ANES 460: Pharm and Intravenous Drugs

Pharmacokinetics

• Absorption: rate of transfer of drug to systemic circulation
• Distribution: movement and dilution of drug into plasma, then tissues
• Clearance/Elimination: removal of drug from tissues

Factors Affecting Absorption

• Delivery method
• Bioavailability
• First-pass metabolism

Delivery Methods

• IV: 100% absorption rate
• IM: lower absorption rate than IV, varies depending on vascularity of muscle tissue
• PO: lower absorption rate than IV, affected by digestion and metabolism
• SQ (subcutaneous): slower absorption rate, typically around 24 hours
• Transdermal: slow absorption through the skin
• Intrathecal (spinal): higher absorption rate than epidural
• Epidural: lower absorption rate than intrathecal

Rate of Drug Flow

• Proportional to the concentration gradient

Absorption Curve

• Drug dosage does not affect the peak and shape of the curve, only the concentration
• Rate of absorption is a first-order transfer

Bioavailability

• Extent and rate of absorption of the active drug ingredient
• Affected by delivery method, e.g., PO bioavailability starts at 0, increases during digestion, and then decreases

First-Pass Metabolism

• Process by which drug concentration is significantly reduced before reaching systemic circulation
• Associated with the liver

Volume of Distribution

• Volume of drug distribution at equilibrium
• Determined by drug solubility in tissues versus blood

Central and Peripheral Volume of Distribution

• Central volume: volume of blood/tissue that a drug has had time to mix with immediately after injection
• Peripheral volume: most commonly fat, lipid-soluble drugs will be more concentrated in this volume

Distribution of a Drug

• Determined by vascularity: vessel-rich group, muscle group, fat group, and vessel-poor group

Clearance and Metabolism

• Two types of metabolism: hepatic metabolism (liver biotransformation) and tissue metabolism (plasma enzymes)
• Cytochrome P-450 system in the liver utilizes oxidation/reduction, conjugation, and hydrolysis
• Examples of drugs that undergo tissue metabolism: Remifentanil, Succinylcholine, Esmolol

Rate of Drug Metabolism

• R = Q(Cinflow - Coutflow)
• Q: liver blood flow, C: concentration of the drug

Flow-Limited Clearance and Capacity-Limited Clearance

• Flow-limited clearance: rate of blood flow is the only factor that limits clearance
• Capacity-limited clearance: clearance limited by the liver's ability to metabolize the drug

Elimination and Clearance

• Having a large store of body fat can slow down the process of clearance depending on the drug
• Elderly patients may have changes in CO, hepatic metabolism, and neurological changes that affect drug effects

Absolute Contraindications

• Reasons to avoid intervention that fully prevent the drug administration

Propofol

• Speed of onset: 30-60 seconds, short duration: 3-8 minutes
• Mechanism: GABA(A) receptor agonist, potentiates movement of Cl-, inhibitory effect
• Metabolism: rapid in liver, excreted to kidneys, clearance from plasma is greater than hepatic blood flow
• Effects: hypnotic, anticonvulsant, fast onset, and short duration
• Cardiovascular effects: decrease systemic arterial BP due to vasodilation
• Respiratory effects: respiratory depression
• GI effects: antiemesis
• Risks: allergic reactions, severe hypotension

Fospropofol

• Pro-drug of propofol, created as an alternative with no pain, not stored in liquid emulsion

Benzodiazepines

• Speed of onset: 2 minutes, peak: 5-10 minutes, duration: 15-20 minutes
• Mechanism: GABA(A) receptor agonist, high degree of lipid solubility
• Metabolism: highly protein bound in plasma, metabolism occurs in liver
• Safety profile: good, minimal respiratory and cardiovascular effects
• Reversal: selective antagonist (flumazenil)

Ketamine

• Speed of onset: 30 seconds, peak: unknown, duration: 5-10 minutes
• Mechanism: NMDA receptor inhibition
• Metabolism: partial water soluble, highly lipid soluble, metabolized in liver, and redistributes
• Chemical characteristics: PCP derivative, racemic mixture
• Effects: myoclonic activity, sedation/hypnosis, hallucinations, analgesia
• Risks: hypersensitivity, uncontrolled hypertension, stroke, intracranial mass/bleed

Etomidate

• Speed of onset: 1 minute, duration: 3-8 minutes
• Mechanism: depresses reticular activating system (mimics GABA activity)
• Metabolism: metabolized by hydrolysis in liver/plasma, highly protein bound
• Chemical characteristics: not water soluble, propylene glycol solution, pH 6.9
• Effects: hypnosis, may activate seizures, cardiovascular effects: decrease SVR, minimal HR/CO changes
• Risks: pain on injection, adrenal suppression, hesitant towards 3rd trimester pregnancy and elderly patients

Dexmedetomidine

• Mechanism: alpha-2 agonist
• Effects: hypnosis, analgesia, cardiovascular effects: bolus can decrease HR and BP, pulmonary effects: no respiratory depression

Inhalation Anesthetics

• Potency: determined by oil-gas partition coefficient
• Solubility: directly related to potency, high potency indicates high solubility
• Effects: determined by alveolar ventilation, cardiac output, and metabolism

Alveolar Ventilation

• Increases FA:FI, helps FA:FI approach 1, and speeds up induction
• Uptake: removal of anesthetic from the alveoli to the blood
• Equation: Uptake = [(solubility)(cardiac output)(PA-PV)]/PB

Factors Affecting Induction

• Increase inspired partial pressure
• Increase alveolar ventilation (VA)
• Decrease solubility
• Decrease cardiac output
• Hyperthermia (lower solubility)
• Decrease inspired concentration
• Hypoventilation
• Increase solubility
• Increase cardiac output
• Large circuit volume