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Foundations 2 > ADME > Flashcards

ADME Flashcards

1
Q

Three factors to Drug Absorption

A
  1. Route of Administration
  2. Bioavailability
  3. Bioequivalence
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2
Q

Route of Drug Administration: Enteral

A

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
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3
Q

Routes of Drug Administration: Parenteral

A
  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
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4
Q

Routes of Drug Administration: Mucosal

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

2. Intranasal/Ocular/Intravaginal

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5
Q

Routes of Drug Administration: Inhalation

A

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

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6
Q

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

A
  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
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7
Q

8 Factors that Affect Oral Absorption of Drugs

A
  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
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8
Q

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

A
  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

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9
Q

Bioequivalence vs. Pharmaceutical Equivalence

A
  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
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10
Q

How do generic drugs differ from Brand-Name drugs?

A 
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
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11
Q

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

A

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)

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12
Q

Features of BBB

A
  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
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13
Q

Features of Blood-Cerebrospinal Fluid Interface

A
  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
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14
Q

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

A
  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
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15
Q

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

A
  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
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16
Q

Goal, Strategies, and Generalization of Drug Metabolism

A

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)

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17
Q

List the Classes & Sub-classes of Phase I Reactions

A
  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
18
Q

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

A
  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
19
Q

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

A

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)
20
Q

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

Cyp-independent Oxidations (Type, Drug)

A

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)

21
Q

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

A

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
22
Q

Sulfation Reaction (Type, Scheme, Drugs)

A

Phase II metabolism Reaction

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

23
Q

Acetylation Reaction (Type, Scheme, Drugs)*

A

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)
24
Q

Glucuronidation Reaction (Type, Scheme, Drugs)

A

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)

25
Q

Glutathione Reaction (Type, Scheme, Good/Bad)

A

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

26
Q

Methylation Reaction (Type, Scheme, Example)

A

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
27
Q

List locations and mechanisms for drug elimination

A

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)

28
Q

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

A
  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.

29
Q

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

A
  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
30
Q

Tubular Secretion (Location, Transport Types, Drugs)

A
  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]
31
Q

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

A
  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)
  4. 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
32
Q

Hepatic Clearance (Equation, Extraction Ratio Types)

A

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

33
Q

Biliary Drug Excretion (Process, Drug)

A
  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
34
Q

Enterohepatic Cycle (process, drugs)

A
  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)
35
Q

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

A

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

36
Q

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

A
  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
37
Q

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

A

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)

38
Q

Half-Life (Definition, Equation, Relationships)

A

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

39
Q

6 Characteristics of First Order Pharmacokinetics

A
  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
40
Q

6 Characteristics of Zero Order Pharmacokinetics

A
  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
41
Q

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

A
  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
42
Q

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

A
  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)

Foundations 2 (12 decks)

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