Learning Objectives for Disease and Defense

Week 1

Absorption and Distribution

1.  Identify the factors that determine a given drug’s ability to cross biological membranes.

  1. Molecular size: smaller MW drugs will be absorbed more readily, size also affected by the drug binding to plasma protein (increases size, decreasing absorption)
  2. Lipid solubility: increased lipid solubility leads to increased absorption (drug can easily cross lipid bilayer of membranes), estimated by oil:water partition coefficient
  3. Degree of ionization: affected by pH, will influence lipid solubility (more unionized=more lipid soluble=increased absorption), requires H-H equation
  4. Concentration gradient: high concentration created at site of drug administration, drug will move from [high] to [low].

2.  Describe the mechanisms by which drugs cross biological membranes (diffusion, transport, etc.).

  1. Passive diffusion
  2. MOST IMPORTANT ROUTE, driven by concentration gradient
  3. Aqueous diffusion/filtration (drug flows through aqueous channel): limited capacity, channel size varies (generally for drugs of MW less than 100-200)
  4. Lipid diffusion (drugs pass via hydrophobic bonding with membrane lipids): favored if drug has high lipid:water partition coefficient, often pH dependent, unionized moiety crosses membrane down concentration gradient, most important mechanism for drugs with MW of 500-800.
  5. Carrier mediated diffusion
  6. Facilitated diffusion: driven by concentration gradient (no energy required)
  7. Active transport: energy dependent, selective, saturable, unidirection, for durgs which resemble endogenous compound. Many cells also contain less selective membrane transporters that are specialized in expelling foreign molecules (ie: P-glycoprotein). Drugs are inhibitors of these transporters can be involved in certain drug-drug interactions via alteration of substrate drug levels in tissues.
  8. Endocytosis
  9. Of minor importance to drug passage, pinocytosis or phagocytosis

3.  Summarize the therapeutic advantages and disadvantages of the various routes of drug administration, especially with regards to bioavailability and rate of onset of effect.

ROUTE / BIOAVAILABILITY / RATE / OTHER FACTORS
Enteral (GI tract) / Oral / 0-100%: depends on survival in GI environment, ability to cross GI membrane, efficiency of drug metabolism by gut wall or liver (1st pass) / Slow (15-30 min for immediate release)
Slower (hours) for enteric/sustained release) / Most common, drug absorption occurs via passive diffusion (favors lipophilic/nonionized drugs), rate of absorption of drug from intestine ˃stomach (because of large SA of intestine), increased GI motility and empty stomach=increased absorption, duration: min-hrs
Enteric drug coat: protects stomach from irritation and protects drugs from low stomach pH
Controlled-release prep: rate of absorption is slowed by slowing rate of product dissolution (allows for fewers administrations, increased compliance, overnight therapy, elimination of peaks/troughts, BUT greater interpatient variability and formulation could fail giving pt entire doseà “dose dumping”
Enteral (GI tract) / Rectal / Variable, but generally ˃ oral / Not rapid / Useful with oral route is unavailable (vomiting, unconscious, post-GI surg, uncooperative pt), 50% of dose will BYPASS liver (first pass metabolism is ˂ for oral, absorption is irregular/incomplete
Parenteral (Outside GI) / Sublingual
Buccal / Generally high / Within minutes (5-10 min) / Absorbed from mouthàSuperior vena cava (protects drugs from hepatic 1st metabolism + faster onset), useful for drugs that are lipid soluble and relatively potent (˂1mg dose) as there is smaller SA for absorption relative to GI tract
Parenteral / Intravenous / 100% / MOST Rapid (Sec-min) / Most direct route, circumvent all factors related to membrane passage/absorption, accurate and fast drug delivery, used for drugs with narrow therapeutic window, requires aseptic technique, most haxardous route b/c easy to reach irreversible toxic levels quickly, duration= t1/2-dep
Parenteral / Intramuscular / Approaches 100% / Aqueous soln-rapid (5-10 min), slower in depot form / Absorption/onset effected by blood flow/muscle activity at site of injection, depot form in oil or suspended= slower/sustained absorption, used if drug is too irritating for subQ, absorption may be erratic/incomplete with solubility is limited, disadvantage: pain, tissue necrosis (if high pH), microbial contamination
Parenteral / Subcutaneous / Approaches 100% / 5-10 min,
Slower, constant rate for depot (hours) / Only for non-irritating drugs, volume of dose is limiting, period of drug absorption can be altered via particle size, protein complexation, pH (insulin), addition of vasoconstrictor (local anesthetics), pellet implantation (contraceptives)
Parenteral / Inhalation
Gaseous: Gas/volatile liquids
OR
Suspension:
Aerosol or microparticles / Variable-100%
a. about 100%
b. variable / Rapid (˂5 min for gaseous)Negligible / Gas: used for rapid onset of systemic drug effects (nicotine, crack, general anesthetics), rapid rate of absorption due to large SA and high blood flow in pulmonary tissue
Particle: applied at site of action in lung, increases local topical effects (reduces systemic effects), example- asthma, depends on particle size
< 0.5 mM: exhaled from lungs à no effect
1-5  mM: deposited in small airways à therapeutic
> 10 mM: deposited in oropharynx à side effects
Irritant drug may induce bronchospasms
Parenteral / Transdermal / Slow (hours) / Apply patch to skin for tx of systemic conditions, prolonged drug levels attained, 1st pass metabolism is avoided, drug must be potent (dose ˂2 mg), must permeate skin w/o irritation, examples: estrogens, testosterone, fentanyl, nicotine, nitroglycerin
Topical / Localized application via skin/mucous membrane (vaginal, nasal, eye) for tx of local conditions, minimal systemic absorption, in children potential for 3-fold greater system availability that in adult (body SA: weight is greater)

4.  Explain the influence of pH on the ionization of weak acid / weak base drugs.

  1. Most drugs are either weak acids or weak bases, therefore they are present in biological fluids are ionized or non-ionized species.
  2. Non-ionized forms are more readily absorbed. Ionized forms DO NOT cross lipid membranes.
  3. Weak Acids:
  4. HA (or R-COOH) ↔ H+ + A- (R-COO-)
  5. R-COOH is the protonated/non-ionized form of the acid and can cross biological membranes (in acidic environment)
  6. R-COO- is the un-protonated form of the acid and will be “ion-trapped”
  7. Weak Bases:
  8. BH+ (R-NH3+) ↔ H+ + B (R-NH2)
  9. R-NH3+ is the protonated form of the base and will be “ion-trapped”
  10. R-NH2 is the un-protonated/non-ionized form of the base and will cross biological membranes (in basic environment)

5.  Be able to use the Henderson-Hasselbach equation to qualitatively predict the ratio of ionized to unionized species of a weak acid or weak base drug in various body compartments.

  1. HH equation: determines the extent of ionization of an acid or a base (dependent on the strength of the acid or base (pka) and the pH of the body fluid). Allows quantitation of the fraction of the total amount of drug that is ionized or unionized and allows predictions of a pH that at which the majority of the drug will be non-ionized and thus will be absorbed.
  2. pH-pKa= log (non-protonated: A- or B)/ (protonated: HA or BH+)
  3. pH= pH of the biological compartment the drug is in
  4. pKa= pH of a solution at which concentrations of the protonated and unprotonated forms of the drug are equal.
  5. If pH is lower than pKa (lots of protons): protonated form of weak acid (unionized-lipophilic) or weak base (ionized) will predominate
  6. If pH is higher than pKa (fewer protons): unprotonated form of weak acid (ionized) or weak base (unionized) will predominate.
  1. “Ion Trapping”: lipid barriers may separate two aqueous solutions with different pH’s. Only non-ionized drugs can diffuse through membrane and this form of the drug will equilibrate and be the same on both sides of the membrane. At equilibrium, un-ionized concentration of drug is the same on both sides of the membrane, but total concentration of drug is greater on the side where ionization is greater.
  2. Acidic drugs will be trapped in BASIC solutions. Basic drugs will be trapped in ACIDIC solutions. They are trapped where they are predominantly ionized.
  3. Clinical significance: altering urinary pH to ion trap weak acids or bases and hasten renal excretion (in aspirin overdose situations), greater potential to concentrate basic drugs in more acidic breast milk

6.  Explain the therapeutic consequences of anatomic “barriers” to distribution and selective accumulation of drugs.

  1. Tissues with tight junctions between cells (GI mucosa, BBB, placenta, renal tubules), require that drugs pass through lipid membranes to or from this compartment and into or out of the blood. Drugs that can’t pass through membranes (large size, protein bound, highly charged, high water solubility) will be UNABLE to move between these compartments and blood.
  2. GI mucosa: negligible absorption of drug into blood in administered orally
  3. BBB/placenta: limited distribution of drug from blood into brain or into fetal circulation, due to structural differences between brain and non-brain capillaries

7.  Describe how drug binding to plasma proteins can effect drug distribution and elimination as well as be a potential source of drug-drug interactions.

  1. Will influence distribution as only FREE DRUG is diffusible.
  2. Acidic dugs bind to albumin and basic drugs bind to alpha-1 acid glycoprotein
  3. As drug binding to protein increases:
  4. Decreased concentration of free drug (can limit fetal exposure to drug)
  5. Decreased metabolic degradation and rate of excretion (will decrease elimination rate and increase half-life), acis as circulating drug reservoir that can prolong drug action
  6. Decreased volume of distribution by enhancing apparent solubility in blood (because only free drug can get out)
  7. Decreased ability to enter CNS across BBB (because only free drug enter brain more readily)
  8. Mediates protein binding/displacement drug-drug interactions
  9. Displacement of 1st drug from protein binding site by 2nd drug results in increased levels of unbound 1st drug, but levels of total drug are unchanged because administration is unchanged.
  10. Unlikely to be of clinical significance unless the displaced drug has narrow therapeutic index, displacing drug is started in high doses, Vd of displaced drug is small, or response to drug occurs more rapidly than redistribution.

8.  Explain the derivation and clinical relevance of the following pharmacokinetic parameters. Describe their use in designing dosage regimens:

  1. Bioavailability (F): Adjustment of dose for oral vs parenteral administration.
  2. Bioavailability (F or f[%]): fraction of unchanged drug reaching the systemic circulation, determined by comparing AUC following single dose of drug given by any route to the AUC following single dose by IV route.
  3. F = Fraction Bioavailable = AUCORAL / AUCIVA
  1. Volume of distribution (Vd): Converting drug dose to plasma concentration, selecting loading dose, implications of high or low values.
  2. Vd: size of compartment necessary to account for total amount of drug in the body if it were present throughout body at same concentrations found in plasma. It is the volume of the body fluids into which the drug distributes following administration. Gives indication of the extent to which a drug passes from plasma to extravascular tissues
  3. High values of Vd indicate drugs located mostly outside of plasma (increased tissue binding, high lipid solubility)
  4. Low values of Vd indicate drugs located mostly inside the plasma or ECF (extensive binding to plasma proteins or large size)
  5. Vd varies between patients due to: Body Weight, Fat vs. Lean and Changes in Protein Binding
  6. Vd allows determination of the necessary single dose of drug (loading dose) to fill the distribution volume with enough drug to achieve desired steady state level (Cp)
  7. Vd also allows prescriber to determine effect of any given dose (D) will have on the plasma concentration
  8. Loading Dose (LD)= Cp (desired) x Vd
  9. Cp= Dose/Vd
  10. Vd (L)= DOSE (mg)/concentration of drug in plasma (mg/L)
  11. DOSE (mg)= concentration of drug in plasma (mg/L) x Vd (L)
  12. Concentration of drug in plasma (mg/L)= DOSE (mg)/Vd (L)

Metabolism and Excretion

1.  Describe the general principles and consequences of drug metabolism.

  1. Drug metabolism: drugs undergo enzyme-catalyzed chemical structure transformation after administration to the patient (if only terminated only by renal excretion, the duration of action would be prolonged)
  2. Drug metabolizing enzymes have endogenous substrates and play a role in normal metabolism
  3. Liver is primary site of drug metabolism, but lungs (30%), intestines (6%), kidney (8%), skin (1%), placenta (5%) and bacteria have enzymes capable of drug metabolism
  4. Oxidation is most common pathway, but other types of chemical transofmration can occur. Many transformation are catalyzed by membrane-bound enzymes of the SER called CYP450
  5. Lipid-soluble compounds are generally converted to more H20-soluble (more polar) compounds that are more readily excreted
  6. Generally, metabolism is detoxifying process (active drug to inactive or less active compound), but can also metabolize active drug into MORE active compound (ie: codeineà morphine), metabolize inactive compound into active ingredient, metabolize to toxic metabolite

2. Describe the general characteristics of Phase I (oxidation [CYP450 and non-CYPP450 (non-microsomal)],

reduction, hydrolysis) and Phase II reactions (conjugations: glucuronide, sulfate, glycine, glutathione) as related to:

Qualitative and quantitative role in drug metabolism

Classifications of reactions [ex., O-dealkylation is phase I oxidation (P450)]

PHASE I: inserts or unmasks a functional group on the drug that renders molecule more water-soluble and the molecule can then undergo conjugation in Phase II rxn. / PHASE II: endogenous substrate combines with pre-existing or metabolically inserted functional group on the drug forming a highly polar (water soluble) conjugate that is excreted via the urine.
Reactions / 1. Oxidation—P450 dependent or P450 independent (most common)
2. Reductions (azo, nitro, carbonyl reductions)
3. Hydrolysis / Conjugations:
1. Glucuronidation
2. N-acetylation
3. Glutathione conjugation
4. Sulfate conjugation
Enzymes involved / 1. CYP450 (includes NADPH, flavoprotein NADPH-cytochrome P450 reductase, and O2) or non-CYP450
2. Reductase
3. Esterases or amidases / 1. Transferases (ie: glucuronyl transferases, N-acetyltransferases)
Genetic Polymorphisms / YES
Examples: Amplichip test available to detect polymorphisms in CYP2D6 / 2C19
Lab tests available to detect genetic variation in anticoagulant response. Warfarin metabolizing enzyme: CYP2C9. Warfarin target enzyme: vitamin K reductase [VKORC1] / Yes (less)
General developmental patterns of activity and age-related changes in activity / YES (decreases with age in 1/3 of pts) / Yes (especially UGT)
Inhibitory/Inducibility / YES/YES / YES (less)
Relative ease of saturability at high drug substrate levels / Minimal / Substantial Limited supply of reactants renders Phase II reactions more easily saturable (become zero order elimination kinetics) than phase I reaction

3. Explain the therapeutic consequences of induction and inhibition of metabolism. List the clinically relevant