Pharmacokinetics and Pharmacodynamics

• Pharmacokinetics and pharmacodynamics are essential aspects of administering and monitoring medications and intravenous therapy.

Learning Objectives

• Pharmacokinetics is a process and has four phases, it needs to be clearly understood.
• Terms such as bioavailability, hepatic first pass, loading dose, half life and therapeutic index must be described accurately.
• Pharmacodynamics need to be precisely defined.
• A clear differentiation between agonist and antagonist drugs is required.

Physiological Factors Influencing Drug Absorption (Oral Route)

• Several physiological factors influence drug absorption from the oral route and determine the time required for medication to fully digest.
• Age, weight and gender affect sensitivity and absorption.
• Time of day, amount of physical activity level and stress levels affect absorption.
• Stomach contents, pH levels in the gastrointestinal tract and the presence of other medications play a role.
• In the oral cavity, absorption is enhanced by lined epithelium, acidic saliva, and high vascularity, but reduced by short contact time.
• In the small intestine, a large surface area increases contact with the absorptive surface.
• Protease activity using pepsin digests proteins, preventing oral use of insulin or heparin.
• Contact time varies based on physical status, diet, activity, and posture.
• pH levels of the small intestine vary (pH 4-5 enhances acidic drug absorption, pH 7-8 enhances basic drug absorption).
• Digestive enzymes and bile activation in the small intestine increase absorption.
• The small intestine is the major site of drug absorption in the GIT.
• Few drugs are absorbed in the stomach; most are absorbed in the small intestine.
• Drugs travel from the small intestine to the liver before entering the bloodstream for target site transport.
• Ferrous sulfate, for treating iron deficiency, is absorbed in the stomach.
• Decreased surface area in the large intestine results in decreased absorption.
• Absorption of water enhances absorption of water-soluble drugs in the large intestine.
• Digestive enzymes are inactivated in the large intestine
• Absorption is the movement of a drug from its administration site into the bloodstream.
• Administering medication via a subling route avoids the hepatic first-pass effect.
• Examples of subling preparations include prochlorperazine and ondansetron

Considerations when Administering Drugs (Oral Route)

• Most drugs are absorbed through simple diffusion.
• Drugs must dissolve or be soluble for bloodstream absorption.
• Water-soluble drugs stay mainly in the bloodstream and interstitial space and cannot easily cross cell membranes
• Lipid-soluble drugs (lipophilic) can cross cell membranes readily.

Administering Medications (Inhalation Route)

• A large surface area and vascularity of the respiratory tract allow rapid absorption, for drugs delivered as gases or aerosols.
• Blood moving from the lungs goes directly to the brain in 5-8 seconds.
• Inhaled drugs reach the brain faster than intravenous drugs (up to 15 seconds).
• Due to there being no drug depot in the body, the effects of inhaled drugs decline rapidly after administration stops.

Pharmacokinetics - The 4 Phases

• Absorption, distribution, metabolism and excretion are the four phases of pharmacokinetics.
• They determine concentration, time course and magnitude of medication action in the body.
• The acronym ADME is helpful when remembering these phases.

Pharmacokinetics: Absorption

• Absorption brings the medication from the administration site into the circulatory or lymphatic system.
• The medication subsequently moves between interior compartments, most importantly, the blood.
• The small intestine is the major site of drug absorption in the GIT.
• Most medications must be absorbed before having any bodily effect, aside from those administered intravenously, or topically.
• Glyceryl trinitrate avoids the hepatic first-pass effect when administered sublingually or transdermally.
• Administering Glyceryl trinitrate via the sublingual or transdermal route achieves the intended therapeutic effect.
• Insulin would be rendered inactive if given orally given its quick interaction when administered intravenously.

Pharmacokinetics: Factors Influencing Absorption

• Medications given via routes other than IV, need to pass lipid cell membrane barriers to reach circulation.
• Active transport absorbs drugs similar to occurring naturally substances. This moves molecules from a lower to higher concentration.
• Passive transport absorbs most drugs, also known as diffusion, moving molecules from higher to lower concentration.
• Smaller molecules diffuse more rapidly than larger ones.
• Lipophilic substances cross cell membranes easily and quickly.
• Body fluid pH can influence the proportion of certain drug molecules.
• A larger surface area results in greater and faster absorption.
• A drug administered via the PO route ( by mouth) needs to pass through the GIT which slows down the absorption.
• A tablet or capsule needs to desintegrate and dissolve in gastric juices to be absorbed.
• There is immediate bioavailability for a drug administered via the IV route (intravenously) due to directly entering the blood stream.
• An intramuscular injection must be absorbed through the muscle into the blood stream.
• A subcutaneous administration (under the skin) requires absorption into connective tissue, but as a slower rate given a poor blood supply
• Impermeability of skin means chemicals make topical and transdermal absorption slow.
• Skin absorption increases if the skin is broken or uses an occlusive dressing.
• Faster gastric emptying will speed up drug absorption, but slowed peristaltic activity aids drug absorption.
• Optimal absorption of a drug is pH specific and in the small intestine, medication absorption is at its greatest.
• Highly vascular areas will absorb a drug quickly.
• Absorption will vary based on amount of, and type of food present.
• Fluid can be taken with medications to help enhance passage into the small intestine and dissolve it.
• Liquid preparations are usually more rapid to absorb than solid preparations, as well as
• Acidic drugs will be absorbed in the stomach, alkaline drugs in the intestine
• The presence of an enteric coating slows drug absorption.
• Lipid-soluble drugs easily diffuse across the cell membrane. An example is Vitamin D (Colecalciferol).

Pharmacokinetics: Distribution

• After absorption, distribution depends on tissue perfusion into the tissues and organs via the bloodstream to reach its specific action site.
• The rate of distribution will depend on chemical properties of the medication and physiological status of the patient.
• Organs with high vascular structure like the heart, liver and kidneys will acquire the medication rapidly.
• The client's level of activity, and local temperature have an affect on the distribution for medicines to the muscles and skin.
• Changes to body fluid based on age may affect the distribution and effects that drugs have.
• Adipose tissue stores energy in the form of lipids and is located in skin's subcutaneous layer, and in bone marrow and on visceral organs.
• Infants with lower adipose tissue, and increased levels with age, will influence drug effects.
• Fat-soluble drugs are distributed to adipose tissue, acting as a reservoir, thus minimising the available drug. - Prolonging the effects if there are blood clots.
• Calcium containing structures like bone can store drugs bound to calcium - Tetracycline.
• Capillaries in the cerebral circulation differs from normal capillaries. This protects the CNS as it prevents harmful substances
• Only substances that are lipophilic or that are actively transported can pass into the central nervous system (CNS).
• The blood-brain barrier allows passage of certain drugs may result in unwanted effects eg. antihistamines causing drowsiness.

Other Barriers to Drug Distribution

• Placental barrier exists between mother and fetus from their blood vessels.
• As a rule, medications withheld during pregnancy or MIMs and medication references reviewed to see harmful ingredients to the fetus.
• Bioavailability is the amount of administered medication reaching circulation and available for use.
• Drugs administered via IV may be considered bio-available as the are directly administered into circulation.

Pharmacokinetics: Metabolism

• Drug metabolism processes in the body alters drugs to make them more excretable. The principal site where this happens is the liver, but also occurs in kidneys, lungs, intestinal muscosa, placenta and in plasma.
• Metabolites are the waste product of metabolism.
• Drug toxicity is greater for patients who have altered organs and liver disease.
• Enzyme induction occurs where drugs become more effective and increases the rate of metabolism, which requires larger doses to be produced to get results.
• This is called drug tolerance!
• Hepatic first-pass effects is metabolism by the liver.
• Drug concentration reduces when administered orally during the hepatic first-pass effect.
  Medications can be inactivated by liver i.e. Glyceryl trinitrate and Insulin.
• Age, neonate status, and delayed metabolite production influences drug toxicity and effects.

Pharmacokinetics - Excretion

• Removal of metabolites (drug waste) by kidneys and GIT through urine or bile.
• Other avenues exist exhalation, perspiration, tears, breast milk, and saliva
• Molecular size and blood flow affect kidney filtration rates for drug excretion.
• The influence of perspiration, tears, and saliva depend on fat solubility.
• Drug metabolism, coupled with drug excretion, impacts a drug's half-life.
• Less time for a drug in circulation if excretion and metabolism happen quickly - this will affect tissues available
• Dosage frequency relies on drug half-life to keep the levels of drugs toxic, or effective. The goal is to create a frequency at a dose level within a range that is neither toxic, or ineffective.
• In drug composition, a loading dose may be effective when an effective level of the drug must be administered quickly. Once this has been administered, only continue with dose needed.
• Regular and continued intervals to maintain plasma levels is a maintenance dose.

Pharmacokinetics : Therapeutic Index

• A therapeutic index requires calculating plasma levels frequently when drug has a narrow ratio. Medications to consider are digoxin and lithium.
• The therapeutic index must be effective to be minimally effective, and the plasma levels should be closely monitored.

Pharmacodynamics

• Pharmacodynamics relates to how drugs create therapeutic change.
• These come from enzymes that attach to receptors, or create chemical actions.
• Diseases can be an alternation of body parts, which affect homeostatic stages, where drug use can help balance, and modify, or return the disease.
• Abnormal body functions can be reversed via drug therapy, but only via actions on enzymes, or receptors.
• Receptor stimulation occurs and is known as an agonist, but if drug action blocks the receptor it is an antagonist.