ADME

Question 1

Three factors to Drug Absorption

Answer 1

1. Route of Administration
2. Bioavailability
3. Bioequivalence

Question 2

Route of Drug Administration: Enteral

Answer 2

Via the GI tract

1. Oral: 30-90min depending on drug; easy, inexpensive, safe; slow, requires consciousness + working gut, limited bioavailability
2. Rectal: 5-30min due to capillary network; easy, good absorption, no 1st pass metabolism; not preferred by patients

Question 3

Routes of Drug Administration: Parenteral

Answer 3

1. Intravenous: 30-60s; instantaneous delivery, no absorption, 100% bioavailability; need IV cannula, expensive, painful, invasive
2. Intramuscular/Subcutaneous: 10-30min; quick, no 1st pass metabolism; unpredictable absorption, painful, invasive
3. Transdermal: min-hrs; very variable, don’t really need to be absorbed/distributed; easy, non-invasive; slow, hard to absorb through skin

Question 4

Routes of Drug Administration: Mucosal

Answer 4

1. Sublingual: 3-5min; capillary network under tongue

2. Intranasal/Ocular/Intravaginal

Question 5

Routes of Drug Administration: Inhalation

Answer 5

2-3min into pulmonary capillaries; rapid absorption, limited systemic delivery; effectiveness depends on patient technique

Question 6

Routes of Drug Administration: Intrathecal, Intraarticular, Intraosseus, Endotracheal

Answer 6

1. Intrathecal - into CSF of SC (bypass BBB)
2. Intraarticular - into joint, only distributes to joint
3. Intraosseous - 30-60s; fast working on kids; GOOD FOR EMERGENCIES
4. Endotracheal - 2-3min; direct to trachea and pulmonary capillaries; GOOD FOR EMERGENCIES

Question 7

8 Factors that Affect Oral Absorption of Drugs

Answer 7

1. Drug Physical/Chemical Properties (but Surface Area > pH in gut absorption for weak acids/bases)
2. Bioavailability
3. Gastric Acidity + Digestive Enzymes
4. Gastric Emptying Times
5. Relationship to Food Intake
6. Drug Metabolism by Gut Epithelium (CYP3A4)
7. Drug Efflux from Gut Epithelium (PGP)
8. Co-administration of other drugs/inhibitors of CYP3A4 + PGPs

Question 8

Bioavailability (Definition, Loss Factors, Why do we still administer low F drugs orally?, Equation)

Answer 8

1. Fraction of administered dose of unchanged drug that reaches systemic circulation
2. Drug that doesn’t make it: in GI lumen, metabolized in GI wall, excreted by PGP, metabolized/excreted in liver
3. FIRST PASS METABOLISM: metabolism in intestinal wall/liver before drug reaches systemic circulation - by CYP3A4
4. Low bioavailability drugs still administered if TI is very high (beta-blockers)

F = AUC(other)/AUC(IV); IV has a F=1; other drugs have F<1; F measures extent of absorption NOT rate

Question 9

Bioequivalence vs. Pharmaceutical Equivalence

Answer 9

1. Drug preparations that exhibit the same F & pharmacokinetics - same absorptive + distributive effects
2. Different drug preparations with the same active ingredient, concentration, dose, route of admin, but may have different absorptive and distributive effects

Question 10

How do generic drugs differ from Brand-Name drugs?

Answer 10

Must deliver same amount of active ingredient into bloodstream in same amount of time as original drug
Must be:
1. Pharmalogically Equivalent
2. Bioequivalent
3. Effective and Safe

Question 11

How does tissue distribution influence drug action? (2 compartments, 2 types)

Answer 11

Compartments: IC Fluid (largest) + Interstitial Fluid (75% ECF)
Distributes to: Target side, Reservoirs, Unwanted sites, Liver biotransformation, Excretion mechanisms
Types:
1. Perfusion-Limited: First Phase (delivered to organs with high blood flow - heart/brain/liver/kidney); Second Phase (slow delivery to moderate blood flow - muscle/skin/fat)
2. Permeability-Limited: Certain compartments have restricted access (BBB)

Question 12

Features of BBB

Answer 12

1. Only lipid soluble drugs penetrate BBB
2. Tight junctions, continuous endothelia, astrocyte architecture
3. PGP + other drug efflux transporters further prevent drugs from entering CNS*
   * inhibiting transporters could improve penetration

Question 13

Features of Blood-Cerebrospinal Fluid Interface

Answer 13

1. ex: intrathecal delivery to SC (lumbar puncture)
2. access CSF from SC to choroid plexus (fenestrated endothelia in brain)
3. CSF circulates brain and can penetrate through loose epithelium layer - WAY TO BYPASS BBB

Question 14

Effect of Drug-Protein Binding in Pharmacokinetics + Pharmacodynamics (Types of proteins, Result, Reversible binding, Disease)

Answer 14

1. ALBUMIN binds weak acids & alpha-acid glycoprotein binds weak bases
2. When drug is bound, can’t reach target, no therapeutic effect (only free drug can enter tissue)
3. High binding - less available free drug - less metabolism and elimination - longer 1/2 life
4. Reversible binding - acts as storage depot to prolong drug action
5. hypoalbuminemia: low protein in blood, higher free drug concentration without affecting total plasma drug concentration

Question 15

Why do we have drug metabolizing enymes (DME)? (2 reasons)

Answer 15

1. Xenobiotics - DME has evolutionary advantage to eliminate these substances not natural to body and cause toxic effects (from foods/pharmacological agents
2. Cometabolism - enzymes that metabolize both endogenous agents AND xenobiotics

Question 16

Goal, Strategies, and Generalization of Drug Metabolism

Answer 16

Goal: metabolize lipophilic drugs to make them more polar = more easily excretable
Phase I: add functional group to 1. make drug more polar 2. make drug less active 3. provide reaction center for phase II
Phase II: covalently conjugate drug at reaction center to 1. make drug more polar 2. inactivate drug

Generalization: Drug - Phase I: CYP3A4 - Phase II: Glucuronidation (most prevalent reaction sequence)

Question 17

List the Classes & Sub-classes of Phase I Reactions

Answer 17

1. Oxidation Reactions a. CYP-dependent (i. Hydroxylation ii. S-oxidation iii. N-oxidation iv. Oxidative dealkylation [N-dealkylation & O-dealkylation]) b. CYP-independent oxidation
2. Hydrolysis Reactions a. ester hydrolysis b. hydrolases

Question 18

CYP-dependent oxidation reactions (reactions, location, structure, steps)

Answer 18

1. oxidation reactions include hydroxylation + oxidative dealkylation
2. location: on ER of liver & intestine epithelium
3. structure: contains Fe-heme group to bind molecular oxygen for oxidations
4. paired with near by reductase, which feeds CYPs with electrons and protons to perform oxidation reactions
   STEPS:
5. drug binds CYP oxidase
6. reductase gives e- to CYP, Fe atom goes from +3 to +2, which better binds O2
7. Fe+2 binds O2
8. Reductase feeds e- to O2 forming an ROS (O2-, activated oxygen)
9. Reductase feeds to protons, one oxygen freed as water and the other forms ROS with Fe, Fe-OH radical ferric oxene
10. Drug gets hydroxylated, Fe becomes Fe+3

Question 19

Hydroxylation, S-oxidation, N-oxidation (Type, Scheme, Drugs)

Answer 19

All are CYP-dependent oxidation reactions in Phase I metabolism

1. add hydroxyl group to drug (Midazolam, B[a]p, Propanolol) - CYP3A4
2. adds oxygen on sulfur group to make sulfonyl (Cimetidine on H2 Histamine Receptors)
3. adds oxygen onto N’s (Benedryl on H1 Histamines - not important)

Question 20

N-dealkylation and O-dealkylation (Type, Scheme, Drugs)

Cyp-independent Oxidations (Type, Drug)

Answer 20

Both are CYP-dependent oxidation reactions, and oxidative dealkylation sub-reactions in Phase I metabolism

1. removal of alkyl group from amine (Methylxanthines - Caffeine + Theophylline)
2. removal of alkyl group from ester (codeine, hydrocodone)

Cyp-independent oxidations: Ethanol (plays role in acetominophen toxicity)

Question 21

Ester Hydrolysis and Hydrolase Reactions (Type, Scheme, Drugs)

Answer 21

Both are hydrolysis reactions in Phase I metabolism

1. Split drug at the ester (Succinylcholine: degraded twice by pseudocholinesterases*) - polymorphisms can reduce activity
2. convert epoxides (electrophiles cause cancer by binding DNA) into diols - Toxicity reduction

Question 22

Sulfation Reaction (Type, Scheme, Drugs)

Answer 22

Phase II metabolism Reaction

1. sulfotransferases (SULTS) require PAPS cofactor to add -SO3H group on hydroxyl (Acetaminophen & Albuterol

Question 23

Acetylation Reaction (Type, Scheme, Drugs)*

Answer 23

Phase II metabolism Reaciton

1. N-acetyltransferases (NATs**) require Acetyl CoA cofactor to add acetyl group to reaction center (Isoniazid - don’t need to know)
   * inactivates drug as drug becomes LESS POLAR
   * *NATs reactions can be fast or slow due to the number of enzymes synthesized (slow cause toxic drug buildup)

Question 24

Glucuronidation Reaction (Type, Scheme, Drugs)

Answer 24

MOST COMMON PHASE II METABOLISM REACTION
1. UDP-Glucuronyl Transferases (UGTs) located in smooth ER near CYPs require UDP Glucuronic Acid to Glucuronidate Drugs at reaction centers (B[a]p’s, Acetaminophen)

Question 25

Glutathione Reaction (Type, Scheme, Good/Bad)

Answer 25

Phase II Metabolism Reaction 1. Glutathione protects against toxic electrophilic metabolites by reducing toxicity via glutathione s-transferases (GSTs*) Good: prevents cancer by reducing ROS Bad: when cancer develops, high GSTs cause cancer cell proliferation and resistance to chemotherapy (harder to kill tumor cells) Null GST genotypes can't neutralize electrophiles - increased risk for cancers like CML

Question 26

Methylation Reaction (Type, Scheme, Example)

Answer 26

Phase II Metabolism Reaction 1. Methyltransferase requires SAM as methyl group donor to methylate aromatic rings with N, O, S 2. Thiopurine Methylation - important in PHARMACOGENOMICS

Question 27

List locations and mechanisms for drug elimination

Answer 27

66% elimination in kidney 33% hepatobiliary excretion 1. Glomerular Filtration (kidney) 2. Tubular Secretion (kidney) 3. Passive Tubular Reabsorption (kidney - anti-eliminating mechanism) 4. Biliary Drug Excretion (Liver) 5. Excretion from lung via exhalation (volatile drugs very minor)

Question 28

Clearance (definition, equation for general clearance, total clearance, renal clearance)

Answer 28

1. rate a substance is removed from the plasma per unit concentration; hypothetical volume of plasma cleared of drug per unit time (VOLUME/TIME) Clearance* = Elimination rate (mg/hr) / Plasma Conc (mg/L plasma) *Total Body Clearance = sum of renal, hepatic, lung, and other eliminating mechanisms Renal Clearance = [Urine Conc. * Urine Flow Rate]/Plasma Conc.

Question 29

Glomerular Filtration (Location, Filtration Factors, GFR, Effect due to Age)

Answer 29

1. GC network within kidney nephrons - flow from GC to renal PT through fenestrated endothelial cells 2. Larger, Negative Molecules filtered less; Smaller, Positive Molecules filtered more; protein-bound drugs can't be filtered 3. Filtration = GFR*[drug]p (normal GFR = 125mL/min) 4. As age increases, GFR decreases - drugs then require lower dose and longer dosing intervals

Question 30

Tubular Secretion (Location, Transport Types, Drugs)

Answer 30

1. PT 2. Ionized drugs preferred transport cellularly with ABC and SLC transporters Organic Cation Transport (weak bases): basolateral OCT (ABC) + Apical PGP (ABC) and SLC [Digoxin & Quinidine - cardiac medications with drug:drug interference here - TOXIC] Organic Anion Transport (weak acids): basolateral OAT (SLC) + Apical ABC [Penicillin & Probenecid - helpful drug:drug interference here to prolong penicillin function]

Question 31

Passive Tubular Reabsorption (Location, Transport Factors) Why do lipid soluble drugs have generally longer half lives? How do you trap drugs in ionized form?

Answer 31

1. From renal tubule beyond PT to PC via diffusion or transporters 2. Preferred reabsorption of filtered lipid-soluble + non-ionized drugs - why lipid soluble drugs have longer half lives 3. High flow rates (diuresis impair reabsorption) 3. Promote elimination by changing tubular fluid pH to trap drugs Alkalization - give SODIUM BICARBONATE - increase ionized form of weak acid - can't be reabsorbed - easy excretion Acidification - giving acidic molecules - increases ionized form of weak base - can't be reabsorbed - easy excretion

Question 32

Hepatic Clearance (Equation, Extraction Ratio Types)

Answer 32

Hepatic Clearance = hepatic blood flow * extraction ratio Extraction ratio = (Cin-Cout)/Cin high E Drugs (E>0.7) = Flow-Limited - limited only by Q low E Drugs (E<0.3) = Intrinsically Limited - sensitive to intrinsic hepatic metabolism capacity and protein-binding

Question 33

Biliary Drug Excretion (Process, Drug)

Answer 33

1. Drug transferred from plasma to bile (then gut and feces) using transporters - SLCO1B1 (OATP1B1) transport statins for bile excretion - polymorphisms cause increased sensitivity - toxic buildup - myotoxicity - muscle injury

Question 34

Enterohepatic Cycle (process, drugs)

Answer 34

1. Drugs that are conjugated (Phase II metabolized) in liver are secreted in bile 2. Bacteria in gut cleave glucuronides + liberated drug is reabsorbed 3. Drug half-life prolonged Drugs: Digoxin, Morphine, Estradiol (birth control) Antiobiotics - eliminate gut bacteria - drug not reabsorbed, decreases drug half-life, drug may lose therapeutic effect (causes unplanned pregnancy with reduced estradiol half life)

Question 35

Distribution v. Metabolism Phase on [Drug] v. time curve

Answer 35

Distribution phase: drug leaves systemic circulation to other targets/reservoirs - represented by early, steep drop in plasma drug concentration Metabolism/Elimination phase: Drug is inactivated and cleared - represented by later, constant slow drop in plasma drug concentration

Question 36

Volume of Distribution (Definition, Equation, Clinical Utility, Effect of Plasma + Tissue Protein Binding)

Answer 36

1. Apparent volume of fluid required to contain all drug in the body at same concentration as in plasma 2. Vd = D (mg) / [drug]p (mg/L) 3. Use Vd to establish [drug]p rapidly 4. High plasma protein binding = more drug in blood = lower Vd; High tissue protein binding = less drug in blood = higher Vd

Question 37

Clearance (Definition, General Equation, Oral Dose Equation, What happens when one variable changes)

Answer 37

Clearance = Rate of Elimination (mg/hr) / [drug]p (mg/L) Volume of plasma cleared of a substance per unit time Oral Doses: Cl = F*[D (mg) / tau (hr)]/[drug]p tau = dosing interval (time) Equation is NOT a relationship: Increasing [drug]p does not cause an increase in Cl (for 1st order rxns, Cl is constant and elimination rate increases as [drug]p increases)

Question 38

Half-Life (Definition, Equation, Relationships)

Answer 38

Definition: time required for plasma concentration of drug to decrease by half Equation: t(1/2) = [0.693*Vd]/Cl Relationship: Increasing Vd will increase half-life Increasing Cl will decrease half-life

Question 39

6 Characteristics of First Order Pharmacokinetics

Answer 39

1. Linear Pharmacokinetics - a constant proportion of drug is eliminated per time (ex: 50%) 2. Increasing [drug]p causes increase in elimination rate - clearance stays constant 3. if you double the dose, the [drug]p is doubled 4. half-life is constant for drug no matter the dosage 5. no saturation of elimination rate (it can compensate) 6. MOST COMMON FOR DRUGS

Question 40

6 Characteristics of Zero Order Pharmacokinetics

Answer 40

1. Nonlinear Pharmacokinetics - a constant amount of drug is eliminated per time (ex: 5mg/L/hr) 2. Increasing [drug]p does not change elimination rate - clearance decreases 3. if you double the dose, there is an unpredictable response to [drug]p due to changing half-life 4. Half-life changes as clearance changes (Not constant) 5. Saturation/Capping of Elimination Rate (it cannot compensate) 6. Least common for drugs: ex: Phenytoin (anti-epileptic), Lidocaine

Question 41

Steady-State Concentration (Definition, Equation, Timing, Rules of Thumb)

Answer 41

1. Concentration at steady state - goal to target for therapeutic effect - when infusion rate balances clearance 2. C(ss) = [IV infusion rate]/Cl = (D/tau)*(F/Cl) [(mg/hr)/(L/hr)] 3. It requires 3.3 half-lives for drug to reach 90% C(ss) - mirror image of half-life for decay [Longer for Lidocaine and Phenytoin] 4. Half-life of drug should approximate dosing interval 5. Narrow TI requires monitoring of [drug]p

Question 42

Loading Dose (Equation, Factors) + Maintenance Dose (Equation)

Answer 42

1. D(l) = Vd * C(ss) An increase in Vd causes an increase in D(l) First dose should be larger to bring [drug] up to therapeutic zone Vd influenced by age, weight, sex - which alter D(l) 2. D(m)/tau = Cl * C(ss)