Introduction to Pharmacokinetics Lecture (Dr. Segars) Flashcards
Pharmacokinetics
1) How the BODY HANDLES the drug
- All drugs have pharmacokinetic parameters
- Majority of drugs are not clinically managed with pharmacokinetic calculations
- Calculations only performed on meds with:
a) Concentration-dependent efficacy/toxicity
b) Narrow therapeutic index
When treating your patients, a drug may be handled in up to 4 possible stage
- Absorption
- Distribution
- Metabolism
- Elimination
Absorption (A of ADME)
A) Routes of administration:
- oral; rectal; topical; injectable, inhalation, etc.
- Time for dissolution (if solid formulation)
- Time for absorption (considered 0-time for IV)!!!!
- Time for circulation (Site/Onset of action)
B) Gaining access across membranes regardless of anatomical location
- PASSIVE & ACTIVE processes are utilized by body
Passive Absorption (Simple)
1) FILTRATION:
- Through Pores or Channels
a) Determined by Osmotic/Hydrostatic pressure differential
- DIFFUSION:
- Through cell membranes
a) Determined by concentration gradient
b) Most commonly utilized by drugs
Passive processes DON’T require ENERGY and CAN’T proceed against gradients
3) Passage also depends on IONIZATION STATUS of medications (Lipid-to-Water partition coefficient)
4) MOST drugs are chemically either…:
- WEAK BASES:
a) generic names end in Chloride, Hydrochloride, Sulfate, Acetate
- WEAK ACIDS:
a) generic names end in Sodium, Potassium
Absorption (A of ADME) Cont
A) At any point in time when a drug is in the body, the drug resides in one of two ionization forms:
1. IONIZED
a.k.a.; Charged/ Polar/ Protonated
- UNIONIZED
a.k.a.; Un-charged/ Non-polar/ De-protonated
Total % of both forms ALWAYS = 100%**
General statements related to Ionization
1) IONIZED COMPOUNDS:
- Lower lipid solubility
a) Higher water solubility
- These compoundsDO NOT EASILY diffuse across lipid bi- layer of membranes in the process of absorption or re- absorption
2) UNIONIZED COMPOUNDS: - Higher lipid solubility
a) Lower water solubility
- These compounds EASILY diffuse across LIPID BI-LAYER OF MEMBRANES in process of absorption or re-absorption
Ionization Status depends on 2 factors
1) pKa of Medication
2) pH o Membrane-Gradient/ milieu
Ionization status: pH and pKa
1) pH:
- Measure of the acidity of a solution (measured on a scale of 0 to 14) and is a function of the amount of H+ in the Solution
a) pH’s can VARY in different physiological locales
2) pKa:
- Propensity of a compound to DONATE (acids) or ACCEPT (bases) a PROTON
Henderson-Hasselbalch equation used to calculate ratio of Ionized: Unionized**
2 Important Areas of the Body where pH varies and Commonly impacts Ionization status (and therefore, transmembrane passage)
1) GI Tract
2) Kidneys
Memorization Fact
When pKa = pH; there is a 50% : 50% RATIO of Ionized: Unionized!!!
General statements related to Ionization and GI Tract and Kidneys:
1) HIGHLY IONIZED Drugs DO NOT readily get ABSORBED in GI tract OR re-absorbed from the renal tubules back into the systemic circulation – Therefore, drugs ARE ELIMINATED!!!!!!!!!
2) HIGHLY UNIONIZED Drugs DO readily get ABSORBED in GI tract OR re-absorbed from the renal tubules back into the systemic circulation – Therefore, drugs are NOT ELIMINATED!!!!!!!!!
Active Absorption/ Transport (Carrier Mediated) Associated with:
1) Energy-requiring
2) Saturable
- Can experience Competitive Inhibition by other Drugs
3) Movement AGAINST GRADIENTS
- Electrochemical and Concentration Gradients
Facilitated Diffusion differs Slightly
- Does NOT REQUIRE Energy
- Does NOT PROCEED AGAINST gradients
Distribution (D of ADME)
1) Elements discussed in Absorption, also involved with Distribution…
- Movement across cells/membranes (after systemic access gained)
a) Active & Passive Transporting
b) Ionization status
c) Lipid-to-Water partition coefficient
2) Protein Binding…
2 States of Drugs related to Serum Protein Binding
1) Bound
2) Unbound
Unbound (Free Drug) is ACTIVE
1) Binding to serum-based albumin, pre-albumin, alpha1-acid glycoprotein, etc…
– Not the proteins associated with receptors!
2) (ALPHA) represents UNBOUND Fraction
- Small (0.1; 10%) vs. Large (0.8; 80%)
a) Drug Interactions can change alpha (Unbound)
i) Changing efficacy or toxicity…
***** ALPHA is OPPOSITE of % Protein BOUND!!!!!!
Metabolism (M of ADME) aka Biotransformation
1) Consider Primary goal of metabolism (biotransformation) ways the body uses to INCREASE the likelihood of DRUG ELIMINATION from the body
2) Alteration of a drug to 1 or more chemically DIFFERENT compounds (metabolites), which can be:
- Pharmacologically Active or Inactive
3) Pharmacologically-active metabolites can be
MORE or LESS ACTIVE than ‘Parent’ compound (original drug)
** LIDOCAINE – extensively metabolized to 2 metabolites; with 100% & 25% potency of lidocaine, respectively****
2 Main Types of Biotransformation Reactions used by Body
1) Phase 1 Reactions
- Oxidation, Reduction, Hydrolysis
2) Phase 2 Reactions
- Covalent Linkages, Glucuronidation, Sulfating, Acetylation
Phase 1 Reactions
1) Formation of new or modified functional group or cleavage (e.g., Oxidation, Reduction, Hydrolysis)
2) Cytochrome P450 Enzyme System (CYP450)
Cytochrome P450 Enzyme System (CYP450):
1) Naming-Designations (e.g., 2C19):
- FAMILY (arabic #; e.g., 1, 2, 3)
- SUBFAMILY (capital letter; e.g., A, B, C, D)
- INDIVIDUAL (arabic #; e.g., 3/4, 6, 19)
2) Main Sites of Action:
- Liver
- G.I. tract (e.g., stomach)
- Brain
- Kidney
3) SUBSTRATE:
- Normal rate of activity
- Polymorphisms (genetics)
a) Slow
b) Rapid
c) Ultra-Rapid
* Uses the CYP450 System to get metabolized*
4) INDUCER’S vs. INHIBITOR’S
* * Induces or Inhibits the CYP450 System**
Phase 2 Reactions
- Involve CONJUGATION (covalent linkages; Glucuronidation, Sulfation, Acetylation) with an ENDOGENOUS Substance (e.g., glucuronic acid, sulfate, glycine, etc…)
First Pass Metabolism/ Effect:
- Orally administered Drugs
1) LIDOCAINE – extensively metabolized on first pass by CYP1A2 (MAJOR) & CYP3A4 (MINOR)
2) PROPRANOLOL is extensively metabolized on first pass; yet ATENOLOL is negligibly metabolized by the liver
Elimination (E of ADME)
1) Liver & Kidneys PRIMARY ROUTES, others include:
- Lungs
- Skin (sweat)
- Bile/Feces
2) ‘Parent’ drug vs. Metabolite:
- Active vs. Inactive
- Ionization status of some drugs
3) Reduced RENAL or HEPATIC function – may NECESSITATE a DOSING CHANGE
* In severe ASPIRIN OVERDOSE, urine ALKALIZATION with SODIUM BICARBONATE Increases IONIZED FRACTION,
REDUCES Reabsorption & INCREASES Elimination***
Renal Elimination- 3 Main Processes
- PASSIVE GLOMERULAR FILTRATION
- Blood flow DEPENDENT - PASSIVE TUBULAR DIFFUSION
- Proximal or Distal tubules
- Ionization & Concentration status dependent - ACTIVE TUBULAR SECRETION
- Weak Acids/ Bases SECRETED into PROXIMAL Tubules
** eGFR via Creatinine Clearance equation…***
Two Main Kinetic Properties of Drugs
1) First Order
- RATE of ELIMINATION proportional to Cp, OR
- AMOUNT of DRUG REMOVED per unit of time will
vary proportionately with Cp
- The PERCENTAGE (fraction) of the total amount of the Cp change REMAINS CONSTANT over time
2) Zero Order
- Saturable (Vmax)!!!!!!!!
- Rate of elimination NOT Proportional to Cp, OR
- FRACTION of Drug REMOVED per unit of time STAYS THE SAME over time
- The PERCENTAGE (fraction) of the total amount of the Cp change is NOT CONSTANT over time
Graphical Relationship between PLASMA DRUG LEVELS and PHARMACOLOGICAL RESPONSE
- Time of Maximum Drug Concentration (Tmax)
- Maximum Drug Concentration (Peak or Cmax)
- Duration of Activity
- Minimum Drug Concentration (Trough or Cmin)
- Minimum Effective Concentration (MEC)
- Maximum Therapeutic Concentration (MTC)
- Therapeutic
- Index/Range/Window
Mathematical Modeling, the basis for medication dosing for NARROW THERAPEUTIC RANGE AGENTS
Clinical Application:
- Dosing Amount Determination
- Conc. in plasma (Cp) Estimation & Interpretation
- Dosing Interval Determination
- Modification of the above based on known values, changes in Physiology, or illness severity
Bioavailability (F)
- Has NO UNITS!!!!
- Represents Fraction (F) of a dose that enters circulation (0 to 100%)
a) Describes EXTENT of absorption!!!!!!!
i) Does NOT describe RATE of absorption!!!!
b) ALWAYS considered 100% (F=1) for IV route!!!
**Exception to 100% Rule: Lidocaine – extensively metabolized on first pass by CYP1A2 (major) & CYP3A4 (minor)… F =
Determining Bioavailability
- Ionization status in various locales
- First Pass & GI Metabolism
- Dissolution
a) Extent vs. Rate
“Salt” Factor (S) (No Units)
- Think of it as an “EQUIVALENCY-FACTOR”, and represents percentage of a dose that EQUALS primary serum-assessed drug (0 to 100%)
* 80 mg of Aminophylline (IV) = 100 mg of Dose Theophylline (PO) [S for Bioavailability (F) Aminophylline = 0.8]**
3 Terms Determining AMOUNT OF DRUG ABSORBED
1) Dose
2) Bioavailability (F)
3) Salt Factor (S)
Volume of Distribution (Vd)
UNITS= Liters!!!!!
- Represents implied VOLUME of compartment necessary to account for total amount of Drug in body and Drug-Concentration in plasma
a) NOT NECESSARILY a physiological value!!!!!!! - Numerically-represents EXTENT of DRUG DISTRIBUTION
a) BIGGER VALUE represents a LARGER Body-Distribution
b) Book-referenced values in L/kg (so multiply by body weight!)****
Ideal Body Weight (IBW)
UNITS= Kg
FEMALE:
- 45 kg+(2.3 kg x (height(in inches)-60 inches))
- 2.3 kg for every inch over 5 feet + base-weight of 45kg
MALE:
- 50 kg+(2.3 kg x (height(in inches)-60 inches))
- 2.3 kg for every inch over 5 feet + base-weight of 50kg
ADJUSTED DOSING BODY WEIGHT (AdjBW)
- For ABW > 40% Higher than IBW
- Adj. Body Weight = (0.4 x (ABW – IBW)) + IBW
Clearance (Cl)
UNITS= L/ hr
- Represents the volume of blood per unit of time that is cleared of drug
Tau
UNITS= Hr
- Represents dosing interval (q8h)!!!!!!
Ex: 8!!!!!
Elimination Rate Constant (Kel)
UNITS= X^-Hours
- A function of Clearance (Cl)
- Represents a ‘RATE’ of Drug Eliminated, described as a PERCENTAGE (fraction) of drug removed per unit of time
Half Life (T1/2)
UNITS= Hr
- Represents time required for 50% of drug to be eliminated [blood concentration to lower by 50%]
a) ELIMINATION:
i) Accumulation element also applicable
Steady State (Cpss)
UNITS= W/ V #
- Represents an EQUILIBRIUM between Drug & Body (administration & clearance), where RATE IN = RATE OUT
- Related to Dose, Cl, Kel and Half-Life (t1/2)
** Usually takes about 4 to 5 HALF LIVES to achieve Cpss!!!!!!!!!!!!!!!
**At Cpss= D - D/ D - L
Amount of Drug Absorbed
Equation
= (S) (F) (Dose)
*** Answer in WEIGHT Units!!!
Dose of Different Dosage Form
Equation
= (Amount (mg) Absorbed from Current form) / ((S) (F) of New Dosage Form)
** Changing DOSAGE FORMS!!! (IV to Capsule Switch)
** Answer in Weight Units*
Concentration in Plasma (Cp)
Equation
= ((S) (F) (Dose)) / (Vd)
Answer in W/V Units
- Reference value for Vd may be in L/Kg of Body weight (Multiply REFERENCE Vd Value by Patients Body Weight in Kg)
Loading Dose
Equation
= (Vd) (Cp)/ ((S) (F))
Answer in Weights Units
1) PURPOSE of ‘Loading’ Dose:
– Quickly FILL Vd
– Quickly REACH DESIRED serum drug CONCENTRATION
a) Does NOT get to steady-state faster, just Drug Concentration (level) desired ONCE Steady-State is physiologically reached
2) REFERENCE value for Vd may be in L/kg of Body Weight
– Multiply REFERENCE Vd value by pts. body weight (in kg)!!!
Supplemental Loading Dose (sLD)
Equation
= (Vd) (Cp desired - Cp initial)/ (S) (F)
* Answer in Weight Units*
- Essentially the same as Equation #4, but factors in the known, INITIAL (starting) drug concentration (if any) prior to load
- One could use Equation #5 for all LD calculations, simply using 0 for patients with no drug in their system
- REFERENCE value for Vd may be in L/kg of body weight
a) Multiply REFERENCE Vd value by pts. body weight (in kg)
Clearance (Cl)
Equation
= ((S) (F) (Dose/ Tau))/ (Cp)
* Answer in L/ Hr*
CREATININE CLEARANCE (eGRF): - Creatinine & Route of Elimination (Male vs. Female)
- Several commonly utilized mathematical models to use:
a) Cockroft-Gault
i) MDRD (6 and 4 variable calculations) for Renal Disease pts. - ** [(140-age) x IBW(in kgs) ÷ (72 x SCr)] ***
- x 0.85, if patient is female
Maintenance Dose
Equation
= ((Cl) (Cp) (Tau))/ (S) (F)
* Answer in Weight Units*
- Simply a rearrangement of Equation #6, solving
for Dose - REFERENCE value for Cl may be in L/kg of body weight/hr
a) Multiply REFERENCE Cl value by pts. body weight (in kg)
Elimination Rate Constant (Kel)
Equation
= (Cl) / (Vd)
* Answer units in ^ -Hour*
Half Life (t 1/2)
Equation
0.693/ (Kel)
* Answer in Units in Hours*
