Topic III: Curve Fitting & Rate Order Review/Absorption

What is linear regression?

Describes linear relationship b/w an independent variable (input, x) & a dependent variable (output, y)

What is non-linear regression?

Describes a relationship in a non-linear trajectory using a parametric model (curves) when function is known (exponential, power, log)

What is the correlation coefficient (r)?

Describes the strength of a linear relationship

What is coefficient of determination (r²)?

Describes variability of outcome that can be explained by input factor

What is formulation critical to?

Drug absorption

What are the steps to liberation?

1. Disintegrate

2. Deaggregation

3. Dissolution

What is absorption?

Process involving movement of a substance from site of administration across/through biological membranes to biological fluids

• Primary pK factor determining length of time it takes for a drug to produce desired pharmacological effect

What can absorption greatly impact?

Bioavailability

What are the organelles & intracellular contents of our cells ensheathed by?

A phospholipid bilayer membrane but it is much more than that

What did Lodish & Rothman identify about the cell in 1979?

Flexible, dynamic phospholipid layer embedded w/ proteins that can move about freely → fluid mosaic model

What do carbohydrates often attach to?

Proteins (glycoproteins) or lipids (glycolipids) & play a role in cell signaling & regulation, while inserted cholesterol can provide structural support

What are many proteins?

Receptors that allow for cellular communication & response to external stimuli

What do the properties of components of cell membrane collectively allow for?

Coordinated maintenance of cellular homeostasis

• Regulating ion concentrations, pH & other factors essential for cellular function

What can small, nonpolar molecules (O2, CO2) do w/ the cell membrane?

Easily cross, while large & charged molecules require specific transport mechanisms → proteins & amino acids

How do other molecules (drugs) move about biological barriers?

Passive & active transport

What is passive diffusion?

Movement of drug across a membrane w/o the input of energy

What is flux (J)?

Rate associated w/ transfer of drug molecules from an area of high concentration, across a membrane to an area of lower concentration

What is passive diffusion how?

Most drugs move across membranes, particularly for PO administered therapeutics

What is the driving force of passive diffusion?

Increased concentration on luminal side of GI epithelium relative to aerosol (blood) side & described by rate equation for passive diffusion → dw/dt = P*A*C1

What can properties of the drug itself impact?

Rate of diffusion across a membrane

• Portion coefficient (K), more lipid soluble a drug is, higher the K & faster diffusion

What can the surface area of the environment in which drug is diffusion across can do?

Vary dramatically w/in body

What does the duodenal area of the small intestine have?

Largest surface area due to anatomical feature of → villi, microvilli

How does lipophilicity & hydrophilicity impact drugs?

Some drugs have both lipophilic & hydrophilic moieties

• Drugs w/ overall more lipophilic profile will, compared to more hydrophilic molecules, transverse biological membranes more easily → increased K → faster diffusion

What is the diffusion coefficient (D)?

Constant & differs for all drugs, but describes rate at which a drug diffuses across a specified area per unit of time

What is membrane thickness (h)?

Meaningful contributor to diffusion rate

• Constant for most sites of absorption & only differs in situations where cellular architecture presents additional challenges

• Blood-brain barrier (not technically absorption) & skin

  • Skin: 10-20 micrometer

  • GI tract: ~30 micrometer (mucus makes 50-500 micrometer)

What can different pathological or ill-health conditions alter?

Stability & integrity of biological membranes

• Cancer

• Meningitis

• Burns

What impacts the degree of permeability among drugs that are weak acids & bases?

Ionization state

What happens as the pH of a given environment changes?

Ionization state of a given drug will too

• Reflective of both pH of environment & pKa of drug itself → Henderson Hasselbaulsh

What does the pH-partition hypothesis impart?

3 important conditions across a biological membranes where pH is different on either side

1. Drug will be ionized to different extent on respective sides of membrane

2. Total concentration of drug (ionized plus unionized) will be unequal**

3. Compartment in which drug has greatest extent of ionization will contain highest amount of drug

How do we protect drugs that may be subject to degradation or cause adverse events if absorbed in the wrong anatomical region?

Enteric & physical coating

• Ex. PPIs

What do many drugs have a high binding affinity for?

Plasma &/or tissue proteins

What do influx (or uptake) transporters shuttle?

Naturally occurring molecules across GI epithelia & into systemic circulation

What are some examples of the influx transport in small intestine?

Transporters for vital nutrients

• Glucose transporter (glucose), L-type amino acid transporter-1 (LAT1; L-dopa, methyldopa)

  • Amino acids, electrolytes, cholesterol

What is the gabapentin indication?

Seizures

What is the levodopa indication?

Parkinson’s

What is the methyldopa indication?

HTN

What is the rate of absorption?

A dynamic process for drugs that undergo active transport into blood stream, meaning that they follow Michaelis-Menten kinetics

What do many transporters in the body have?

A bidirectional capacity, & whether they participate in absorption or exsorption is determined by total flux & cellular needs

What is the body able to prevent?

Absorption of many drugs/toxic chemicals, particularly from GI tract into systemic circulation, by actively pushing them back into the GI lumen in process known as active efflux (ATP Binding Cassette)

What are the 2 most common efflux transporters?

MDR-1 (ABCB1, P-go) & BCRP (ABCG2)

What is Paclitaxel?

• MOA: tubulin stabilizaton

• Substrate for MDR1 in GI tract & activates Steriod X receptor (SXR)

• Paxlitaxel moves through GI tract, some effluxed by MDR1

• Remaining activates SXR, induces enhanced transcription of MDR1 & CYP3A4 & CYP2C8

• Process is example of co-ordinated metabolism & efflux

Whta is oral dosing?

Most common & popular ROA but can demonstrate great variability for a variety of reasons including:

• Drugs may pass through any portion of alimentary canal but most important site for absorption of orally administrated drugs occurs in duodenum

• Total transit time for meal to make it from oral cavity to anus is roughly 14-58 hours, w/ average time of 28 hours

What is the main secretion in oral cavity that is responsible for drug dissolution & provides basis for absorption in oral cavity?

Saliva

What is Abilify?

ODT. Saliva helps break down tablet into small pieces from which drug can be absorbed in remaining GI tract

What is Actiq?

Sublingual lozenge (actually a lollipop) form of fentanyl used to combat breakthrough pain in pts w/ cancer

• Important instructions: do not chew!

What prevents most drugs from being absorbed in stomach?

pH of stomach, membrane thickness

What can stomach pH be greatly altered by both meals in relation to?

Their chemical make-up (fats, carbohydrates, protein), stimulation of physiological processes, or by presence of secondary health conditions

Why is stomach pH important for drugs?

Drugs that are enteric coated, coating will not dissolve at normal pH in stomach- but if drug is taken w/ meal or during time of increased pH in stomach, enteric coating may be dissolved releasing drug in stomach potentially rendering them useless

What can help prevent drugs being absorbed in stomach & becoming useless?

Proper clinical counseling & understanding individual pt conditions

What is Nexium?

For GERD & PUD. An enteric coated product (methacrylic acid copolymer). Pts are instructed to take w/o food!

What causes stimulation of acid secretion?

• Cephalic digestion phase

• Gastric digestion phase

• Protein

• Tea

• Coffee

• Milk

• Ethanol

What causes inhibition of acid secretion?

• Intestinal digestion phase

• Fats

• Carbohydrates

• H2RAs

• PPIs

• Achlorhydria

What does the functional anatomy of initial portion of small intestine allow for?

Both increased surface area & blood flow

What are protein drugs most often unable to be?

Delivered in an oral formulation b/c of proteolytic enzymes

What happens to some drugs referred to as prodrugs?

Hydrolyzed in duodenum during absorption of carboxylesterase

What is Candesartan cilexetil?

Hydrolyzed by human carboxylesterase 2 (hCES2) in enterocytes of small intestine to Candesartan, a powerful ARB indicated in HTN

What happens once a drug is given per orally?

It’s hard to pinpoint its exact location, as GI motility will move drug through alimentary canal at vary rates for multiple causes, resulting in change in amount of time a drug is at the site of maximum absorption

What do drugs that are given orally each have a period of contact w/ a specific point of GI tract where drug may be?

Most efficiently absorbed & absorption before/after this point is decreased dramatically- window is called anatomic window of absorption

What must drugs formulated in controlled released dosage forms?

Completely release their API into this absorption window to be absorbed before GI motility moves dosage form into large bowel

What is the largest impact of drug movement in GI tract & therefore drug absorption?

Presence of recently ingested meal in alimentary canal

• Why? Migrating motor complex

What are the different phases of the fasted/interdigestive state alternating cycles of activity known as MMC propel food bolus through upper GI tract & into cecum?

• Phase I- quiescence

• Phase II- low amplitude, irregular contractions

• Phase III- regular high altitude contractions

• Phase IV- descending amplitude, regulations contractions

• Fed state- regular, low amplitude contractions

Where does an orally administered therapeutic rapidly make its way to?

Stomach

How long does it take same dosage form to reach duodenum?

It varies

What are some drugs unstable in?

Acidic environment of the stomach & may decomposed (penicillin), while others may cause irritation to mucosal membranes of stomach if they remain in prolonged contact (aspirin; 2 ways)

What are the various constituents of a meal (digestive & indigestible solids, liquids) are emptied from stomach at?

Different rates

• Liquid are generally emptied much faster that solids

What kind of meals delay gastric emptying time?

• High in fat

  • Pyloric sphincter tighten & physical impediment to emptying

• Cold beverages

  • Physically slow stomach contractions

• Anticholinergic drugs

  • Pharmacological slowing of emptying

What are liquids & small particles (<11) generally not?

Retained w/in stomach & emptied rather rapidly due to sieve-like effect of pyloric sphincter

• increase basal pressure in stomach

What are larger particles, particularly those size of tablets & capsules, delayed from emptying into duodenum by presence of?

Food in stomach by roughly 3-6 hours

• Meals w/ a high quantity of indigestible solids may exacerbate this more, as they are typically emptied in interdigestive phase

What is peristaltic movement in GI tract functions?

Mix the contents w/in duodenum

• Brings both food & drug into intimate contact w/ microstructural anatomy of GIT

What must a drug spend sufficient time in contact w/ for a drug to have optimum absorption?

Brush border

What is residence time?

Time in which a drug spends in intimate contact w/ this area of small intestine

What can conditions that impart a substantial decrease in transit time through GI tract, particularly through small intestine, decrease?

Residence time of a drug, & decrease overall absorption

• Bouts of diarrhea

What does the splanchnic circulation receive of cardiac output?

28% & increased after meals

What will any condition/period w/ decrease blood flow to area will do to absorption?

Decrease

What does high perfusion through this area maintain?

A constant concentration gradient across GI epithelial

What is the lymphatic system important for dietary absorption of what sort of molecules?

• Some poorly water soluble, highly lipophilic drugs may be absorbed thorough lymphatic system

• Bile salts released from gallbladder help to emulsify these drugs & shunt them into enterocytes for packing & systemic recirculation w/in Chylomicrons

• Avoid 1st pass metabolism: yes

What are examples of the lymphatic system of drug absorption?

• Halofantrine

• Certain testosterone derivatives

• Temarotene

• Ontazolast

• Vitamin D-3

What does the FDA highly recommend use of?

High calorie & high fat dieters to exam impact on bioavailability &/or bioequivalence

What are the most common effects of food on bioavailability of a drug?

1. Delay gastric emptying

2. Stimulation of bile flow

3. Changes in pH of GIT

4. Increased blood flow

5. Altered luminal metabolism

6. Physiochemical make-up of meals & alterations of absorption

What is Griseofulvin?

Oral antifungal, has highest absorption following a meal containing a high fat content

What does the presence of a high fat meal induces?

Release of bile, which helps to solubilize lipid heavy contents of stomach, & therefore increase solubility of lipid soluble drug

What is ketoconazole?

Basic drug w/ low aqueous solubility, has increased absorption following a meal

What does food intake stimulate?

Release of hydrochloric acid, decreasing pH, causing rapid drug dissolution & increased absorption

What can fluid volume in stomach greatly impact?

Drug bioavailability

What do erythromycin, a macrolide antibiotic, & aspirin have?

Decreased oral absorption when taken w/ a meal compared to taken when fasted & w/ 250 mL

• Why? Concentration

What can intensity of contractions during digestion sometimes be capable of?

Damaging controlled release dosage forms

• Absorption from Theo-24, a controlled released form of theophylline, experiences a pattern known as dose dumping

What is the double peak phenomena?

• Some drugs display a plasma concentration curve consisting of 2 peaks

• Attributed to variability in stomach emptying, intestinal mobility, presence of food, enterohepatic recycling, or failure of dosage forms

What are examples of drugs w/ double peak phenomena?

• Ranitidine (off market)

• Cimetidine

• Dipyridamole

When does ranitidine produce a double peak phenomenon after?

Both IV & oral administration

• Following general circulation after IV delivery, ranitidine concentrates in bile

• When bile is released from gallbladder, drug-containing bile is expelled into GI tract, where it is later absorbed creating a second absorption peak even after IV administration

• Example of enterohepatic recycling

What results in dissolution of drug in stomach & partial emptying of drug into duodenum some drugs w/ high water solubility?

First absorption peak

What causes a second absorption peak?

A delay in emptying of stomach

How does congestive heart failure pts alter GI absorption?

• Often present w/ persistent edema & decreased splanchnic blood flow (a secondary effect can be seen on GI motility)

• Decreased & erratic oral absorption of furosemide (lasix) in pts w/ a CHF diagnosis

How does advanced Parkinson’s Disease pts, caused by impaired coordination of voluntary/involuntary neuronal muscular control & those taking tricyclic antidepressants (imipramine, amitriptyline, nortriptyline) or any antipsychotic medications w/ anticholinergic activity alter GI absorption?

Presents w/ varying degrees of impaired GI motility causing delayed absorption, especially from extended-release dosage forms

• Alter acetylcholine neurological signaling

How does pts w/ achlorhydria & those prescribed protein pump inhibitors (Omeprazole, lansoprazole) alter GI absorption?

Greatly reduced stomach acidity, which is essential for solubilizing insoluble free bases, which causes many weak bases to remain undissolved & unable to be absorbed

• No dissolution =/= drug absorption

How does celiac’s disease alter GI absorption?

Caused by sensitivity to gluten, is an inflammatory disease affecting mostly small intestine, resulting in increased gastric emptying & increased GI permeability

• Cephalexin (hydrophilic) in these pts has been shown to have increased absorption