ADME Flashcards
Three factors to Drug Absorption
- Route of Administration
- Bioavailability
- Bioequivalence
Route of Drug Administration: Enteral
Via the GI tract
- Oral: 30-90min depending on drug; easy, inexpensive, safe; slow, requires consciousness + working gut, limited bioavailability
- Rectal: 5-30min due to capillary network; easy, good absorption, no 1st pass metabolism; not preferred by patients
Routes of Drug Administration: Parenteral
- Intravenous: 30-60s; instantaneous delivery, no absorption, 100% bioavailability; need IV cannula, expensive, painful, invasive
- Intramuscular/Subcutaneous: 10-30min; quick, no 1st pass metabolism; unpredictable absorption, painful, invasive
- Transdermal: min-hrs; very variable, don’t really need to be absorbed/distributed; easy, non-invasive; slow, hard to absorb through skin
Routes of Drug Administration: Mucosal
- Sublingual: 3-5min; capillary network under tongue
2. Intranasal/Ocular/Intravaginal
Routes of Drug Administration: Inhalation
2-3min into pulmonary capillaries; rapid absorption, limited systemic delivery; effectiveness depends on patient technique
Routes of Drug Administration: Intrathecal, Intraarticular, Intraosseus, Endotracheal
- Intrathecal - into CSF of SC (bypass BBB)
- Intraarticular - into joint, only distributes to joint
- Intraosseous - 30-60s; fast working on kids; GOOD FOR EMERGENCIES
- Endotracheal - 2-3min; direct to trachea and pulmonary capillaries; GOOD FOR EMERGENCIES
8 Factors that Affect Oral Absorption of Drugs
- Drug Physical/Chemical Properties (but Surface Area > pH in gut absorption for weak acids/bases)
- Bioavailability
- Gastric Acidity + Digestive Enzymes
- Gastric Emptying Times
- Relationship to Food Intake
- Drug Metabolism by Gut Epithelium (CYP3A4)
- Drug Efflux from Gut Epithelium (PGP)
- Co-administration of other drugs/inhibitors of CYP3A4 + PGPs
Bioavailability (Definition, Loss Factors, Why do we still administer low F drugs orally?, Equation)
- Fraction of administered dose of unchanged drug that reaches systemic circulation
- Drug that doesn’t make it: in GI lumen, metabolized in GI wall, excreted by PGP, metabolized/excreted in liver
- FIRST PASS METABOLISM: metabolism in intestinal wall/liver before drug reaches systemic circulation - by CYP3A4
- 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
Bioequivalence vs. Pharmaceutical Equivalence
- Drug preparations that exhibit the same F & pharmacokinetics - same absorptive + distributive effects
- Different drug preparations with the same active ingredient, concentration, dose, route of admin, but may have different absorptive and distributive effects
How do generic drugs differ from Brand-Name drugs?
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
How does tissue distribution influence drug action? (2 compartments, 2 types)
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)
Features of BBB
- Only lipid soluble drugs penetrate BBB
- Tight junctions, continuous endothelia, astrocyte architecture
- PGP + other drug efflux transporters further prevent drugs from entering CNS*
* inhibiting transporters could improve penetration
Features of Blood-Cerebrospinal Fluid Interface
- ex: intrathecal delivery to SC (lumbar puncture)
- access CSF from SC to choroid plexus (fenestrated endothelia in brain)
- CSF circulates brain and can penetrate through loose epithelium layer - WAY TO BYPASS BBB
Effect of Drug-Protein Binding in Pharmacokinetics + Pharmacodynamics (Types of proteins, Result, Reversible binding, Disease)
- ALBUMIN binds weak acids & alpha-acid glycoprotein binds weak bases
- When drug is bound, can’t reach target, no therapeutic effect (only free drug can enter tissue)
- High binding - less available free drug - less metabolism and elimination - longer 1/2 life
- Reversible binding - acts as storage depot to prolong drug action
- hypoalbuminemia: low protein in blood, higher free drug concentration without affecting total plasma drug concentration
Why do we have drug metabolizing enymes (DME)? (2 reasons)
- Xenobiotics - DME has evolutionary advantage to eliminate these substances not natural to body and cause toxic effects (from foods/pharmacological agents
- Cometabolism - enzymes that metabolize both endogenous agents AND xenobiotics
Goal, Strategies, and Generalization of Drug Metabolism
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)
List the Classes & Sub-classes of Phase I Reactions
- Oxidation Reactions a. CYP-dependent (i. Hydroxylation ii. S-oxidation iii. N-oxidation iv. Oxidative dealkylation [N-dealkylation & O-dealkylation]) b. CYP-independent oxidation
- Hydrolysis Reactions a. ester hydrolysis b. hydrolases
CYP-dependent oxidation reactions (reactions, location, structure, steps)
- oxidation reactions include hydroxylation + oxidative dealkylation
- location: on ER of liver & intestine epithelium
- structure: contains Fe-heme group to bind molecular oxygen for oxidations
- paired with near by reductase, which feeds CYPs with electrons and protons to perform oxidation reactions
STEPS: - drug binds CYP oxidase
- reductase gives e- to CYP, Fe atom goes from +3 to +2, which better binds O2
- Fe+2 binds O2
- Reductase feeds e- to O2 forming an ROS (O2-, activated oxygen)
- Reductase feeds to protons, one oxygen freed as water and the other forms ROS with Fe, Fe-OH radical ferric oxene
- Drug gets hydroxylated, Fe becomes Fe+3
Hydroxylation, S-oxidation, N-oxidation (Type, Scheme, Drugs)
All are CYP-dependent oxidation reactions in Phase I metabolism
- add hydroxyl group to drug (Midazolam, B[a]p, Propanolol) - CYP3A4
- adds oxygen on sulfur group to make sulfonyl (Cimetidine on H2 Histamine Receptors)
- adds oxygen onto N’s (Benedryl on H1 Histamines - not important)
N-dealkylation and O-dealkylation (Type, Scheme, Drugs)
Cyp-independent Oxidations (Type, Drug)
Both are CYP-dependent oxidation reactions, and oxidative dealkylation sub-reactions in Phase I metabolism
- removal of alkyl group from amine (Methylxanthines - Caffeine + Theophylline)
- removal of alkyl group from ester (codeine, hydrocodone)
Cyp-independent oxidations: Ethanol (plays role in acetominophen toxicity)
Ester Hydrolysis and Hydrolase Reactions (Type, Scheme, Drugs)
Both are hydrolysis reactions in Phase I metabolism
- Split drug at the ester (Succinylcholine: degraded twice by pseudocholinesterases*) - polymorphisms can reduce activity
- convert epoxides (electrophiles cause cancer by binding DNA) into diols - Toxicity reduction
Sulfation Reaction (Type, Scheme, Drugs)
Phase II metabolism Reaction
1. sulfotransferases (SULTS) require PAPS cofactor to add -SO3H group on hydroxyl (Acetaminophen & Albuterol
Acetylation Reaction (Type, Scheme, Drugs)*
Phase II metabolism Reaciton
- 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)
Glucuronidation Reaction (Type, Scheme, Drugs)
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)
Glutathione Reaction (Type, Scheme, Good/Bad)
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
Methylation Reaction (Type, Scheme, Example)
Phase II Metabolism Reaction
- Methyltransferase requires SAM as methyl group donor to methylate aromatic rings with N, O, S
- Thiopurine Methylation - important in PHARMACOGENOMICS
List locations and mechanisms for drug elimination
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)
Clearance (definition, equation for general clearance, total clearance, renal clearance)
- 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.
Glomerular Filtration (Location, Filtration Factors, GFR, Effect due to Age)
- GC network within kidney nephrons - flow from GC to renal PT through fenestrated endothelial cells
- Larger, Negative Molecules filtered less; Smaller, Positive Molecules filtered more; protein-bound drugs can’t be filtered
- Filtration = GFR*[drug]p (normal GFR = 125mL/min)
- As age increases, GFR decreases - drugs then require lower dose and longer dosing intervals
Tubular Secretion (Location, Transport Types, Drugs)
- PT
- 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]
Passive Tubular Reabsorption (Location, Transport Factors)
Why do lipid soluble drugs have generally longer half lives?
How do you trap drugs in ionized form?
- From renal tubule beyond PT to PC via diffusion or transporters
- Preferred reabsorption of filtered lipid-soluble + non-ionized drugs - why lipid soluble drugs have longer half lives
- High flow rates (diuresis impair reabsorption)
- 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
Hepatic Clearance (Equation, Extraction Ratio Types)
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
Biliary Drug Excretion (Process, Drug)
- 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
Enterohepatic Cycle (process, drugs)
- Drugs that are conjugated (Phase II metabolized) in liver are secreted in bile
- Bacteria in gut cleave glucuronides + liberated drug is reabsorbed
- 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)
Distribution v. Metabolism Phase on [Drug] v. time curve
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
Volume of Distribution (Definition, Equation, Clinical Utility, Effect of Plasma + Tissue Protein Binding)
- Apparent volume of fluid required to contain all drug in the body at same concentration as in plasma
- Vd = D (mg) / [drug]p (mg/L)
- Use Vd to establish [drug]p rapidly
- High plasma protein binding = more drug in blood = lower Vd; High tissue protein binding = less drug in blood = higher Vd
Clearance (Definition, General Equation, Oral Dose Equation, What happens when one variable changes)
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)
Half-Life (Definition, Equation, Relationships)
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
6 Characteristics of First Order Pharmacokinetics
- Linear Pharmacokinetics - a constant proportion of drug is eliminated per time (ex: 50%)
- Increasing [drug]p causes increase in elimination rate - clearance stays constant
- if you double the dose, the [drug]p is doubled
- half-life is constant for drug no matter the dosage
- no saturation of elimination rate (it can compensate)
- MOST COMMON FOR DRUGS
6 Characteristics of Zero Order Pharmacokinetics
- Nonlinear Pharmacokinetics - a constant amount of drug is eliminated per time (ex: 5mg/L/hr)
- Increasing [drug]p does not change elimination rate - clearance decreases
- if you double the dose, there is an unpredictable response to [drug]p due to changing half-life
- Half-life changes as clearance changes (Not constant)
- Saturation/Capping of Elimination Rate (it cannot compensate)
- Least common for drugs: ex: Phenytoin (anti-epileptic), Lidocaine
Steady-State Concentration (Definition, Equation, Timing, Rules of Thumb)
- Concentration at steady state - goal to target for therapeutic effect - when infusion rate balances clearance
- C(ss) = [IV infusion rate]/Cl = (D/tau)*(F/Cl)
[(mg/hr)/(L/hr)] - 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]
- Half-life of drug should approximate dosing interval
- Narrow TI requires monitoring of [drug]p
Loading Dose (Equation, Factors) + Maintenance Dose (Equation)
- 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) - D(m)/tau = Cl * C(ss)
