Pharmacokinetics Concepts Flashcards
Easy way to make sense of this Pharmacokinetics concepts
Drugs goes in (front-end kinetics)
Drugs goes out (Back end kinetics)
Drugs given via IV not affected by that part of pharmacokinetics?
Absorption
What is bioavailablity?
Amount of drug reaching systemic circulation UNCHANGED.
What is the key concept of ABSORPTION?
Transfer from depot to Systemic Circulation
What are some of the depot organs?
Stomach, lungs, muscle tissue.
What plays an important role in the rate of absorption
Physical properties of the drug.
2 factors determine polarity of the molecule
pKa in relation to physiologic pH
DIFFUSION depends on concentration gradient between the depot and the systemic circulation (FIRST-ORDER KINETICS)
Absorption of Inhaled anesthetics depends on
Blood-Gas Partition coefficient
What is Blood Gas partition coefficient?
Describes concentration in Blood COMPARED TO that in the ALVEOLAR gas at equillibrium
(ex: blood concentration of drug is 10 , concentration in alveolar gas is 5 –> Partition coefficient is 2 (10/5)
What does a HIGH Blood partition coefficient means?What does it mean clinically?
A lot of drug must be absorbed before equillibrium occurs.
Clinically means it will take longer for the desired effect to be achieved.
Partition coeffecient is dependent on which physical property?
Temperature
What is the formula of VOLUME of distribution
Vd = dose / plasma concentration
Volume of distribution is property of a drug that describes its ability to do what ?
Ability to distribute in human body
How is the CENTRAL VOLUME Of DISTRIBUTION calculated?
Central Vd is
Inject drug IVsly –> then measure arterial concentration
ELUSIVE concept easy way:
Central Vd–> volume in lungs, hearts, great vessels and venous volume proximal to injection site.
What is peripheral volumes of distribution?
solubility in the tissues compared to that of plasma
each tissue have own peripheral Vd
Vd at steady states describes
tissue solubility at steady state for both central and peripheral
BACK end Kinetics: CLEARANCE
Process of removing drugs from a tissue
BACK END kinetics : clearance 2 ways
- Permanent removal (usually by hepatic Metabolism)
2. Intercompartmental Clearance (distribution clearance) from plasma to TISSUE
Most drugs metabolized by
Hepatic Biotransformation
What are the phase 1 Reactions?
Oxidation
Reduction
Hydrolysis
What is a phase 2 reaction?
Conjugation
2 reactions using CYP450
Oxidation and reduction
2 important enzymes inducers (RPPCSC)
Rifampin Phenytoin Phenobarbital Cigarette smoking Carbamezapine (Tegretol)
2 Important inhibitors
CCBs
AMIODARONE
What does CONJUGATION really do?
They combine a hydrophobic molecule to a POLAR group so that they can be easily excreted by the kidneys
After conjugation, those molecules are usually Inactive. What is the exception to that rule? Explain and why it is important?
MORPHINE
Morphine is metabolized into 2 metabolites: Morphine-3-Glucuronide (M3G) and Morphine-6- Glucuronide (M6G) (more potent than morphine itself
Important for patient with renal disease as they may not be able to metabolize the MORE POTENT
What other drugs has an active metabolite of equal potency?
Midazolam ( Versed)
In anesthesia, It is assumed that
rate of metabolism iS PROPORTIONAL to concentration (but remember is some cases liver may become saturated)
Formula to calculate rate of metabolism
Rate = Q (C inside - C outside)
Q blood flow to liver
C inside : concentration flowing in
C outside: concentration flowing out
Another important concept in liver metabolism is _________Calculated as
Hepatic Extraction ratio: liver not able to remove the molecule of a drug from plasma
ER = (C in - C out)/ C in
Clearance = Q x ER
High extraction Ratio means :
The metabolism of such drug said to be “ ____”
Clearance depends on blood flow to the liver (amount of drug metabolized will depend on liver blood flow)
Flow limited
Example of a drug with high ER
Propofol
Why is the concept high ER important for Anesthetists?
Anesthetics decrease HEPATIC BLOOD FLOW
Low extraction Ratio means
The metabolism of such drug said to be “ ____” :
Clearance DOES NOT depend on blood flow to the liver (amount of drug metabolized LESS depend on liver blood flow)
Capacity limited
Example of a drug with LOW ER
Alfentanyl
ONLY Major anesthetic that undergoes 80% renal excretion?
PANCURONIUM
Provides a good summary of determining factors for renal function ______used to calculate___
Cockcroft-Gault Equation; GFR
What is the Cockcroft-Gault Equation
CrCl = 140-age (yr) x weight (kg) / (72 x serum Creatinine)
Renal clearance relationship with age is
INVERSELY PROPORTIONAL
Unique Metabolism of anesthetic drugs: Hoffman degradation
Cisatracurium
Atracurium (plasma)
Unique Metabolism of anesthetic drugs: PSEUDOCHOLINESTERASES (new name butylcholinesterase)
Succinylcholine
Mivacurium (plasma )
Unique Metabolism of anesthetic drugs: NONSPECIFIC ESTER HYDROLYSIS
Remifentanyl
ATracurium
What are 2 major Plasma protein for BINDING of ANESTHETIC drugs?
Albumin
Alpha–1-Acid Glycoprotein
Why is protein binding important to consider?
because the only the unbound portion of the drug can exhibit pharmacological effect
Protein binding depends on ____________ NOT on
Concentration of plasma protein
NOT concentration of the drug
A decrease in protein binding leads to _______Concentration of the free form of the drug
INCREASE
Protein binding and Vd
Decrease in protein binding lead to increase free drugs which will equillibrate with peripheral tissue. This will cause a decrease in plasma concentration and –> decrease Vd
What does ZERO order kinetic means
Also knonw as LINEAR
Human body clear at constant RATE NO MATTER THE DOSE
Ex: ETHANOL, ASA,
What does FIRST ORDER KINETIC MEANS
Dose dependent
CLEARANCE PROPRTIONA TO concentration
3 compartment models
Divide Body into 3 parts:
1.central compartment (plasma)- 100% in plasma f/b –>
2. Rapid equilibrating compartment: vessel rich Brain, GI tract
Slow equilibration compartment : vessel poor tissues, fats
