Drug Elimination and Renal Clearance Part 1 Flashcards
What is drug elimination?
Irreversible removal of drug from the body by all routes of elimination
What does a declining plasma drug concentration indicate?
- Drug is being eliminate but not necessarily differentiate between distribution and elimination
- Doesn’t indicate which elimination processes are involved
What are 2 major components of drug elimination?
- Removal of intact drug
- Biotransformation (drug metabolism)
What is the removal of intact drug?
Nonvolatile and polar drugs are excreted daily renal, where the drug passes through the kidney to the bladder and to urine
What are other excretion pathways?
- Bile
- Sweat
- Saliva, milk
- Volatile compounds (lungs)
What is biotransformation?
Process by which the drug is chemically converted in the body to a metabolite
Usually enzymatic but can be non
Where are most drugs biotransformed?
- Liver
- Kidney, lungs, small intestine, skin
How is drug elimination a complex rate process?
The tissues within the organs are not structurally homogenous, and elimination may vary in each organ
Describe drug elimination in 1st order?
Clearance is based on a well stirred model with uniform drug distribution
What is clearance?
- The process of drug elimination from the body or from a single organ without identifying the individual processes involved
- The volume of fluid removed of the drug from the body per unit of time
- L/h
What is the volume concept?
All drugs are dissolved and distributed in the fluids of the body
Why is clearance more important than half-life
It directly relates to the systemic exposure of a drug
What is clearance vs half-life?
H: Gives info on the terminal phase of drug disposition
C: Account all process of drug elimination regardless of metabolism
Cl = Dose/AUC
Describe drug clearance?
- Drug is dissolved in a fixed volume
- Clearance is a fixed volume (contains drug) removed per unit time
What are the equations of clearance?
Cl= elimination rate/plasma concentration
= CpkVd/Cp
What is the elimination rate equation?
dDe/dt = CpkVd
When is clearance a constant?
If the rate of drug elimination is 1st order
Describe drug clearance at 1st order?
As the plasma drug concentration decreases during elimination, the rate of drug elimination decreases, but clearance remains constant
What is total clearance?
Sum of all of many clearance processes
What is compartmental model?
The calculation of clearance from a rate constant and a volume of distribution
What is physiologic model?
Calculated for any organ or tissue group that irreversibly removes drugq
What are the variable of physiologic model?
Q: organ blood flow
Ca: incoming drug concentration (arterial)
Cv: outgoing drug concentration (venous)
What are the primary organs for excretion and biotransformation?
Kidney and liver
How is organ clearance defined?
Fraction of blood containing drug that flows through the organ and is eliminated of drug per unit time
Cl (organ) = Q (organ) x E (organ)
What happens if Ca is greater than Cv?
Drug has been extracted by the organ
What is the extraction ratio?
E = Ca - Cv/Ca
What is organ clearance dependent on?
- Blood flow
- Extraction ratio
What does organ clearance look at?
Constant volume in which drug is distributed or removed per unit time
Why is physiologic model not commonly used for hepatic clearance?
Hard to measure organ blood flow and extraction ratio directly
What is renal clearance used for?
- More transitional models can be used
- Can easily direct measurements of blood flow and extraction ratio by plasma blood concentration and urine
How is clearance calculated in noncompartmental model?
AUC
What are the advantages of non-compartmental model?
- Cl can easily be calculated without making assumptions relating to rate constants
- Vd is presented in a clinically useful context as it is related to systemic exposure and the dose administered
- Estimation is robust in the context of rich sampling data as very little model is involved
- Approach still assumes log-linear terminal elimination phase
How is Non-Com Cl model calculated?
Cl = Dose/AUC
Cl = F*Dose/Auc
What is λz?
Rate constant in one and two referring to k, k10, B
What is λI?
Rate constant referring to the distributional rate constant in two compartment models (a)
What are the assumptions of most PK models?
- CL and volume are independent parameters
- IOW: a change in Cl in a patient will not affect, volume, or vic-versa, but will affect elimination rate constant
In what instances can CL and V change without changing elimination rate constants?
A sudden change with an edematous condition
What occurs during a edematous condition?
- Cl and Vd increase
- Renal and hepatic function is unchanged
- Dose interval will not need to be changed
- Dose will need to be changed
What equation is used to represent constant infusion is achieved by Css?
Cl = F*R/Css
When would you use Cl=k10*Vc?
When the PK of a drug is well described by any compartment model when the drug displays linear PK
What are the main kidney functions?
- Remove metabolic waste
- Maintain fluid volume
- Maintain electrolyte balance
- ENdocrine function by increasing renin (BP) and erythropoietin (RBC production)
Describe the anatomy of a kidney?
- Cortex: outer
- Medula: inner
- Nephron: basic functional unit
- Glomerulus: of each nephron starts in the cortex
What is the function of the nephron?
- Removal of metabolic waste
- Maintenance of water and electrolyte balance
What are cortical nephrons?
Short loops of Henle that remain exclusively in the cortex
What is the juxtamedullary nephron?
Long loops of Henle that extend into the Henle
What is the purpose of having longer loops of Henle?
Allow for greater ability of the nephron to reabsorb water and produce more concentrated urine
What supplies the kidney with blood?
Renal artery subdivided into the interlobar arteries penetrating within the kidney and branching further into the afferent arterioles
Where does filtration of the blood ht occur?
Bowman’s capsule
Where do afferent arterioles carry blood?
Toward a simple nephron into the the glomerular portion, Bowman’s capsule
After Bowman’s capsule where does the blood flow?
Efferent arterioles and into second capillary network that surrounds the tubules including loop of Henle where water is reabsorbed
How do you calculate RPF?
RPF = RBF (RBF*Hct)
RPF: renal plasma flow
RBF: renal blood flow
Hct: hematocrit (45%)
What is the average RBF?
1.2L/min
What is the average RPF?
0.66L/min
What is the average GFR?
120mL/min
How is GFR based on body BSA?
Less in women and decreases with age
What factors are proportional to blood flow?
Arteriovenous pressure difference (perfusion pressure) across the vascular bed
What factors are indirectly porportional to blood flow?
Vascular resistance
What is the normal renal arterial pressure?
100 mmHG and falls 45-60mmHG
What causes an renal arterial pressure difference?
The increasing vasculature resistance provided by the small diameters of the capillary network
What causes a renal arterial pressure difference?
The increasing vasculature resistance provided by the small diameters of the capillary network
What controls GFR?
Changes in the glomerular capillary hydrostatic pressure (push)
What is the property of RPF and GFR under normal kidney?
Relatively constant even with large differences in mean systemic blood pressure
What is autoregulation?
- The maintenance of a constant blood flow in the presence of large fluctuation in arterial blood pressure
- Maintains a relatively constant blood flow, the filtration fraction (GFR/RPF) also remains fairly constant in this pressure range
How much is filtered by the kidney?
180L/day
1-1.5 L/day is excreted
How much fluid is reabsorbed?
99%
What are the small molecules that are flitered?
- Proteins and protein bound substances are not filtered
- Essential nutrients and water are reabsorbed
- Waste is excreted and urine is concentrated with waster material
What is GFR?
Volume of filtrate formed per minute by both kidneys
Normal GFR?
120-125mL/min
What is GFR directly proprortional to?
- NFP: primary pressure is hydrostatic in glomerulus
- Total surface area available for filtration
- Filtration membrane permeability
What is the purpose for a constant GFR?
Allows kidneys to make filtrate and maintain extracellular homeostasis
What are the goals of intrinsic goals?
Maintain GFR in kidney
How does GFR affect systemic blood pressue?
Increased GFR -> Increased urine output -> Decreased BP
What are the goals of intrinsic control?
Maintain systemic blood pressure
What is MAP?
MAP = Diastolic pressure + 1/3 pulse pressure (difference between systolic and diastolic pressure)
What is intrinsic control?
- Renal autoregulation that act locally within kidney to maintain GFR
- Maintains nearly constant GFR when MAP in range of 80-180mmHg
- Autoregulation ceases if out of the range
What is extrinsic controls?
- Nervous and endocrine mechanisms that maintain BP, can be negative
- Take precedence over intrinsic controls if systemic BP (MAP) < 80 or > 180 mmHg
How does glomerular hydrostatic pressure control GFR?
- If rises -> NFP rises -> GFR rises
- If falls by as little as 18% -> GFR = 0
What are the types of renal autoregulation?
- Myogenic mechanism
- Tubuloglomerular feedback mechanism
What is myogenic mechanism?
Smooth muscle contracts when stretched
How can myogenic mechanism increased BP?
Muscle stretch -> constriction of afferent arterioles -> restricts blood flow into glomerulus
Protects glomeruli from damaging high BP
How can myogenic mechanism decrease BP?
Dilation of afferent aterioles
What is tubuloglobomerular feedback?
Flow dependent mechanism
Macula densa cells respond to filtrate NaCl concentration
How does tubuloglobomerular feedback increase GFR?
Filtrate flow rate increase -> decrease reabsorption time -> high filtrate NaCl levels -> decrease NFP and GFR -> more time for NaCl reabsorption
