Where does most drug absorption occur and why?
Small intestine (lots of surface area and pH = 7 which allows weak acid/base drugs to exist as uncharged)
What does paraenteral mean?
SubQ, IV, intramuscular
What determines if a drug will cross a biomembrane?
It's charge (uncharged/un-ionized drugs will cross while ionized drugs will not)
Draw out weak acid dissocation equation
Draw out weak basic dissocation equation
Explain hepatic encephalopathy
It is a condition resulting in a loss of brain function due to the liver's inability to remove toxins from the blood.
Normally, NH3 in teh gut is taken to the liver by the portal vein and is detoxified by the urea cycle. In pathologies such as liver cirrhosis (can't detox) or shunting issues (can't get toxin to the liver) you get NH3 accumulation. This results in confusion, coma, and death
Treatment is lactuloase which causes NH3 to become NH4
What limits the ability of a drug to be filtered by the kidneys?
Being bound (only unbound drugs can be filtered by the kidneys)
In what state must a drug be in order to undergo secretion and reabsorption in the kidney?
Drugs have to be non-ionized in order to be able to undergo secretion and reabsorption
*If a drug is charged (ionized) it will be directly excreted and will not undergo secretion or reabsorption
What effect does acidification of urine have on weak basic drugs?
Increase renal elimation (B under acidic conditions becomes BH+ which is ionized and thus cannot be secreted or reabsorbed
What effect does alkalinization of urine have on weak acid drugs?
Increase renal elimination (AH in basic conditions becomes A- which is ionized and thus does not undergo secretion or reabsorption)
What effect does vitamin C and cranberry juice have on urine?
It acidifies it (thus it will increase the renal elimination of weak basid drugs)
Does low pH add or remove a H to drugs?
Does high pH add or remove a H to drugs?
What is the hasselbalch equation?
What is the first pass effect?
When a drug is ingested, it goes from the mouth, to the stomach, and then to the liver (via the hepatic portal vein) where it gets partially metabolized. The remaining drug goes to the heart (via the hepatic portal vein) where it is then pumped systemically.
*Applies to oral drugs
What plasma protein binds acidic drugs?
If a patient has liver damage, how should you adjust his drug dose?
Lower it (there is likely less albumin to detox weak acid drugs)
Why should pregnant women not take weak basic drugs when pregnant?
Placental plasma is acidic and thus basic drugs (B) can cross the placena and become hydroganted (BH+) and thus get stuck in the placental plasma.
This is refered to as basic trapping
How do you calculate the Volume of distribution of a drug?
Vd = Volume of distribution
C0 = Total plasma [ ] (bound and unbound)
D = Dose (i.e. amount of drug)
*This equation should only be used for IV. For drugs whose bioavailability is less than F, the equation should read
(D)(F) = Vd x C0
What does a low volume of distribution indicate of a drug?
That it is mostly bound by plasma proteins or it is being sequested in select areas
Explain the role of p-gp?
What enzymes make up phase I drug metabolizers?
How do these drugs work?
Flavin containing monooxygenases
Dehydrogensae, hydrolyase, esterase, amidase
Phase I work by adding a polar group to the drugs
What enzymes make up phase II drug metabolizers?
How do these drugs work?
Glucoronidation (addition of glucuronic acid via UGT)
Acetylation via NAT
Sulfation via SULT
Glutathione (GSH) (addition of glutathione via GST)
Phase II work by conjugating the drugs
What is the formula for rate of elimination?
Rate of elimiation = GFR + active secretion - reabsorption
What is clearance?
Clearance is the voume of blood that is cleared of a drug per unit of time
What is the clearance for protein-bound drugs?
There is none. Drugs must be unbound in order to be renally eliminated
What is the equation for clearance?
Cl = Free Fraction of drug x GFR
How many half-lives to reach steady state?
4 to 5
What molecule is used to estimate GFR?
Insulin is not sereted or reabsorbed thus Rate of elimiation = GFR + active secretion (0 for insulun) - reabsorption (0 for insulin)
What is the equation for t1/2
t1/2 = (0.7) (Vd / Cl)
What is the equation for loading dose?
LD = (Vd x C0) / f
What is the equation for maintenance dose?
MD = (Css x Cl x DI) / F
Dose/DI = (Cl x Css) / F
DI - Dosing interval
Css - Steady-state concentration
What is the equation for the equilibrium dissociation constant?
What does a small KD indicate?
KD = (L x R) / LR
Small KD means there is high affinity between the ligand and its receptor
What is the relationship between ligand and KD when half of the receptors are bound?
When LR=RT/2, then L=KD
What is the relationship between ligand and EC50 when half of max effect is reached?
When E=Emax/2, then L=EC50
What is the equation for fraction of effect?
E/Emax = (alpha x LR) / RT
Alpha is the intrinsic factor
Alpha = 1 for agonists
Alpha = 0 for antagonists
0 < alpha < 1 for partial agonists
What are spare receptors?
They are receptors that exist in excess to that required to produce a max response
-Assume it takes 4 receptors to stimulate one effector. If 25% of receptors are bound, on left only 1 effector will be stimulated. On right, all 3 effectors will be stimulated
What is the dose interval for a patient taking a drug 3 times a day and 24 times a day?
Drug 3x/day then DI = 8hr
Drug 24x/day than DI = 1hr
What does hyporeactive refer to in drug response?
The patient has low sensitivity to the drug and thus requires a higher dose to feel the effect
*In contract with hyperreactive
How does a competitive reversible antagonist work and how does it effect the graph of a drug?
Reversible competitive inhibitors: These drugs bind to the receptor at the same site as the drug; thus by increasing the drug concentration you can overcome the effect.
These types of antagonists shift the curve to the right causing an increase in EC50 but the same Emax
How do you calculate the new EC50 value by a competitive reversible antagonist?
EC50' = EC50 (1 + [Angtagonist] / KI)
KI = KD of inhibitor
How does a competitive irreversible antagonist work and how does it effect the graph of a drug?
Compettivie irreverisble inhibitors bind covalenty to the receptor and thus their effect cannot be surmounted by increase drug concentration UNLESS there are spare receptors present, in which case the graph will be similar to that of a competitive reversible inhibitor.
Without spare receptors, the Emax is decreased but the EC50 is the same
How does a noncompetitive antagonist work and how does it effect the graph of a drug?
Noncompetitive antagonists bind to an allosteric site and thus the drugs cannot bind efficently to the receptor (spare receptors thus make no difference)
Same affect as a competitive irreversible with no spare receptors (decrease in Emax but the same EC50)
What is the difference between a Grade Dose-Resonse curve and a Quantal Dose-Respones curve?
Graded is when the value varies in degrees (i.e. there are variable degrees of effects) while quantal is all-or-nothing (the drug either had an effect or it did not)
What is the theurpeutic index?
It is the ration between the amount of therapeutic agent that causes the therapeutic effect to the amount that causes death
TI = LD50 / ED50 (ratio for letah dose)
TI = TD50 / ED50 (ratio for toxic dose)
What are the two types of memranes are there?
Surface bound and intracellular
How do intracellular membranes work?
Steroid enters the cell. Binds to an intracellular membrane receptor. Induce the nucleus to produce TF
What are the three types of surface membrane receptors?
Ion-channel linked (e.g. GABA binding to GABA receptor causes the opening of Cl channels)
GPCR (binding to GPCR stimulates G-protein to shed its GDP and bind GTP)
Enzyme-linked (e.g. TKR)
What is GEF and GAP?
GEF: Add GTP
GAP: Hydrolzes GTP
G-proteins are activated by GEF and inhibited by GAP
How is acetaminophen (tylenol) metabolized?
What is the difference between potency and efficacy?
Potency is the amount of drug required to acheive a desired effect
Efficacy is the maximal effect a drug can acheive
What are the functions of Gs, Gi, and Gq
Gs: Increases cAMP production; stimulate PKA
Gi: Decreases cAMP production
Gq: Activates phospholipase C
What does phospholipase C do?
It cleaves PIP2 into IP3 and DAG
-IP3 stimulates Ca release from the ER which then binds to calmodulin kinase. Calmodulin kinase with DAG stimulate PKC
Which ANS receptors are associated with Gs, i and q
M1, M3, alpha1: Gq
M2, alpha2, D2,: Gi
B1, B2, D1: Gs
What is the difference between zero and first order kinetics graphs?
Zero order: Contant AMOUNT of drug is eliminated per unit time
First order: Contact FRACTION of drug is eliminated per unit time
Describe first-order drugs
Describe zero-order drugs
The elimination system is not saturated is first-order
The eliminated system is saturated in zero-order
-Increase concentration will increase rate of elimination
-Increase concentration won't effect half-life
-Increase concentration won't effect clearance
-Increasing concentration won't effect rate of elim.
-Increase concentration increase half-life
-Increase concentration will decrease clearance
*If you had 100mg of a first-order drug, that means 50% will be eliminated every half-life. In one half-life, you eliminate 50mg. If you increased the concentration to 200mg, after one half-life you would have eliminated 100mg which is greater than 50 (thus increasing concentration of first-order drugs will increase the rate of elimination). Conversely, if you had a 100mg of a zero-order drug, that means you eliminate 10mg per hour. Even if you increase the dose to 200mg, you still only eliminate 10mg/hr (first order - eliminate a constant fraction (50% per half life); zero order - eliminate a consatnt amount (xmg per time)
*The half life of a first-order drug will always be the same no matter what the concentration. Since a zero-order drug's elimination is a constant amount/unit time, then increasing hte concentration will increase the half life (if a 100mg has 50mg eliminated per hour, the half life will be one hour. If you increase the dose to 200mg, the half life is now two hours)
*The clearance of a first-drug won't change with increasing concentration because the system is not saturated. In a zero-order drug, the system is already saturated so any increase in dosage will cause more drug within the same volume of blood causing clearance to decrease
What are therapeutic antibodies made of?
What do the following refer to in Ig names:
Momab: Mouse (MO)
Ximab: Chimeric (XI)
Zumab: Humanized (ZU)
Umab: Human (U)
If the clearance of insulin is 120ml/min, what is the GFR?
Cl = GFR x Free Fraction
Free fraction of insulin is 1 since it is neither secreted nor reabsorbed
Why do lipid drugs have to be bound by plasma proteins in the blood?
Blood is polar and thus non-polar lipids are not soluble and therefore require plasma proteins to be bound to
A subject is found to have a renal clearance of insulin of 120ml/min. When given a drug, its clearance was found to be 18ml/min. If the drug is 40% plasma protein bound, how much of this drug is being reabsorbed?
Cl = FF x GFR
GFR = 120
FF = 60%
Therefore Cl of the drug is 72ml/min. Since only 18ml/min was detected, that means 72-18 - 54ml/min of the drug was being reabsorbed within the renal tuble
What percent of body weight is water?
What type of Phase II metabolizers contain genetic polymorphisms?
Acetylation enzymes (some people are slow acetylators)
If a drug is known to distribute into total body water, what dose is needed to obtain a plasma level of 5mg/L in someone weighing 70kg?
Since 60% of body weight is water, then 70kg*60% = 42L.
C = D/Vd or D = (C)(Vd) = 52*5 = 210mg
Is the rate of elimination constant in first-order kinetics?
No it is proportional to the drug concentration (as you increase the concentration of drug, you increase the rate of elimination
A 500mg dose has a therapeutic efficacy of 6h. If the half-life is 8h, how long would a 1g dose be effective?
Assuming that a 1g dose is still within the therapeutic window, at 8 hours you have 500 mg left and thus so far, you had 8 hours of effect. We were told that 500 mg has 6 hours of effect and thus the answer is 8+6 = 14h
If a drug achieves a plasma level of 16mg/L after administration, and the half life and dosing interval are both 6 hrs, what is the dose before the 5th dose?
16 at 1st dose
24 (16/2 + 16) at 2nd dose
28 (24/2 + 16) at 3rd dose
30 (28/2 + 16) at 4th dose
Right before hte 5th dose, the drug drops down to 15mg
An IV infusion of a drug is 400mg/h. If Cl = 50L/h, what is the plasma level at steady state?
MD = (Css x Cl x DI) / F
D/DI = (Css x Cl) / F
400mg/h = Css x 50L/h :: F = 1
Css = 8mg/L
Give the equations for MD, LD, and T1/2
T1/2 = 0.7 x (Vd/Cl)
*Kel = 0.7/T1/2
MD = (Css x Cl x DI) / F
LD x F = Vd x C
What is Km?
Km is the concentration of substrate at which v = Vmax/2
The higher the Km, the lower the affinity between the ligand-enzyme
Draw out a line burk weaver plot.
Draw a graph showing the effect that a competitive and non-competitive inhibitor would have on an enzyme (note changes, if any, for Vmax and Km
Yellow - No inhibitor
Orange - Competitive; same Vmax, higher Km since you require more ligand to reach Vmax/2
Purple - Non-competitive; lower Vmax, same Km since you are not targetting the enzyme and thus effecting ligand-receptor affinity
Draw a line weaver burk plot showing the effect that a competitive and non-competitive inhibitor would have on an enzyme (note changes, if any, for Vmax and Km
Competitive - No change in vmax but an increase in Km (right shift)
Non-competitive - No change in Km but a decrease in Vmax (upward shift)
What are the percentages for the first 4 half-lives?
Efficacy and potency are similar to?
Vmax and Km
*A higher potency means a lower Km
What is the difference between clearance and rate of elimination?
Clearance is the volume of plasma from which certain substance is removed in a given amount of time. (If urea clearance is 100ml/min, then it takes the kidneys 1 minute to remove all of the urea present in 100ml of plasma)
2) Rate of elimination shows how the amount of the substance in the plasma that has been metabolized
PUT A BETTER WAY
Clearance is the VOLUME of fluid "cleared" of the drug per unit time. (volume cleared/time)
Elimination refers to the AMOUNT of the DRUG that was cleared. (mass)