Clinical Pharmacology: Pharmacokinetics

• Clinical pharmacology principles include pharmacokinetics and pharmacodynamics.
• Patient demographics influence anesthetic behavior.

Pharmacokinetics

• This is what the body does to the drug.
• It describes the relationship between drug dose and concentration in plasma at the effect site over time.
• Absorption, distribution, metabolism, and excretion govern the relationship between drug dose and drug concentration.
• ADME is absorption, distribution, metabolism, and excretion.
• Absorption is not relevant with intravenously administered drugs.
• Time course of intravenously administered drugs is a function of distribution volume and clearance.
• Pharmacokinetic parameters are derived from mathematical formulas.

Volume of Distribution

• The volume of distribution is the apparent size of the tank required to explain a measured drug concentration from the "tank water" once the drug mixed within the "tank".
• Distribution volume is estimated using the relationship between dose (mg) and measured concentration (mg/L).
• Formula to find volume of distribution = Amount of dose (t) / Concentration (t)
• Human bodies are not water tanks, as a drug begins to be cleared from the body immediately after injection.
• If elimination occurs as a first-order process, which means elimination that is proportional to the concentration at that time, the calculated volume of distribution will be constant.
• With intravenous administration, some of the drug stays in the vascular volume, however most distributes to peripheral tissues.
• Distribution is represented as tanks connected to control plasma.
• Soluble peripheral tissue increases total volume of distribution.
• Volume of distrbution is increased when drugs distribute to the peripheral tank.
• Total volume of distribution can exceed the total volume of the two tanks combined. Volume of distribution does not remain constant over time.
• Some anesthetics have distribution volumes that are much larger than an individual, and larger than extracellular volume (0.07 L/kg).

Steady-State Volume of Distribution

• the overall volume of distribution can change over time, dependent on how the drug is administered (bolus or continuous infusion).
• A bolus dose increases distribution volume, as the drug distributes to peripheral tissue, which decreases plasma concentration.
• A constant infusion increases plasma concentration to a steady state over several hours.
• Steady state is also described as the drug´s plasma concentration and all other tissues in the body.
• Lipid soluble drugs have a greater volume of distribution then to H2O soluble drugs.
• Propofol has a very large volume of distribution and skeletal muscle relaxants have a small volume of distribution.

Tissue groups

• Vessel-rich group is 10% body weight, recieves 75% of cardiac output.
• Muscle group is 50% body weight, recieves 19% of cardiac output.
• Fat group is 20% body weight, recieves 6% of cardiac output.
• Vessel-poor group is 20% body weight, recieves <1% of cardiac output.

Clearance

• Clearance describes the rate of drug removal from the plasma/blood.
• Two processes contribute to drug clearance including systemic and intercompartmental clearance.
• Systemic clearance permanently removes the drug from the body either by eliminating the parent molecule or by transforming it into metabolites.
• Intercompartmental drug clearance is the movement of drug between plasma and peripheral tissue.
• Clearanceis defined in units of flow, which is the volume completely cleared of drug per unit of time (Liters/minute).
• Clearance = Q X E (Q = blood flow; E = extraction ratio).
• It is not to be confused with elimination rate (ex. mg/minute).
• It is a better descriptor because it is independent of drug concentration.
• For long infusions, drug concentrations reach a steady state, the rate of drug elimination is in equilibrium with the rate of drug administration. This occurs in approximately 4-5 half-times.
• Clearance is directly proportional to administered dose, and inversely related to the half-life of the drug.
• As the drug's half-life increases, the volume that is cleared per unit of time decreases.
• Because the kidneys are not effective at excreting lipophilic drugs, they rely on the liver to convert them into water-soluble metabolites through phase one and phase two reactions.
• Drug extraction occurs by metabolic organs.

Physiologic Model of Clearance

• States that rate at which drug flows out of metabolic organs is the rate which drug flows into them minus the metabolic rate.
• Fraction of inflowing drug extracted by the organ is the extration ratio (ER)
• Clearance can be estimated as organ blood flow multiplied by the ER
• Clearance = Q X E (Q = blood flow; E = extraction ratio)
• ER of 1.0 = 100% of drug to clearing organ is removed; ER of 0.5 = 50%
• The rate-limiting step in metabolism is the flow of drug to the liver, and is referred to as "flow limited.”
• Clearance is limited by the liver's capacity to take up and metabolize a drug - "capacity limited”.
• Capacity can change d/t liver disease or enzymatic induction.

Extrahepatic Metabolism

• Some anesthesia medications are not cleared by hepatic metabolism.
• Remifentanil, succinylcholine, and esmolol are cleared in the plasma and tissues by ester hydrolysis.
• Pancuronium undergoes clearence via the kidney.
• Three of the four plasma pathways are enzymatic, with Hofmann elimination being based on pH and temp as well.

Enterohepatic Circulation

• Describes the liver's process of excreting a substance into the bile, with the substance subsequently reabsorbed from the small intestine and transported back to the liver.
• Drugs that undergo Enterohepatic circulation tend to have a long effect. Examples include diazepam and warfarin.

Hepatic Biotransformation

• Most anesthetic drugs are cleared by hepatic biotransformation which includes oxidation reduction hydrolysis or conjugation
• Oxidation and reduction occur in the cytochrome P450 system.
• Conjugation and hydrolysis often occur outside the P450 system.
• Conjugation results in the transformation of hydrophobic molecules into water-soluble molecules through the addition of polar groups, and thus render the metabolites easier to excrete via the kidneys.
• Metabolites generated by the liver are generally inactive, but some like morphine and midazolam have active and potent metabolites.
• Genetic polymorphism can occur in all of these pathways, accounting for clearence variability in the population.

Phase I, II, III Reactions

• Primary job of metabolism is to change a drug to a more water soluble, inactive byproduct.
• This increases rate of ionization and decreases Vd.
• Phase I: Modification - Increase polarity (water solubility). Carried out by P450 system – oxidation, reduction and hydrolysis.
• Phase II: Conjugation - synthetic reactions in the body with addition of water-soluble substrate. These include the process of enzyme induction through st johns wart, or Enzyme inhibition from some ca channel blockers and anitbiotics.
• Phase III: Elimination: utilizes ATP-dependent carrier proteins in the liver to move drug.

Enzyme Inducers

• Increase clearance, decreased drug plasma level:
• Examples of inducers: Tobacco smoke, Barbiturates, Ethanol, Phenytoin, Rifampin, Carbamazepine.

Enzyme Inhibitors

• Decrease clearance, increased drug plasma level: dose decrease may be required:
• Examples of inhibitors include: Grapefruit juice, Cimetidine, Omeprazole, Isoniazid, SSRIs, Erythromycin, Ketoconazole.

Renal Elimination

• Elimination of metabolism-produced waste into ourine is key function of the kidney.
• A drug´s fate is determined by polarity and pH of the glomular fluid.
• Lipophilic drugs need to undergo biotransformation before kidney excretion.
• Getting the drug to the urine happens by glomerular filtration and organic ion transporters.
• Urine pH influences whether a drug will be excreted or reabsorbed with likes reabsorbing likes.
• Ammonium chloride or cranberry juice will acidify urine, facilitating excretion of basic drugs.
• Sodium bicarbonate or acetazolamide will alkalize urine, promoting excretion of acidic drugs.

Pharmacokinetic Models

• Provide estimates of drug concentrations over time to dosing regimens (bolus or infusion).
• Physiologic models are based on organ and tissue physiologic and anatomic data, in regards to drug flow.
• Compartment pharmacokinetic models are strictly empirical, fitting equations to measured plasma concentration.
• Central clearance accounts for metabolism and excretion. Clearances between central and peripheral compartments is “intercompartmental” clearance.

Zero-Order and First-Order Kinetics

• The rate of metabolism is dependent on concentration of drug at site of metabolism/intrinsic rate of metabolic process.
• Kinetic models take into account that there is limited quantity of enzymes to metabolize a drug.
• Zero Order Kinetics happens at a Constant amount/time and rate, measured in (mg/min)
  • When biotransformation process is saturated as seen in ETOH and Aspirin)
• First Order Kinetics occurs at a constant fraction per Time – Rate proportional to amount of drug present at time (1/time)
  • Where half of the drug is reduced independent of concentration.
  • 4-5 half lives = fully eliminated.
  • Directly proportional to Vd and Inversely proportional to rate of clearance.
• If enzymes are saturated? First can transition to Zero Order,

One Compartment Model

• Includes first-order kinetic elimination. The amount of drug at a given time (t) is described, in which the initial drug amount (I.E initial dose) undergoes a first-order kinetic elimination at a constant rate.

Multicompartmental Models

• Plasma concentrations over tiem resemble curves after IV bolus.
• Initial Curve represents charicteristics common to IV boluses.
• First, the concentrations continuously decrease over time (rapid-distribution).
• Second, the rate of decline steep initially but becomes less steep (slow-distribution).
• Then the curve path is log-linear (terminal/elimination phase).
• During log-linear stage, plasma concentration is less than in tissue concentrations.
• A rapid-distribution phase begins immediately after injection of the bolus; rapid drug movement from plasma to equilibrating tissues.
• Second is a slow-distribution phase, movement of drug into less equilibrating tissues in return to rapidly equilibrating tissues.
• The terminal Phase is often called "elimination", where primary mechanism for reducing drug concentrations is eliminating drugs from the body.
• At terminal phase, drug returns from rapid and slow distribution volumes to plasma, and permanently leaves plasma by excretion or metabolism.

Plasma Protein Binding

• Represents intravascular drug storage compartment and Drugs bond.
• Albumin is plentiful with half like of 3 weeks while basic drugs have a more rapid interaction with acidic glycoproteins.
• Only the unbound fraction of a drug is active.
• Also, Vd inversly related to protein binding with solubility.
• Plasma AND tissue proteins in the target tissue.

Front-End Kinetics

• Refers to description of intravenous drug behavior immediately after administration.
• How drug moves from blood to peripheral tissues directly influence peak plasma drug concentration.
• Once injected in arm it appears in circulation 30-40 seconds, and to be patient.

Back-End Kinetics

• Useful to describe behavior of intravenous agents after administered in continuous infusions.
• Dcrement time (context-sensitive half time), which predicts needed time to reach certain concentration once infusion is terminated.
• Context-sensitive refer to infusion in context, and half like reffers to decrment in 50%.

Hysteresis

• Hysteresis accounts for the time needed for a drug to diffuse from the plasma to site of action + time requirement for the drug side of action to take effect.
• An additional concept includes two different plasma concentrations corresponding to one drug effect - This would mean the change in desired concentration of drug would cause a delayed effect in the patient.

Various Influences on Kinetics

• These kinetics can include consideration for gender, where females need 20-30% less doses of some drugs. However with some procedures, can recall 3 x more then males.
• Increased temperature increases elimination of propofol.
• Bioavailability
• Refers to degree drug reaches site of effect from administration.
• Rate dug is absorbed, is based on the blood at the site of administration, the pH of the absorption site, PKA of the drug.
• First pass, through the liver, after being disolved is ~ 67% metabolized.

Enteral and Parenteral Medication Administration

• Undergo presystem elimination and stomach acid, or deactivated elimination to the first-pass metabolism of hepatic elimination. Also in more distal areas of intestine.
• IV has 100% bioavailability but alveolar endothelium can have pulminary affects.

Additional Routes

• Also Include IM / Subcoutaenous
• Epidermisis 20-30 times thicker on hands and regenerates approximately every 7 days

Pharmocodynamics

• What the drug does to the body
• Describes the relationship betwee dug concentration for pharmacologic effect
• Related to relationship Dose , receptor and ificancy
• Used measurement to demonstrate the rate of effect and increased effect
• Histersis Loop
• ascending portion of loop represents rising concentration.
  • While ascending, the concentration rises at drug effects lags behind the concentrate .
• The descending loop has the drug effects lower than the centrate
• Standard model on The Hill equation

Effective dose range

• The higher is better

Addition and synergy

• Inhalant agents are strictly additive as far as actions
• Interactions various Iv and IH are synergist
• Interractions btw IV and hypotics can be variable

Drug Displays models

• Known as response surface models including the use of effect site to visualize actions
• Use demographics and visual display for use

Dosing for the obese

• Obese dosing recommendations are to stay on per KG
• Scaled weight are smaller then TBN for dosing recommendations
• TBW for infusion and LBM for doesing.
• Volume of distribution
• Normalized weight and volume of distribution is lager so midzaliam to adipoctye ratio is higher

Inhalation

• Volume dose to adipose decrease as tissue does the same