ADME: part 1

what is pharmacology?

pharmacodynamics + pharmacokinetics

what is pharmacodynamics?

• effects of the drug on the body
• study of the biochemical and physiological effects of drigs and their MOA

what is pharmacokinetics?

• effects of the body on the actions of a drug
• study of the ADME

why bother to determine ADME in drug discovery and development?

critical for drug efficacy and safety

what are the major causes of attrition in the clinic?

ADME, lack of efficacy

what is absorption?

the process of a drug entering the central blood circulation within the body

what do effective responses require?

• dose (or the exposure) high enough to produce the response
• route of administration appropriate to produce the response

what are the advantages and disadvantages of the enteral route?

advantages:

• simple, inexpensive, convenient, painless, no infection, no special equipment

disadvantages:

• drug exposed to harsh GI environments and first-pass metabolism

• slow delivery to the site of pharmacologic action

• compliance required

• not rapid

• erratic absorption

what are the advantages and disadvantages of the parenteral route?

advantages:

• rapid delivery to site of pharmacologic action

• high bioavailability

• not subject to first-pass metabolism or harsh GI environment

• titrate dose

disadvantages:

• irreversible

• infection, pain, fear

• skilled personnel required

what are the advantages and disadvantages of the mucous membrane route?

advantages:

• rapid delivery to site of pharmacologic action

• high bioavailability

• not subject to first-pass metabolism or harsh GI environment

• low infection

• direct delivery to affected tissues (e.g. lung)

disadvantages:

• few drugs available to administer via this route

what are the advantages and disadvantages of the transdermal route?

advantages:

• simple, convenient, painless

• excellent for continuous or prolonged administration

• not subject to first-pass metabolism or harsh GI environment

disadvantages:

• requires highly lipophilic drug

• slow delivery to site of pharmacologic action

• may be irritating

what are the advantages and disadvantages of the subcutaneous route?

advantages:

• may be used to administer oil-based drugs

• rate of absorption controlled by vasculature

disadvantages:

• slow onset

• small volumes

• irritation

what are the advantages and disadvantages of the intramuscular route?

advantages:

• intermediate onset

• may be used to administer oil-based drugs

• slow release from repository

disadvantages:

• can affect lab tests (creatine kinase)

• IM hemorrhage

• painful

what are the advantages and disadvantages of the intravenous route?

advantages:

• rapid onset

• controlled drug delivery

• least dependent on absorption processes

• can be large volumes

• can dilute irritating solutions

disadvantages:

• peak-related drug toxicity

• not for oily solutions/suspensions

what are the advantages and disadvantages of the intrathecal route?

advantages:

• bypasses BBB by directly injecting into cerebrospinal fluid

disadvantages:

• infection

• highly skilled personnel required

what additional routes are there?

• rectal: local application to colon
• sublingual: vasodilators, angina
• inhalation: gases
• regional perfusion: delivery to certain organs
• intraperitoneal: vaccines, chemo
• implantation

what are the reasons for different routes of administration?

• convenience
• maximize concentration at the site of action (and minimize it elsewhere)
• prolong duration of drug absorption (transdermal)
• avoid first-pass effect/elimination

what are the physiological factors affecting oral absorption?

• gastric motility and residence time
• pH of the GI tract
• intestinal surface area and transit time
• intestinal microflora

what are the physicochemical properties of drugs affecting oral absorption?

• hydrophilicity and lipophilicity
• ionizability and charge
• chemical stability
• molecular and particle size

what is the lipinski's rule of five?

• poor absorption/permeation are more likely
• >5 H-bond donors
• molecular weight > 500
• octanol/water partition coefficient: logP >5
• >10 H-bond acceptors

what is bioavailability (F)?

• fraction of drug available to the systemic circulation
• compare amount of drug in the system by different routes of administration
• reference is IV dosing
  F_IV = 1

what is presystemic elimination?

• entry of orally (PO) administered drugs

• intestinal enterocytes, portal venous system, hepatocytes

• avoid first pass with sublingual tablets: direct access to systemic veins

• only a fraction of rectal dose can be assumed to bypass the liver

some drugs undergo near-complete presystemic metabolism:

• limit oral bioavailability

• require other routes of administration: e.g. nitroglycerin*

• require higher oral doses: e.g. verapamil

what are the suppositories for presystemic elimination?

• lower rectum: drugs are absorbed into vessels that drain into the inferior vena cava (bypass liver)
• upper rectum: drugs are absorbed into veins that lead to the liver

what is the first pass effect?

• excretion and metabolism in enterocytes and hepatocytes
• reduce the amount of drug delivered to systemic circulation (bioavailability)

what is the hepatic extraction ratio?

• ratio of first pass on bioavailability
• maximum hepatic clearance = ~1.5 L/min
• ranges from 0-1
  ER = (C_in - C_out)/C_in
  CL_liver = Q x ER
• Q: blood flow (~90 L/h or 1.5 L/min)

what are the layers of GI walls?

outer to inner:

• serosa
• muscularis mucosa: longitudinal muscle, circular muscle, submucosa
• mucosa

what components of the GI are involved in the ENS?

myenteric plexus:

• controls GI motility

• sympathetic and parasympathetic

• within muscularis mucosa

submucosal (meissner's) plexus:

• controls GI secretion

• parasympathetic primarily

• nearest lumen

what is the parasympathetic autonomic NS?

• supplied by the vagus nerve
• stimulation of the parasympathetic fibers increases most activities of the GI tract
• cranial, sacral nerves

what are cranial nerves?

• innervate the upper and lowermost portions of the GI tract: esophagus, stomach, pancreas, and large intestine
• little innervation to small intestine

what are sacral nerves?

innervate the lowermost portions of the large intestine

what is the sympathetic autonomic NS?

• sympathetic nerves innervate all portions of the GI tract
• stimulation of sympathetic fibers inhibits most activities of the GI tract

what are mixing movements of the GI?

• local constrictive contractions of small segments of the gut walls

• increase luminal fluid to mucosal surface to promote absorption action of colon

what are propulsive movements of the GI?

• contractile ring appears in a segment of the GI tract and then moves forward
• the material in front of the contractile ring is moved forward
• "mass action" contractions

what are the common side effects of drugs on the GI?

• constipation: analgesics, antacids, antihistamines, corticosteroids
• diarrhea: antimicrobials, stool softeners, laxatives

what are drug-food interactions?

• tetracycline and milk products
• warfarin and vitamin K-containing foods
• grapfruit juice

what are DDIs in the GI tract?

• sucralfate, some milk products, antacids, and oral iron preparation: block absorption of quinolones, tetracycline, and azithromycin
• omeprazole, lansoprazole, H2 antagonists: reduce absorption of ketoconazole, delavirdine
• didanosine (given as a buffered tablet): reduces ketoconazole absorption
• cholestyramine: binds raloxifene, thyroid hormone, and digoxin

what is the plasma membrane?

• bilayer of amphipathic lipids with hydrocarbon chains inward and hydrophilic heads outward

• components: cholesterol, membrane proteins

• highly ordered in domains

• charged chemicals cannot pass through by diffusion

what is passive transfer?

• diffusion: drug molecule penetrates by diffusion along a concentration gradient by virtue of solubility in the lipid bilayer
• paracellular transport: filtration in glomerulus with the exception of CNS capillaries ("tight")
• endocytosis

what is passive transfer proportional to?

• magnitude of concentration gradient
• lipid-water partition coefficient
• membrane surface area exposed to drug

what is active transport?

• proteins with drug molecules bound are too large and polar for crossing membrane
• usually just unbound drug crossing membrane
• bulk flow transfer of drugs with water through membrane p to 100-200 Da
• energy is required
• transport is possible against a concentration gradient
• more frequently occurs for endogenous metabolies, but a number of drugs are also actively transported

what are most drugs?

• weak acids (R-COOH)/bases (R-NH2)
• exist either in the ionized/unionized form, depending upon the pH of the solution and the pKa of the drug
• pKa: pH at which half the drug is in its ionized form
• acids release protons, bases acquire them

what is the henderson-hasselbalch equation?

pH = pKa + log([basic form]/[acidic form])

what is aniline absorption and H-H?

• if the ratio of RNH2/RNH3+ in the stomach and plasma are 1/1000 and 1000/1, we can calculate the amount absorbed by setting the value of the uncharged form on either side of 1
• to maintain the calculated ratios, we can change the value of RNH2 to 1
• the new ratios are stomach = 1/1000 and plasma = 1/0.001
  concentration:
• in the stomach, 1 + 1000 = 1001
• in the plasma, we have 1 + 0.001 = 1.001
• there will be little/no absorption of aniline from the stomach to plasma

what is aspirin absorption and H-H?

• if the ratio of RCOO-/RCOOH+ in the stomach and plasma are 1/100 and 10000/1, we can calculate the amount absorbed by setting the value of the uncharged form on either side of 1
• to maintain the calculated ratios, we can change the value of RCOOH to 1 on both sides
• the new ratios are stomach = 0.01 and plasma = 10000/1
  concentration:
• in the stomach, 1 + 0.01 = 1.01
• in the plasma, we have 10000 + 1 = 10001
• there will be good absorption of aspirin from the stomach to plasma