Dexmedetomidine

Mechanism of Action:

-It is an imidazole derivative and is a specific alpha-2 adrenoceptor agonist that acts via post-synaptic alpha-2 receptors primarily in the locus ceruleus to increase conductance through K+ channels.

Uses and Dose:

-Its main actions are sedation, anxiolysis, and analgesia

-It is a clear, colorless isotonic solution containing 100 g/ml of dexmedetomidine base and 9 mg/ml of sodium chloride in water. The solution is preservative-free and contains no additives.

-Dexmedetomidine can be administered intravenously, intramuscularly, and transdermally.

1. ICU Sedation:

-Used for sedation of initially intubated and mechanically ventilated patients in ICU.

-Loading: 1 mcg/kg IV over 10 minutes; loading dose may not be required for adults converted from other sedative therapy.

-Maintenance 0.2-0.7 mcg/kg/h. continuous IV infusion; not to exceed 24 h.

-The duration of use should not exceed 24 hours.

-Dexmedetomidine has been infused in mechanically ventilated patients before, during, and after extubation; it is not necessary to discontinue dexmedetomidine before extubation.

2. Procedural Sedation:

Indicated for sedation of non-intubated patients before and/or during surgical and other procedures.

Loading: 1 mcg/kg IV over 10 minutes.

Maintenance 0.6 mcg/kg/h. IV titrate to effect (usually 0.2-1 mcg/kg/h.).

3. Awake Fiberoptic Intubation:

Loading: 1 mcg/kg IV over 10 minutes.

Maintenance 0.7 mcg/kg/hr IV until endotracheal tube secured.

Dosage Modifications:

-Dose reduction may be required if co-administered with other concomitant anesthetics, sedatives, hypnotics, or opioids.

-Consider dose reduction in patients with hepatic impairment or aged ≥ 65 y.; clearance decreases with increasing severity of hepatic impairment.

-Renal impairment: No dosage adjustment required.

Pharmacokinetics

Distribution: It is 94% protein-bound in the plasma; the volume of distribution is 1.33 l/kg. The distribution half-life is 6 minutes.

Metabolism: The drug undergoes extensive hepatic metabolism to methyl and glucuronide conjugates.

Excretion: 95% of the metabolites are excreted in the urine. The elimination half-life is 2 hours, and the clearance is 39 l/hour.

Pharmacodynamics:

1. Cardiovascular System: It causes a predictable decrease in the mean arterial pressure and heart rate.

2. Respiratory System: It causes a slight increase in PaCO₂ and a decrease in minute ventilation, with minimal change in the respiratory rate—these effects are not clinically significant.

3. Central Nervous System: The drug is sedative and anxiolytic—ventilated patients remain easily arousable and cooperative during treatment. Reversible memory impairment is an additional feature.

4. Metabolic / Other: It causes a decrease in plasma epinephrine and norepinephrine concentrations. It does not impair adrenal steroidogenesis when used in the short term.

Side Effects:

Hypotension, bradycardia, nausea, and a dry mouth are the most commonly reported side effects of the drug.

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Sodium Nitroprusside Toxicity

Sodium Nitroprusside Toxicity:

Mechanism of Action:

After parenteral injection, sodium nitroprusside enters red blood cells, where it receives an electron from the iron (Fe⁺²) of oxyhemoglobin. This non-enzymatic electron transfer results in unstable nitroprusside radical and methemoglobin (Hb Fe⁺³). The former moiety spontaneously decomposes into five cyanide ions and the active nitroso (NO) group. 

The cyanide ions can be involved in one of three possible reactions: 

1) Binding to methemoglobin to form cyan-methemoglobin.

2) Undergoing a reaction in the liver and kidney catalyzed by rhodanase enzyme to form thiocyanate + thiosulfate.

3) Binding to tissue cytochrome oxidase, which interferes with normal oxygen utilization.

N.B. Sodium nitroprusside toxicity is usually related to prolonged administration or occurs in patients with renal or hepatic failure. 

Mechanisms of Toxicity:

1) Direct vasodilation: resulting in hypotension and dysrhythmias (most common).

2) Thiocyanate toxicity: (occurs infrequently).

3) Cyanide toxicity: (in rare cases).

4) Methemoglobinemia: (in very rare cases).

Thiocyanate toxicity :

Symptoms:

Anorexia, nausea, abdominal pain, fatigue, and mental status changes, including psychosis, weakness, seizures, tinnitus, and hyperreflexia. 

Treatment: 

-Toxicity can be minimized by avoiding prolonged administration of nitroprusside and by limiting drug use in patients with renal insufficiency (as thiocyanate is usually excreted in the urine). 

-Thiocyanate can be removed by dialysis (if necessary). 

Cyanide toxicity:

-An early sign of cyanide toxicity is the acute resistance to the hypotensive effects of increasing doses of sodium nitroprusside (tachyphylaxis). (It should be noted that tachyphylaxis implies acute tolerance to the drug following multiple rapid injections, as opposed to tolerance, which is caused by more chronic exposure). 

-Acute cyanide toxicity occurs when the cyanide ions bind to tissue cytochrome oxidase and interfere with normal oxygen utilization. This leads to metabolic acidosis, cardiac arrhythmias, and increased venous oxygen content (as a result of the inability to utilize oxygen). 

Symptoms: 

-Cyanide toxicity is often associated with the odor of almonds on breath and can result in metabolic acidosis, tachycardia, mental status changes, respiratory arrest, coma, and death. 

Treatment: 

-Cyanide toxicity can usually be avoided if the cumulative dose of sodium nitroprusside is less than 0.5 mg/kg/h. 

-Mechanical ventilation with 100% oxygen to maximize oxygen availability. 

-Administering sodium thiosulfate (150 mg/kg over 15 min) or 3% sodium nitrate (5 mg/kg over 5 min), which oxidizes hemoglobin to methemoglobin, or by limiting the administration of nitroprusside. 

Methemoglobinemia:

-Methemoglobinemia occurs due to excessive doses of sodium nitroprusside or sodium nitrate, if the level is greater than 15 %, it can result in symptomatic cellular hypoxia.

Treatment: 

-Methylene blue (1–2 mg/kg of a 1% solution over 5 min), which reduces methemoglobin to hemoglobin.

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Drugs Avoided in Patients with Renal Failure

Drugs Avoided in Patients with Renal Failure

➧ The excretion of water-soluble drugs and their active metabolites will be impaired. For drugs that are renally excreted the half-life increases slowly with deteriorating renal function until severe nephron loss at which point the half-life increases sharply with further reductions in renal function. Dialysis can only usually replace a small part of the excretory capacity of the healthy kidney. 

Antibacterial agents:

1-Injectable penicillin G or carbenicillin: may be associated with neuromuscular toxicity, myoclonus, seizures, or coma. 

2-Vancomycin 

3-Amphotericin 

4-Tetracyclines: except doxycycline (Vibramycin), have an antianabolic effect that may significantly worsen the uremic state in patients with severe disease. 

5-Aminoglycosides 

6-Imipenem/cilastatin (Primaxin): can accumulate in patients with chronic kidney disease, causing seizures if doses are not reduced. 

7-Sulphonamides 

8-Nitrofurantoin (Furadantin): has a toxic metabolite that can accumulate in patients with chronic kidney disease, causing peripheral neuritis. 

Anesthetic drugs:

1-Muscle relaxants:

➧ Depolarizing muscle relaxant:

-Suxamethonium: should be avoided if hyperkalemia is present. 

➧ Non-depolarising muscle relaxants (NDMRs): 

-NDMRs depend on the kidney for elimination)

-Gallamine: should be avoided 

-Pancuronium, pipecuronium, alcuronium, curare, and doxacurium: should be used with caution. Potentiation of neuromuscular blockade may occur in the presence of metabolic acidosis, hypokalemia, hypermagnesemia, or hypocalcemia and with medications such as aminoglycosides. Monitor neuromuscular blockade whenever possible. 

-Vecuronium and mivacurium: are safe to use in renal failure as only small percentages are excreted renally.

2-Opioids:

-Morphine: is metabolized in the liver to morphine-6-glucuronide which has about half the sedative effect of morphine with a markedly prolonged half-life. 

-Pethidine: is partially metabolized to norpethidine which is less analgesic and has excitatory and convulsant properties. 

-Tramadol and codeine: Metabolites can accumulate in patients with chronic kidney disease, causing central nervous system and respiratory adverse effects.

3-Inhalational agents:

➧ There is decreased elimination of the fluoride ions which are significant metabolites of enflurane, sevoflurane, and methoxyflurane which can worsen renal function, so these inhalational agents should be avoided especially if used at low flows. 

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):

➧ NSAIDs should be avoided as all decrease renal blood flow and may precipitate complete renal failure. 

➧ Adverse renal effects of NSAIDs include acute renal failure; nephrotic syndrome with interstitial nephritis; and chronic renal failure.

➧ The risk of acute renal failure is three times higher in NSAID users than in non-NSAID users.

➧ Other adverse effects of NSAIDs include decreased potassium excretion, which can cause hyperkalemia, and decreased sodium excretion, which can cause peripheral edema, elevated blood pressure, and decompensation of heart failure.

➧ NSAIDs can blunt antihypertensive treatment, especially if beta-blockers, ACE inhibitors, or ARBs are used.

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Drugs affecting IOP

Drugs affecting IOP

➧ Normal intraocular pressure (IOP) is between (10 - 20 mmHg). The average value of IOP is 15.5 mmHg with fluctuations of about 2.75 mmHg.

➧ IOP also varies with other factors such as heart rate, respiration, fluid intake, systemic medication, and topical drugs.

➧ Intraocular vascular tone is predominantly affected by CO₂; hypocarbia decreases IOP through vasoconstriction of the choroidal blood vessels and decreases the formation of aqueous humor through reduced carbonic anhydrase activity. The increased IOP associated with hypoventilation and hypercarbia occurs as a result of vasodilation of CBV and increases in central venous pressure. 

A) Drugs that ↑ IOP:

1-Steroid-induced glaucoma:

Mechanism:

Is a form of open-angle glaucoma that is usually associated with topical steroid use, but it may develop with inhaled, oral, intravenous, periocular, or intravitreal steroid administration. 

Risk factors:

-Preexisting primary open-angle glaucoma

-Family history of glaucoma

-High myopia, diabetes mellitus

-History of connective tissue disease (especially rheumatoid arthritis). 

➧ Patients on chronic corticosteroid therapy can remain undiagnosed with an elevated IOP, which can result in glaucomatous optic nerve damage. 

➧ Steroid-induced IOP elevation typically occurs within a few weeks of beginning steroid therapy. In most cases, the IOP lowers spontaneously to the baseline within a few weeks to months upon stopping the steroid. In rare instances, the IOP remains elevated.

2-Topical anticholinergic or sympathomimetic dilating drops, TCA, MAOI, antihistamines, antiparkinsonian drugs, antipsychotic medications, and antispasmolytic agents:

Mechanism:

These medications produce pupillary dilation and precipitate an attack of acute angle-closure glaucoma in anatomically predisposed eyes that have narrow angles. 

3-Sulfa containing medications:

Mechanism:

Induce anterior rotation of the ciliary body causing angle-closure glaucoma. Typically, the angle closure is bilateral and occurs within the first several doses of the sulfonamide-containing medication. Patients with narrow or wide-open angles are potentially susceptible to this rare and idiosyncratic reaction.

4-Ketamine: 

The effect on IOP varies. Early studies reported an increase in IOP after IV or IM administration of ketamine. Ketamine given after premedication with diazepam and meperidine does not affect IOP and IM administered ketamine may even lower IOP in children. 

5-Depolarizing muscle relaxants (Succinylcholine):

Causes a transient (4–6 min) but significant increase in IOP of (10 - 20 mm Hg). Although the mechanism is unclear, the increase is not attributable simply to induced muscle fasciculations. 

6-Large volume Local anesthetic:

Injecting a large volume (8–10 mL) of Local anesthetic into the orbit (e.g. peribulbar block).

7-Tracheal intubation:

Sympathetic cardiovascular responses to tracheal intubation. 

8- Caffeine

B) Drugs that ↓ IOP:

In general, CNS depressants lower IOP.

1-Intravenous anesthetics and volatile agents:

Mechanism:

Relax extraocular muscle tone, depress the CNS (i.e., the diencephalon), improve the outflow of aqueous humor, and lower venous and arterial blood pressures.

➧ e.g. thiopental, propofol, etomidate, decrease in IOP by 14 - 50 % have been noted.

➧ During controlled ventilation and normocapnia, volatile inhaled anesthetics reduce IOP in proportion to the depth of anesthesia.

2-Non depolarizing neuromuscular blocking drugs:

Either do not affect IOP or produce a slight decrease.

3-Benzodiazepines:

IV administered diazepam (0.15 mg/kg) and equipotent intravenous doses of midazolam (0.03 mg/kg).

4-Narcotic premedication:

Causes no change, or only a slight decrease, in IOP. 

5-Neuroleptanalgesia:

Produced by mixtures of (fentanyl and droperidol) decreases IOP by 12 % in normocapnic patients. 

6- Alcohol consumption:

This leads to a transient decrease in IOP.

7- Several pretreatment regimens:

➧ IV lidocaine (1.5 mg/kg) or sufentanil (0.05–0.15 µg/kg) given 3 - 5 min. before induction. 

➧ Oral administration of the centrally acting antihypertensive drug clonidine (5 µg/kg) 2 hrs before induction of anesthesia blunts the IOP response to intubation. 

➧ Intranasal administration of nitroglycerin

➧ β-adrenergic receptor blocking drugs

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Drugs with Rebound Phenomenon

Drugs with Rebound Phenomenon

➧ The rebound effect, or rebound phenomenon, is the tendency of some medications, in sudden discontinuation, to cause a return of the symptoms it relieved, to a degree stronger than they were before treatment first began. Medications with a known rebound effect can be withdrawn gradually, or, in conjunction with another medication that does not exhibit a rebound effect. 

1-Sedative Hypnotics: 

-Benzodiazepine withdrawal can cause rebound anxiety and insomnia. 

-Eszopiclone and Zolpidem) can cause rebound insomnia. 

2-Stimulants:

➧ e.g. Methylphenidate or Dextroamphetamine 

➧ Rebound effects include psychosis, depression, and a return of ADHD symptoms but in a temporarily exaggerated form. 

3-Antidepressants:

➧ e.g. SSRIs

➧ Cause rebound depression and/or panic attacks and anxiety when discontinued. 

4-Alpha-2 adrenergic agents:

➧ e.g. Clonidine and Guanfacine

➧ The most notable rebound effect is rebound hypertension. 

5-Beta-adrenergic antagonists:

➧ e.g. Bisoprolol

➧ Sudden withdrawal leads to rebound tachycardia and anginal pain. 

6-Highly potent corticosteroids:

➧ e.g. Clobetasol for psoriasis

➧ Abrupt withdrawal can cause rebound psoriasis and hypoglycemia. 

7-Warfarin: 

➧ Withdrawal leads to thromboembolism 

8-Alcohol:

➧ Withdrawal leads to alcohol withdrawal syndrome: (anxiety and convulsions). 

9- Painkillers:

➧ Withdrawal can cause rebound headaches. 

10-Topical decongestants:

➧ Nasal sprays e.g. Phenylephrine

➧ Continuous usage can lead to constant nasal congestion, known as Rhinitis medicamentosa, and discontinuation to rebound nasal congestion.

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Ropivacaine (Naropin®)

➧ Ropivacaine is a long-acting amide local anesthetic (LA) drug. The name ropivacaine refers to both the racemic mixture and the marketed S-enantiomer.

➧ It produces effects similar to other LAs via reversible inhibition of sodium ion influx in nerve fibers.

Advantages:

➧ Ropivacaine is less lipophilic than bupivacaine and is less likely to penetrate large myelinated motor fibers, resulting in a relatively reduced motor blockade. Thus, ropivacaine has a greater degree of motor-sensory differentiation, which could be useful when the motor blockade is undesirable. 

➧ The reduced lipophilicity is also associated with decreased potential for central nervous system toxicity and cardiotoxicity.

Uses:

1-Epidural anesthesia 

2-Peripheral nerve block 

3-Postoperative pain management 

4-Intrathecal hyperbaric solution of ropivacaine was tried and found to be less potent than bupivacaine and resulted in a faster onset and recovery from the blocks. Hyperbaric ropivacaine solutions are not commercially available.

Contraindications:

1-Intravenous regional anesthesia (IVRA): However, recent data suggested that ropivacaine (1.2-1.8 mg/kg in 40 ml) can be used, because it has less cardiovascular and central nervous system toxicity than racemic bupivacaine. 

2-Intra-articular infusion: Ropivacaine is toxic to cartilage and its intra-articular infusion can lead to Postarthroscopic glenohumeral chondrolysis.

Adverse effects:

a) CNS effects: occur at lower blood plasma concentrations; CNS excitation followed by depression. 

-CNS excitation: nervousness, tingling around the mouth, tinnitus, tremor, dizziness, blurred vision, seizures. 

-CNS depression: drowsiness, loss of consciousness, respiratory depression, and apnea. 

b) Cardiovascular effects: occurs at higher blood plasma concentrations. 

-Hypotension, bradycardia, arrhythmias, and/or cardiac arrest – some of which may be due to hypoxemia secondary to respiratory depression.

Treatment of overdose:

➧ As for bupivacaine, Intralipid, a commonly available intravenous lipid emulsion, can be effective in treating severe cardiotoxicity secondary to local anesthetic overdose in animal experiments and in humans in a process called lipid rescue.

Read more ☛ LA Toxicity

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Fospropofol disodium (Lusedra®)

Chemistry:

➧ The chemical nature of propofol is 2,6-diisopropyl phenol. When a phosphate group is added to this molecule, it results in the formation of water-soluble propofol that does not contain lipids, egg products, or preservatives, thereby eliminating the allergic, bacterial infections and hyperlipidemic concerns associated with propofol. 

➧ The two phosphorylated propofol prodrugs were named propofol phosphate and phosphonooxymethyl propofol. 

➧ Substitution of hydroxyl by charged phosphate group introduces electronegativity which allows fospropofol to dissolve readily in water, hence does not cross the lipid membrane. The sodium salt of fospropofol is commonly used (2,6-diisopropyl phenoxy methyl phosphate disodium salt).

Mechanism of Action:

➧ Fospropofol is a water-soluble prodrug of propofol, a sedative/hypnotic/anesthetic drug. it is hydrolyzed by endothelial alkaline phosphatases to an active metabolite, propofol, formaldehyde, and phosphate, this process takes 15-20 min. leading to slow onset of action (4-13 min.). Its mechanism of action is uncertain, but it is postulated that its primary effect may be potentiation of the GABA-A and glycine receptors, possibly by slowing the channel closing time.

Uses:

➧ Fospropofol is an intravenous sedative-hypnotic agent. It is currently approved for use in monitored anesthesia care sedation of adult patients undergoing diagnostic or therapeutic procedures such as endoscopy.

Formulation and dose:

➧ Fospropofol is supplied as an aqueous solution designed for intravenous injection. The recommended initial dose of the drug is as follows:

Standard Dosing Regimen:

➧ In adults aged 18 to <65 years, who are healthy or have mild systemic disease, an initial IV bolus of 6.5 mg/kg followed by supplemental IV doses of 1.6 mg/kg (25 % of initial dosage) as needed to achieve the desired level of sedation. 

➧ The dosage of fospropofol is limited by the lower and upper weights of 60 kg and 90 kg.

Modified Dosing Regimen:

➧ For adults>65 years of age or those with severe systemic disease, initial and supplemental IV dosages of 75 % of the standard dosing regimen.

Advantages:

1-Less pain at the site of IV administration. 

2-Less potential for hyperlipidemia with long-term administration. 

3-Less chance for bacteremia.

Side Effects:

➧ Adverse events associated with the use of fospropofol may include, but are not limited to, the following: 

1-Paresthesias 

2-Pruritus 

3-Hypotension 

4-Hypoxemia 

5-Nausea 

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Magnesium Sulphate (MgSO₄)

Magnesium Physiology:

➧ Magnesium is the fourth most abundant cation in the body and is the second most abundant intracellular cation in the human body (potassium being the first).

➧ It has numerous physiological activities including activation of enzymes involved in energy metabolism, protein synthesis, regulation of vasomotor tone, neurotransmission, and signaling.

➧ It serves as a cofactor for more than 300 enzyme reactions that involve adenosine triphosphate (ATP). One of the magnesium-dependent enzyme systems is the membrane pump that generates the electrical gradient across cell membranes. As a result, magnesium plays an important role in the activity of electrically excitable tissues.

➧ Magnesium regulates the movement of calcium into smooth muscle cells, which gives it a pivotal role in the maintenance of cardiac contractile strength and peripheral vascular tone.

➧ Magnesium is required for the transformation of thiamine into thiamine pyrophosphate, so a magnesium deficiency can promote thiamine deficiency in the face of adequate thiamine intake. For this reason, the magnesium status should be monitored periodically in patients receiving daily thiamine supplements.

➧ Magnesium also has antinociceptive effects in animal and human pain models. Magnesium antinociceptive effects appear to be relevant not only to chronic pain but also, to the duration and intensity of postoperative pain. These effects are primarily based on physiological calcium antagonism, that is voltage-dependent regulation of calcium influx into the cell, and noncompetitive antagonism of NMDA receptors which produces a reduction of NMDA-induced currents.

Magnesium Balance:

➧ The average-size adult contains approximately 24 g (1 mole, or 2000 mEq) of magnesium. 

➧ Half of the total body content of magnesium is found in bone.

➧ The muscle and liver are the soft tissues that contain the greatest amount of magnesium.

➧ Thirty percent of extracellular magnesium circulates bound to protein. Therefore, albumin concentration must be known to interpret total magnesium levels.

Corrected Serum Mg = Mg x 0.42 + 0.05 (4 - albumin in g/dL) 

➧ Less than 1% of magnesium is located in plasma. This lack of representation in the plasma limits the value of the plasma magnesium concentration as an index of total body magnesium stores. 

➧ This is particularly true in patients with magnesium deficiency, in whom serum magnesium levels can be normal in the face of total body magnesium depletion.

➧ The serum is favored over plasma for magnesium assays because the anticoagulant used for plasma samples can be contaminated with citrate or other anions that bind magnesium. The normal range for serum magnesium depends on the daily magnesium intake, which varies according to geographic region.

➧ Only 67% of the magnesium in plasma is in the ionized (active) form, and the remaining 33% is either bound to plasma proteins (19% of the total) or chelated with divalent anions such as phosphate and sulphate (14% of the total).

➧ The daily oral intake is 8–20 mmol (40% of which is absorbed). Magnesium absorption occurs throughout the small intestine and is enhanced by 1,25(OH)₂D₃. Regulation of magnesium balance is mainly by the kidneys. Like calcium, magnesium is reabsorbed in the kidney tubules.

➧ When magnesium intake is deficient, the kidneys conserve magnesium and urinary magnesium excretion falls to negligible levels and the serum magnesium remains in the normal range. This illustrates the relative value of urinary magnesium over serum magnesium levels in the detection of magnesium deficiency.

➧ The normal range for healthy adults residing in the United States is shown in Table 1:

Table 1: Magnesium Reference Ranges

Magnesium Sulphate Preparations:

➧ The standard intravenous preparation is magnesium sulphate (MgSO₄). Each gram of magnesium sulphate has 8 mEq (4 mmol) of elemental magnesium.

➧ Saline solutions should be used as the diluent for magnesium sulphate. Ringer's solutions should not be used because the calcium in Ringer's solutions will counteract the actions of the infused magnesium.

Uses of Magnesium Sulphate:

1- Prevention of eclampsia in women with pre-eclampsia and it is also a recommended treatment for established eclampsia.

2- Used to treat atrial fibrillation, to achieve both rate control and reversion to sinus rhythm in many settings, including post-cardiac surgery, and in the emergency department.

3- Intravenous magnesium can suppress digitalis-toxic arrhythmias, even when serum magnesium levels are normal. Intravenous magnesium can also abolish refractory arrhythmias (i.e., unresponsive to traditional antiarrhythmic agents) in the absence of hypomagnesemia. This effect may be due to a membrane-stabilizing effect of magnesium that is unrelated to magnesium repletion.

4- It May be beneficial for patients with acute severe asthma either given intravenously or nebulized. 

5- May also prevent delayed cerebral ischemia due to vasospasm in patients with subarachnoid hemorrhage. 

6- Used in hypomagnesemia and hypomagnesemia associated with cardiac arrhythmias. 

7- Magnesium sulphate when used systemically, has shown antinociceptive effects and has decreased postoperative opioid requirements. A limitation to the parenteral application of magnesium for modulation of antinociception via NMDA channel antagonism is insufficient blood-brain barrier penetration to achieve effective CSF concentrations. 

8- Intrathecally administered magnesium has antinociceptive effects in animals. Intrathecal magnesium, an NMDA antagonist, has been demonstrated to prolong analgesia without notable adverse effects in healthy parturients and in various surgical procedures like lower limb surgeries and in patients undergoing total abdominal hysterectomy.

Contraindications:

➧ Hypocalcemia, heart block (risk of arrhythmias), and oliguria.

Interactions:

➧ Potentiates neuromuscular blockade (nondepolarizing/depolarizing). 

➧ Potentiates CNS effects of anesthetics, hypnotics, and opioids. 

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Sugammadex (Bridion®)

Cyclodextrins

➧ The starting point for encapsulating agents that used since 1953 as solubilizing agents and form low-affinity complexes with lipophilic drugs.

➧ γ-cyclodextrin: 8 sugar molecules forming a rigid ring with a central lipophilic cavity.

➧ Very water-soluble, not metabolized, renally excreted.

Sugammadex (Bridion®)

➧ Sugammadex is a modified γ-cyclodextrin, with a lipophilic core and a hydrophilic periphery.

➧ A selective relaxant binding agent that encapsulates and forms high-affinity complexes with steroidal neuromuscular blocking agents; rocuronium, vecuronium, and to a lesser extent pancuronium, preventing their action that will enable anesthesiologists to rapidly reverse shallow and profound neuromuscular block induced by them.

➧ The +ve charge of ammonium groups of rocuronium or vecuronium are attracted to the -ve charged sugar group in the center of the ring.

➧ Sugammadex is inactive against non-steroidal neuromuscular blocking agents, like succinylcholine and cisatracurium.

Advantages:

1- Can provide immediate reversal when required.

2- Provides complete and rapid reversal of profound neuromuscular blockade.

3- Minimizes the risk of residual postoperative paralysis.

Uses:

➧ Sugammadex is indicated in adults for:

1- Routine reversal of shallow and profound neuromuscular blockade induced by rocuronium or vecuronium.

2- Immediate reversal of neuromuscular blockade at 3 min. after administration of rocuronium.

3- In combination with rocuronium, may provide an alternative to succinylcholine.

4- Avoids the need to use acetylcholinesterase inhibitors (AChEIs) (neostigmine) and muscarinic antagonists (atropine/ glycopyrrolate) and elimination of side effects associated with them and the mechanical mixing of two drugs.

5- Sugammadex has no potential to cause drug-drug interaction (=DDI) due to inhibition or induction of drug-metabolizing enzymes.

Pharmacokinetics:

• Volume of distribution: ≈ 12-15 L

• Plasma half-life: ≈ 2.2 h

• Clearance: ≈ 91 mL/min (≈ GFR)

• Blood-brain barrier penetration (< 3% in rats)

• Placental transfer (< 2-6% in rats and rabbits) 

• Low plasma protein binding, No metabolism

• Sugammadex-Rocuronium complex is almost renally excreted

Dosing Recommendations:

Routine Reversal:

➧ A dose of 2 mg/kg is only recommended if spontaneous recovery has occurred up to the reappearance of T2 (shallow blockade) following rocuronium or vecuronium-induced blockade.

➧ A dose of 4 mg/kg is recommended if recovery has reached 1-2 post-tetanic counts (PTC) (profound blockade) following rocuronium or vecuronium-induced blockade.

Immediate Reversal:

➧ A dose of 16 mg/kg is recommended for 3 min. following the administration of rocuronium.

There are no data to support the use of sugammadex for immediate reversal following the vecuronium-induced blockade.

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