK	DURATION
Aspart (Novolog)	10-30 minutes	30-180 minutes	3-5 hours
Lispro (Humalog)	10-30 minutes	30-180 minutes	3-5 hours
Regular (Humulin-R; Novolin-R)	30-60 minutes	2-4 hours	Up to 10 hours
NPH	2-4 hours	4-8 hours	12-18 hours
Detemir (Levemir)	2-4 hours	Minimal	12-24 hours
Glargine (Lantus)	2-4 hours	Minimal	Up to 24 hours
Degludec (Tresiba)	2-4 hours	Minimal	Up to 48 hours

GLUCAGON

Produced by the alpha cells of the pancreas and serves as the antagonist to insulin.
Glucagon increases when the blood glucose concentration drops below 90 mg/dL.

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Oral Hypoglycemic Drugs

Overwhelmingly, type 2 diabetes is the far more prevalent form of diabetes mellitus (90%). Obesity is the major risk factor. Conversely, weight reduction can improve the tissues response to it’s own insulin supply and restore normal glucose levels. These patients have some insulin production but it is not enough to maintain normal glucose levels.

Treatment includes diet modification, exercise, and glucose-lowering agents.
Why are ketones produced in diabetes?
- Glucose is the main source for energy for cellular mechanisms and especially brain functions. In diabetes, insulin fails to deliver glucose inside the cell for use. Blood levels are increased but intracellular are low. The body will begin to break down fat for energy to supplement the energy deficit.
Why is glucose “spilled over” into the urine?
- When glucose levels exceed 200 mg/dL, the glomerulus in the kidneys reach their limit for filtration. The excess remains in the glomerulus and eventually ends in the urine. Glucose produces an osmotic diuresis by pulling water into the glomerulus.
What is activated when there is a lack of insulin?
- The hormone-sensitive lipase that leads to uninhibited lipolysis of stored triglycerides, releasing free fatty acids and glycerol into the blood.
- The excess free fatty acids are turned into ketone bodies in the liver. Specifically, the ketone bodies are acetoacetic acid, beta-hydroxybutyric acid, and acetone.

HYPOGLYCEMICS

Used to treat type 2 diabetes mellitus.

Classifications:
- Biguanides
  - Metformin
    - Decreases hepatic glucose production, increases secretion of glucagon-like peptide-1 (GLP-1), and increases peripheral insulin sensitivity
- Sulfonylureas
  - Glyburide
  - Glimepiride
    - Increases insulin production and secretion by pancreatic beta cells
- Meglitinides
  - Increases insulin production and secretion by pancreatic beta cells
- Thiazolidinediones
  - Pioglitazone
    - Decreases hepatic glucose production and increases insulin sensitivity of adipose, muscle, and liver cells
- Incretin mimetics
  - Exenatide
  - Liraglutide
  - Albiglutide
    - Potentiates insulin release, lowers serum glucagon levels, SLOWS GASTRIC EMPTYING, and promotes satiety
- DPP-4 Inhibitor
  - Sitagliptin
  - Saxagliptin
  - Linagliptin
    - Inhibits metabolism of endogenously released incretin hormones; potentiates insulin release, lowers glucagon levels, SLOWS GASTRIC EMPTYING, and promotes satiety

- Alpha-glucosidase inhibitors
  - Blocks the intestinal enzymes that digest starches into absorbable monosaccharides
- Sodium-glucose cotransporter-2 inhibitors
  - Empagliflozin
    - Blocks the transport of glucose from the proximal renal tubule, decreasing renal glucose reabsorption and increasing glucose excretion
  REFERENCE: Nagelhout Nurse Anesthesia 7^th edition, pages 866-874

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Diuretics

Fluid overload occurs when an excess of salt or water becomes evenly or unevenly distributed in the body.
- Even distribution is congestive heart failure
- Uneven distribution is edema
Edema results when Starling forces favor passage of fluid into interstitial spaces.
Normally, < 1% of filtered Na+ will enter the urine (FE_Na is < 1%). The Na+/K+-ATPase pump is responsible for pumping sodium out of cells in exchange for potassium.

SITE	DIURETIC	OTHER
Proximal tubule	Acetazolamide	Exchanges H+ for Na+ = reabsorbs Na+ and acid urine Carbonic acid (H₂CO₃) generates H+ Carbonic anhydrase inhibitors lead to alkaline diuresis (Na+ and HCO₃^–)
Glomerulus	Mannitol	Osmotic diuretic; freely filtered but poorly reabsorbed Treatment of intracranial pressure
Thick ascending limb of Henle loop	Bumetanide Ethacrynic acid Furosemide	Loop diuretics directly inhibit the electroneutral transporter, prevents Na⁺ reabsorption 1^st-line treatment for acute CHF Ototoxicity and hypokalemia
Distal convoluted tubule	Thiazide Metolazone	Act in the early part of this segment to block the NaCl cotransport mechanism Treat HTN, volume overload, and pregnancy-induced edema
Distal (collecting duct)	Amiloride, Triamterene. Spironolactone, Eplerenone	NaCl absorption in collecting ducts is not electroneutral here K+ is spared Competitive aldosterone antagonists also work in the collecting duct
Dopamine type 1 (DA₁) receptor agonists	Dopaminergic agonists Dopamine at 1-3 mg/kg/min (IV) Fenoldopam	Modestly increases GFR and reduces proximal Na+ reabsorption
Proximal tubule	SGLT2 inhibitors (sodium-glucose co-transporter 2)	Normally treats hyperglycemia in type 2 DM Prevents reabsorption of 90% of filtered glucose

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Anticoagulants and Antagonists

Heparin and Low-Molecular Weight Heparins

Heparin has an onset is < 1 minute and increases activity of antithrombin.

Heparin Reversal - Protamine

Heparin is commonly neutralized by administration of 1.3 mg of protamine for each milligram of heparin. Protamine is a basic protein that combines to the acidic heparin molecule to produce an inactive complex that has no anticoagulant properties.
Protamine causes an increase in pulmonary vascular resistance.

Antiplatelet Medications

Platelet function becomes abnormal with aspirin therapy.
Aspirin irreversibly inactivates cyclooxygenase for the life of the platelet (7-12 days).

Oral Anticoagulants

Oral Anticoagulant Reversal

Thrombolytics

Thrombin Inhibitors

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Procoagulants

Antifibrinolytics

DDAVP

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Antimicrobials and Antivirals

Antimicrobials

Antibiotics are the second leading cause of intraoperative anaphylaxis (neuromuscular blockers are first).

Antibiotics account for about 15% of anesthesia-related anaphylactic reactions.
- Penicillins and cephalosporins are 70% of these occurrences.

Antibiotics should be given within 60 minutes of surgery.

May potentiate neuromuscular blockade:
- Aminoglycosides
- polymyxinste
- tetracycline antibiotics

REFERENCE: Nagelhout Nurse Anesthesia 7^th edition, pages 204-208, 1060-1064

Antivirals

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Antiepileptic Drugs

Epilepsy describes a group of chronic central nervous system (CNS) disorders characterized by sudden disturbances of sensory, motor, autonomic, or psychic origin.

Regarding clearance and elimination half-times, these drugs can range from hours to days. Because of this, there are many interactions with other drugs.

Patients treated chronically with anticonvulsants (phenytoin and carbamazepine) are relatively resistant to most neuromuscular blocking drugs, like rocuronium, vecuronium, pancuronium, and cisatracurium.
- Acute phenytoin use has been shown to increase neuromuscular blockade.

Factors that may spread the seizure focus into areas of the normal brain:

- Changes in blood glucose concentrations
- Pao2
- Paco2
- pH
- electrolyte balance,
- Endocrine function
- Stress
- Fatigue

Short term treatment of acute seizures can be accomplished with benzodiazepines.

Partial seizures
- Carbamazepine and phenytoin

Generalized seizures
- Valproate, lamotrigine, and topiramate

Generalized nonconvulsive seizures (like absence)
- Ethosuximide, lamotrigine, and valproate

Others:
- Levetiracetam- partial onset
- Phenobarbital- long-acting barbiturate

STATUS EPILEPTICUS

Continuous seizures without recovery of consciousness between seizures.

Treatment:
- Secure airway
- Ventilation, may require intubation
Pharmacology
- Benzodiazepine (diazepam or lorazepam)
- Phenytoin- used in conjunction with benzos for long-acting effects
- Phenobarbital

ACUTE OR CHRONIC PAIN

These drugs can inhibit neuronal excitation and stabilize nerve membranes to decrease repetitive neural ectopic firing, which is common in neuropathic pain.
Second generation antiepileptics, like gabapentin and pregabalin, are similar to GABA receptors and exhibit anticonvulsant, anxiolytic, and antihyperalgesic effects.

REFERENCE: Nagelhout Nurse Anesthesia 7^th edition, 1302, 1316; Barash Clinical Anesthesia 9^th edition, page 1529

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Lipid - Lowering Agents

Statins reduce endovascular inflammation and stabilize endothelial plaque.

Drugs used to treat increased plasma low-density lipoproteins (LDLs) do so by:
- Bile acid binding in the intestine
- Inhibition of the rate-limiting enzyme in cholesterol synthesis (3-hydroxy-3-methylglutaryl coenzyme A reductase, or HMG-CoA reductase)
- Inhibition of lipolysis in adipose tissue
- Antioxidant effects
Statins inhibit HMG-CoA reductase. This leads to a decrease in LDL by 60%.
Side effects:
- Persistent increases in plasma aminotransferase.
- Myopathy

REFERENCE: Nagelhout Nurse Anesthesia 7^th edition, pages 188, 586-587

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Herbal Remedies and Dietary Supplements

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Minerals and Electrolytes

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Dantrolene

Dantrolene is the medication that works on the ryanodine receptor for malignant hyperthermia treatment. It is a calcium channel blocker.
Dantrolene decreases the calcium release in skeletal muscle cells at the ryanodine receptor from the sarcoplasmic reticulum. Blocking the supply of calcium to contractile proteins will lead to skeletal muscle relaxation.
The initial dose of dantrolene for MH is 2.5 mg/kg IV.
The initial dose is 2.5 mg/kg IV. Assuming the patient is 100 kg, the patient would need 250 mg of dantrolene. 250 mg / 20 = 12.5 vials. This is a time-consuming process and is generally delegated to 1-2 people.

Characterized by its hypermetabolic nature, malignant hyperthermia is a severe, yet uncommon, disorder that is triggered by inhalational anesthetics and succinylcholine.
MH can lead to acidosis, hyperthermia, and hyperkalemia
The earliest sign of malignant hyperthermia is increased ETCO₂.
Malignant hyperthermia is best characterized by increased sympathetic tone.
Inhalational agents and succinylcholine are the triggers for MH, so the trigger should be stopped first (turn off inhalational anesthetic). Then try to eliminate the agent from the body (hyperventilate with 100% O2), administer dantrolene, and prevent/treat symptoms.
Rocuronium (0.9-1.2 mg/kg) has an onset of action that approaches succinylcholine (60-90 s), making it a suitable alternative for RSIs. Succinylcholine is a known trigger of MH.

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Steroids

Antiemetic
- The antiemetic mechanism of action is unclear but involves decreases in serotonin and inhibition of prostaglandin synthesis.
- A single dose does not increase wound complications.
- Should be given during the induction of anesthesia because the onset is 1 hour.
- Can raise blood glucose levels by 40 mg/dL in type 2 diabetics
- Dexamethasone and methylprednisolone are most common.

Anti-inflammatory
- Phospholipase A2 (PLA2) is the rate-limiting enzyme that catalyzes the liberation of arachidonic acid from membrane phospholipids. The liberation of arachidonic acid is the first step in the production of prostaglandins, leukotrienes, and thromboxanes
- Steroids decrease inflammation by inducing the biosynthesis of a PLA2 inhibitor and preventing subsequent prostaglandin generation.

Perioperative steroid replacement
- Patients on supraphysiologic doses of glucocorticoids may require supplemental coverage for minor to major surgeries for 2 reasons:
  - The adrenal glands may take 12 months to produce normal amounts after cessation of medication.
  - Surgery, and other stressors, can increase the amount of cortisol secretion by up to 7 times.
- Under these conditions, perioperative steroid supplementation may be required:
  - > 20 mg of prednisone is taken per day
  - ≥ 3 weeks on medication
  - Steroid treatment was within the last year before surgery

SURGICAL STRESS LEVEL	PERIOPERATIVE COVERAGE
Superficial surgery Dental Biopsies	NONE
Minor surgery Inguinal hernia Colonoscopy	Hydrocortisone 25 mg IV before induction
Moderate surgery Total abdominal hysterectomy Total joint arthroscopy	Hydrocortisone 50-75 mg IV before induction; taper by half per day over 1-2 days
Major surgery Cardiac Thoracic Liver	Hydrocortisone 100-150 mg IV before induction; taper according to patient’s postop condition

REFERENCE: Nagelhout Nurse Anesthesia 7^th edition, pages 209-210, 883-884

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Tocolytics

Suppress uterine contractile activity.

Tocolysis is warranted when gestational age is less than 37 weeks of age. In the case of premature labor, it can provide enough time for glucocorticoids to be administered to improve fetal lung maturity.

Contraindications:
- Uterine infection
- Severy hemorrhage
- Non-reassuring fetal status
- Fetal death or anomalies incompatible with life

Beta agonists stop premature labor by relaxing smooth muscle in the uterus through stimulation of beta 2 receptors. 2 common drugs:
- Ritodrine
  - Crosses the placenta
- Terbutaline
  - Side effects include hypokalemia, hyperglycemia, and tachycardia.

Magnesium is a tocolytic but its use solely as a tocolytic is not recommended.
- Magnesium relaxes smooth muscle.
- Immediate onset and effective for 30 min.
- Can cause loss of beat-to-beat variability in fetus
- Increases sensitivity to both non-depolarizers and succinylcholine

Calcium channel blockers
Prostaglandin inhibitors

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Uterotonics

Oxytocin

Acts on uterine smooth muscle to stimulate both the frequency and force of contractions.

Adverse actions include:
- Increase in systolic and especially diastolic blood pressure
- Tachycardia
- Arrhythmias in high doses

The antidiuretic effect of oxytocin can lead to water intoxication, cerebral edema, and convulsions.

Do not use oxytocin in patients with pre-eclampsia, hypertension, or cardiac disease.

Uterine Inversion

Once the uterus is replaced after reduction, an infusion of oxytocin is started to keep the uterus contracted to prevent a recurrence of inversion.

Uterotonics

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Intravenous Dyes

Methylene blue dye interferes with the accuracy of pulse oximetry.
Pretreatment with histamine blockers and corticosteroids can help prevent anaphylaxis in the allergic patient.
Breast cancer patients routinely undergo a sentinel node biopsy which is the first lymphatic node from the region in question. To ascertain whether the node is pathologic, the surgeon injects either isosulfan blue vital dye or 99^th-technitium-labeled sulfur colloid. Expect the pulse oximetry to read falsely low briefly.

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Cannabinoids

The most abundant cannabinoids:
- Delta-9-tetrahydrocannabinol (D9THC)
- Cannabidiol

D9THC is the main psychotropically active cannabinoid.

Two principal endogenous cannabis receptors (CB 1 and CB 2) have been identified.

- CB 1 receptors are present in the CNS (especially spinal cord)
- CB 2 receptors are located peripherally and linked with cells in the immune system.
- Both are members of the G protein family and modulate second messenger activity (adenylate cyclase activity) and calcium function.

D9THC uses:
- Long-term treatment of nausea and vomiting
- Cachexia
- Chronic pain management
Potential for psychic and physical dependence
Less risk of side effects than opioids