Pharmacokinetics

Enteral Administration- Defined as anything related to the intestines or digestive system ~administering a drug by mouth:

Safest and most common, convenient, and economical method of drug administration

Oral: provides many advantages ( easily self administered and low risk of infection) and disadvantages. (with having to deal with stomach acid and is subject to First-Pass Effect). First pass effect is the effect of liver enzymes on medications taken orally. ( more later)

Enteric-Coated preparations: ( improves bioavailability)

protects the swallowed drug from stomach acid degradation / enzymatic inactivation by stomach pH which reduces their absorption and delivers the drugs to the less acidic small intestine, where the coating dissolves and allows the drug to be released and absorbed. The pH of the stomach is typically between 1.5 and 3.5, which is acidic.

Many drugs can cause irritation to the stomach if released there; with enteric-coated capsules, the formulation will pass through the stomach without irritating the stomach lining, ie aspirin.

Extended-Release preparations: special coatings and ingredients that control how fast the drug is released from the pill into the body. ( examples = morphine, oxycodone)

Why are drugs given under the tongue or in the cheek????

B. Sublingual – under the tongue

C. Buccal - in the cheek:

Both allow a drug to diffuse directly into capillary networks and enter the systemic circulation directly. ( this bypasses the harsh GI acids and avoids hepatic first pass effect).

Sublingual or Buccal drugs are given under any of the following circumstances:

the drug needs to get into your system more quickly than taking the drug orally. ( Example------Nitroglycerin for chest pain?)

you have trouble swallowing medication

the medication doesn’t absorb very well in the stomach

the effects of the drug would be decreased by digestion and the liver first pass effect

The cheek and area under the tongue have many capillaries, or tiny blood vessels. There, drugs can be absorbed directly into the bloodstream without going through your digestive system and first pass effect.

The First-Pass Effect ( also know as first-pass metabolism or pre-systemic metabolism) is a phenomenon of a drug metabolism whereby the concentration of a drug given orally ( enterally) is greatly reduced before it reaches the systemic circulation.

It is the fraction of lost drug during the process of oral absorption which is related to liver metabolism. Most of the enzymes involved in drug metabolism are present in the liver. This means the liver plays a key role in drug metabolism

After a drug is swallowed, it is absorbed by the digestive system and then enters the Hepatic Portal System. It is then carried thru the hepatic portal vein to the liver to be subjected to hepatic enzymes before it eventually reaches the rest of the body via the Hepatic Vein.

Review:

The portal vein or hepatic portal vein (HPV) is a blood vessel that carries blood from the gastrointestinal tract, gallbladder, pancreas and spleen to the liver.

The liver receives a blood supply from two sources. The first is the hepatic artery which delivers oxygenated blood from the general circulation. The second is the hepatic portal vein delivering deoxygenated blood from the small intestine containing nutrients.

Approximately 75% of total liver blood flow is through the portal vein from the small intestine, with the remainder ( 25%) coming from the hepatic artery proper.

The liver metabolizes many drugs, sometimes to such an extent, that only a small amount of active drug emerges from the liver to the rest of the circulatory system in the hepatic vein.

Alternative routes of administration like suppository, IV, IM, Inhalation , transdermal and sublingual can avoid the FIRST PASS EFFECT

During second-pass metabolism, the drug circulates throughout the body and undergoes further metabolism in the liver or other tissues.

Bioavailability definition: the proportion of a drug or other substance which enters the circulation when introduced into the body that is able to have an active effect.

Parenteral in medicine means the input of drugs or medications into the human body in a way not involving the intestines or the digestive tract

Parenteral Administration introduces drugs directly across the body’s barrier defenses into the systemic circulation, and is used for drugs that are poorly absorbed from the GI tract ( heparin) and drugs that are unstable in the GI tract( Insulin)

Parenteral is not subject to a first pass metabolism or harsh GI environment…!!!!

Provides most control over the actual dose of drug delivered to the body

1. Intravenous ( IV) : Drug injected directly into venous circulation most common parenteral route.( bolus vs. infusion) ( gives immediate and 100% bioavailability of drug to tissues) ( Avoids First Pass effect and provides direct entry into systemic circulation)

2. Intramuscular ( IM ): ( drug injected into muscle tissue “ reservoir”)

The muscle tissues, holds the drug for a while and gradually releases into the bloodstream through the network bed of capillaries running across or surrounding the muscle tissue.

In IM drug administration, the bioavailability may be slightly less than 100% of IV drug administration due to diffusion from muscle through tissue fluid and into the blood.( IM drug examples = vaccines + contraceptive medroxyprogesterone)

3. Subcutaneous ( SC ) ( SQ ): ( drug injected into Subcutaneous tissue reservoir)

The SQ tissues, holds the drug for a while and gradually releases into the bloodstream through the network bed of capillaries running across or surrounding the SQ tissue.

Absorption of drugs from the subcutaneous tissue is influenced by the same factors that determine the rate of absorption from intramuscular sites; however, the vascularity in the subcutaneous tissue is less than that of muscle tissue, and therefore absorption may be slower than after intramuscular administration. (bioavailability also may be less than 100% due to diffusion) Example = a) Insulin

Intravenous (IV), subcutaneous (SQ), and intramuscular (IM) injections all avoid the first-pass effect. This is because they are forms of parenteral administration, delivering medication directly into the systemic circulation or tissues, thereby bypassing the gastrointestinal tract and the liver where first-pass metabolism occurs.

Inhalation; ( oral & nasal ) ; provides rapid delivery of a drug across mucous membranes of the respiratory tract and pulmonary epithelium to the terminal alveoli . Inhaled medications can be absorbed quickly and act locally ( albuterol for asthma) and systemically ( anesthetics).

Intrathecal – injected directly into the cerebrospinal fluid & avoids the BBB. ( amphotericin B for meningitis)

Topical – used for local effect of drug. ( example = clotrimazole)

Transdermal – achieves systemic effects by application of drugs to the skin. Drug diffuses from a reservoir into the SQ tissue, then into systemic circulation blood vessel. Used for sustained delivery of drugs. Examples = NTG, scopolamine, nicotine.

Rectal - absorption thru the rectal mucosa. Prevents destruction of the drugs by liver enzymes or stomach acid. 50% of the drainage of the rectal region bypasses the portal circulation.

Absorption of Drugs Is the transfer of the drug from the site of administration to the bloodstream

The vast majority of drugs cross cell membranes into cells via passive diffusion.

Remember from A & P that cell membranes are lipid-based!

So, lipid soluble (un-ionized- no charge) drugs will passively diffuse MUCH better than water soluble ( ionized- charged) drugs across cell membranes and be absorbed.

There are some water channels available for water soluble drugs, but the drug must be very small ( low molecular weight). ( example = alcohol is water soluble )

The vast majority of drugs cross lipid membranes by passive diffusion in lipid soluble ( un-ionized- no charge ) form. ( vs. facilitated diffusion)

A few are actively transported (Insulin)

Ionized drugs are primarily water-soluble (hydrophilic) and not lipid-soluble (lipophobic). This is because the presence of an electrical charge makes them polar, causing them to be repelled by the lipid (fatty) nature of cell membranes, thus hindering their ability to pass through them.

Ionization inhibits absorption….!!!!

A drug that is a weak acid ( HA) is best defined as a neutral ( unionized -uncharged)molecule that can reversibly dissociate into an anion and a proton ( if needed ) and then become ionized.

B2. Blood flow to the absorption site

Q. What has a greater blood flow, the intestine or stomach?

A = ____intestine________, and absorption from here is favored over the stomach.

B3. Total Surface area available for absorption

Q- what has a larger surface area, the stomach, large intestine or small intestine?

A = the small intestine has a surface rich in brush borders and microvilli which give sit a surface area about 1000 times that of the stomach, and 20 -30 times that of the large intestine making absorption of the drug across the small intestine more efficient.

B4. Contact time at the absorption area.

Q- will a drug a be more or less absorbed if it moves thru the GI tract very quickly?( diarrhea) A =___less absorbed__

Q- what increases GI movement, parasympathetic or sympathetic stimulation?

A – Parasympathetic ( Rest & Digest) ( S.L.U.D.D. = salivation, lacrimation, urination, defecation, and digestion)

Higher the first pass effect=lower oral bioavailibility

lipid soluable drugs are better absorbed

VERY HYDROPHILIC ( lipophobic) DRUGS ARE POORLY ABSORBED BECAUSE OF THEIR INABILITY TO CROSS THE LIPID-RICH CELL MEMBRANE, AND BIOAVAILABILITY WILL DECREASE VERY LIPOPHILIC ( hydrophobic) DRUGS ARE WELL ABSORBED BECAUSE OF THEIR ABILITY TO CROSS THE LIPID-RICH CELL MEMBRANE, AND BIOAVAILABILITY WILL INCREASE

a. Bioequivalence – Is when 2 related drug preparations are bioequivalent, they show comparable bioavailability ( AUC )and similar times to peak blood concentrations. ( Drug A & Drug B have the same AUC)

b. Pharmaceutical Equivalents : FDA considers drug products to be pharmaceutical equivalents if they meet these three criteria:

1. they contain the same active ingredient(s)

2. they are of the same dosage form and route of administration

3. they are identical in strength or concentration

c. Therapeutic Equivalence : Drug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling

Drug distribution is the process by which a drug, now, reversibly leaves the blood stream and enters the interstitual fluid, cell membrane, and intracellular fluuid

The delivery of a drug from the plasma to the interstitium to the tissue cells primarily depends on;

Cardiac Output the regional blood flow, - discussed

Capillary permeability,---discussed

The degree of binding of the drug to plasma proteins.( new)

The plasma protein albumin is able to reversibly bind a drug and sequester the drug in a non-diffusible form, keeping it in the plasma and decreasing the distribution of the drug to the interstitium and cells. ( some drugs are highly plasma protein bound, and some are not).

The volume of distribution ( Vd): a hypothetical volume of fluid into which a drug is dispersed; it is sometimes useful to compare the distribution of a drug with the volumes of the water compartments in the body.

Drug Ex # 1 – Hydrophilic ( water loving), large molecular weight, plasma protein ( albumin) bound drug  will stay in plasma compartment only and have a very low Vd

Drug Ex # 2 – Hydrophilic ( water loving) , low molecular weight (will be able to get through the pores of the membrane), not plasma protein( albumin) bound drug  will be in the plasma compartment + the interstitium as well. ( A higher Vd than drug 1)

Drug Ex # 3 – Hydrophobic ( lipophilic), low molecular weight, not plasma protein bound drug  will be in plasma compartment + interstitium + intracellular fluid. (A higher Vd than both drugs 1 and 2)

Drug metabolism , defined , is the biotransformation of pharmaceutical substances in the body so that they can be eliminated from the body more easily.

Most drugs undergo chemical alteration by various bodily systems to create compounds that are more easily excreted from the body

The majority of drugs are metabolized to increase their water solubility to allow elimination in urine or bile

Once a drug enters the body, the process of elimination begins immediately

Means of Elimination:

Hepatic metabolism

metabolism leads to products with increased polarity, decreased lipid solubility , which allows the drugs to then be eliminated .

Elimination in the bile

Elimination in the urine

First Order Kinetics ( vast majority of drugs) - First order elimination kinetics: a constant proportion (eg. a percentage) of drug is eliminated per unit time; More enzymes that we typically need at any given moment waiting to work.

Rate of elimination increased with drug concentration

With every ( t ½ ) half-life, the concentration reduces by 50% ( 100..50..25..12 ½..)

Half-Life Defined- Time it takes for the plasma concentration of drug in the body to be reduced by 50%.

Example: Ibuprofen is rapidly metabolized and eliminated in the urine. The excretion of ibuprofen is virtually complete 24 hours after the last dose. The serum half-life is 1.8 to 2.0 hours

Zero Order Kinetics – ( only a few drugs – alcohol, dilantin)

Zero order elimination kinetics: a constant amount (eg. so many milligrams) of drug is eliminated per unit time. ( Linear with time)

Example 20mg: 100…80..60…40….20..0.

All our enzymes are at maximum capacity and working on the substrate

Rate of elimination is independent of drug concentration.

The rate of elimination is constant and does not depend on the drug concentration.( only a few drugs follow zero order kinetics; ethanol, phenytoin, aspirin)

The enzyme is saturated by a high free-drug concentration and the rate of metabolism remains constant over time, and depends on the remanufacturing of additional enzyme for future metabolism.

PHASE I METABOLISM- makes more hydrophillic so it can leave the body

Phase II Metabolism:

Involves conjugation - that is, the attachment of an ionized group to the drug, making it more water soluable to be eliminated in the kidney

Drugs that are unionized ( and more lipid soluble) will be reabsorbed back into the blood stream in the kidney and not be eliminated.

Drugs that are ionized ( and more water soluble) will not reabsorbed back into the blood stream in the kidney and be instead eliminated.

Q - So if you want to get rid of aspirin ( a weak acid) ….. would you want to acidify or alkalinize the urine?( Answer= Alkalinize the urine )

This gives an ionized, water soluble drug that will not be reabsorbed in the kidney and then be eliminated.