Anesthetic Pharmacology - Drug Interactions

Interactions between different anesthetic drugs or drugs with other substances during administration, leading to altered effects or adverse reactions.

Certain anesthetic drugs can react with specific materials, generating harmful substances.

Drug interactions influencing the absorption, distribution, metabolism, and elimination processes of drugs, affecting their overall effect.

Some drugs lessen the absorption of others through mechanisms like chemical reactions or by binding to them.

Adding certain drugs can decrease the flow of blood to specific areas, potentially impacting local anesthetic absorption.

How different forms of drugs interact with each other.

Drugs can become trapped in certain body compartments, lessening their effects.

The liver's role in changing the chemical structure of drugs to facilitate their elimination from the body.

When one drug alters the effect of another.

Some drugs can reduce the heart's pumping power, affecting blood flow.

Drugs can compete for binding spots on blood proteins

Some drugs can react badly when mixed.

Sodium bicarbonate reduces the solubility of bupivacaine, causing it to precipitate out of solution.

Sodium bicarbonate inactivates catecholamines, such as epinephrine and norepinephrine.

Neostigmine, an acetylcholinesterase inhibitor, increases the action of ester local anesthetics like procaine, cocaine, and tetracaine.

Etomidate inhibits cytochrome P450 dependent enzymes, specifically 17α-hydroxylase and 11β-hydroxylase, leading to reduced production of cortisol and aldosterone.

Drugs like phenobarbital, phenytoin, rifampicin, carbamezepine, and ethanol stimulate (induce) the activity of certain enzymes in the liver, leading to faster metabolism of other drugs.

Drugs like cimetidine, ketoconazole, erythromycin, disulfiram, ritonavir, etc., inhibit the activity of specific enzymes in the liver, leading to slower metabolism of other drugs.

Phenobarbital, a weak acid, is excreted faster in acidic urine due to the principle of ion trapping.

Probenecid inhibits the renal secretion of penicillin, leading to prolonged blood concentrations of penicillin.

Drugs with high ER (≥ 0.7) are heavily metabolized by the liver, with blood flow being the main factor limiting their metabolism.

Drugs with low ER (≤ 0.3) are less heavily metabolized by the liver, with enzyme activity being the main factor limiting their metabolism.

Lidocaine, a high ER drug, relies on liver blood flow for its metabolism. Reduced cardiac output or vasoconstrictors can increase its concentration.

Diazepam, a low ER drug, is metabolized by hepatic enzymes. Enzyme induction can increase its metabolism, while inhibitors can reduce it.

Drugs with similar mechanisms of action combined have amplified effects.

Drugs with opposing actions counteract each other's effects.

Combining small doses of drugs with different mechanisms results in a greater effect than expected.

Quinidine reduces digoxin's volume of distribution (Vd) and clearance, potentially increasing its concentration.

Propofol can cause dangerously high potassium levels in the blood (hyperkalemia), particularly in children, with prolonged infusions, and in patients with certain underlying conditions.

Propofol infusion can lead to high levels of triglycerides and other fats in the blood (hyperlipidemia), potentially causing fatty liver, heart problems, and muscle damage.

Propofol can affect heart function by causing slow heart rate, heart rhythm problems, and even heart failure. It is particularly concerning in patients with underlying heart conditions.

Early signs of propofol-related complications include metabolic acidosis, elevated lactate levels, and muscle breakdown markers. Watch for these.

Regular blood tests, such as blood gas analysis, triglyceride levels, and lactate levels, help monitor for early signs of propofol-related complications.

Avoiding high doses, minimizing infusion time, considering underlying conditions (like mitochondrial disease), and providing adequate nutrition can help prevent propofol-related complications.

Treatment for propofol-related complications involves stopping propofol, providing alternative sedation, supporting heart function, and managing metabolic issues.

Ketamine, a common anesthetic agent, works by reducing glutamate release in the brain. Glutamate is a neurotransmitter associated with pain signals.

Ketamine enhances the effects of GABA, another neurotransmitter in the brain that promotes relaxation and sedation. This combined action contributes to its anesthetic effects.

Ketamine interacts with multiple types of opioid receptors in the brain, further contributing to its pain-relieving and sedative effects.

Ketamine influences the action of monoamines, a group of neurotransmitters, affecting pain pathways and resulting in its unique pain relief properties.

Ketamine blocks muscarinic receptors, leading to bronchodilation (opening of airways) and sometimes delirium. This explains some of its side effects.

Ketamine's mild local anesthetic properties are partly due to its interaction with sodium channels, which are involved in nerve conduction.

Midazolam is a water-soluble compound due to the presence of an imidazole ring. This ring also contributes to its short duration of action and rapid metabolism.

Midazolam does not have any isomers (different spatial arrangements of atoms).

Midazolam's imidazole ring opens at a pH below 4, making it water-soluble. At physiological pH (above 4), the ring closes, making it highly lipid-soluble.

Midazolam works primarily by acting on benzodiazepine (BZD) receptors, which are closely related to GABA receptors. Facilitating GABA receptor opening leads to chloride channel opening and hyperpolarization of the synaptic membrane.

Midazolam also exhibits kappa opioid agonist activity, explaining its spinal analgesia.

Midazolam's short duration of action is due to its high lipid solubility and rapid redistribution.

Midazolam is metabolized by the liver and small intestine using cytochrome P450 enzymes. It's converted into 1 and 4 hydroxy-midazolam, with 1-hydroxy-midazolam having half the activity of original midazolam.

Midazolam is excreted in urine as glucuronide conjugates. Renal impairment only slightly impacts its elimination.

Midazolam can be used for induction of anesthesia, typically at a dose of 0.1–0.2 mg/kg IV. It causes a slower onset of unconsciousness compared to thiopental.

Midazolam is a commonly used premedication, especially in children for conscious sedation. It is given orally as a syrup (2 mg/mL) at a dose of 0.25 mg/kg at least 20 minutes prior to surgery.

Midazolam can be used for IV sedation at a dose of 0.03–0.05 mg/kg. Continuous IV infusion can be used at 4 µg/kg/min. It is useful for procedures under local anesthesia and monitored anesthesia care.

Midazolam can cause emergence delirium, which is characterized by confusion and agitation upon waking from anesthesia.

Midazolam can cause myoclonus, which is characterized by involuntary muscle twitches or spasms.

Midazolam injection can be painful, especially with aqueous preparations. This can be reduced with propylene glycol, cyclodextrin, and medium chain fatty acid formulations.

Midazolam interacts with several drugs, affecting its metabolism. Cimetidine, erythromycin, calcium channel blockers, and fentanyl all inhibit the metabolism of midazolam.