Lecture notes Chapter 1 Drug Action

Pharmacology for 2nd year Nursing

Pharmaceutic Phase (Dissolution)

"First phase of drug action"

Dissolution
"A drug in solid form (tablet or capsule) must disintegrate into small particles to dissolve into a liquid,
a process know as dissolution."

Pharmacokinetic Phase
1. Absorption
2. Distribution
3. Metabolism (Biotransformation)
4. Excretion (Elimination)
"Pharmacokinetics is the process of drug movement to achieve drug action.

*Knowledge of pharmacokinetics is applied when assessing a patient for possible adverse drug
effects".

Absorption
*" Most oral drugs are absorbed into surface of the small intestine through extensive mucosal villi.
Absorption is reduced if the villi are decreased in number because of disease, drug effect, or removal
of the small intestine. Protein based drugs such as insulin and growth hormones are destroyed in the
small intestine by digestive enzymes."
"The movement of drug particles from the GI tract to body fluids by passive absorption, active
absorption, or pinocytosis."

Passive Absorption
"Occurs mostly by diffusion, (higher to lower concentration and therefore the drug does not require
energy to move across the membrane)"

3. G protein-coupled Receptor Systems

"Three components:
1. The receptor
2. The G protein that binds with guanosine triphosphate (GTP)
3. The effector that is either an enzyme or an ion channel
(Drug ---> activates receptors---> G protein ---> effect)"

4. Nuclear Receptors
"Found in the cell nucleus, not on the surface of the cell membrane."

Agonists
"Drugs that produce a response."

Antagonists
"Drugs that block a response"

Excipients
*Note: "Some additives in drugs, such as the ions potassium (K) and sodium (Na) in penicillin
potassium and penicillin sodium, increase the absorbability of the drug. Penicillin is poorly absorbed
by the GI tract because of gastric acid; making the drug a potassium or sodium salt, allows penicillin to
be absorbed."
"Fillers and inert substances that are used in drug preparation to allow the drug to take on a particular
size and shape and to enhance drug dissolution. "

Disintegration
"The breakdown of a tablet into small particles."

Dissolution
"The dissolving of the smaller particles in the GI fluid before absorption."

Rate of Dissolution

*"Note: Drugs both disintegrate and absorb faster in acidic fluids with a pH of 1 or 2 rather than in
alkaline fluids. Very young or very old patients tend to have less gastric acidity, therefore increasing
the drug absorption rate for those drugs absorbed primarily in the stomach."
"The time it takes the drug to disintegrate and dissolve to become available for the body to absorb it.
(Drugs in liquid form are more rapidly available for GI absorption than are solids."

Enteric-coated drugs

"(May remain in the stomach for a long time) Tablets or capsules and sustained-release, (beaded)
capsules should not be crushed. Crushing would alter the place and time for absorption."
"Resist disintegration in the gastric acid of the stomach, so disintegration does not occur until the
drug reaches the alkaline environment of the small intestine."

Half-life (t1/2)
"The time it takes for one half of the drug concentration to be eliminated. Both metabolism and
elimination affect he half-life of a drug."

Elimination (Excretion)
"The main route of drug elimination is through the kidneys, (urine). Other routes include bile, feces,
lungs, saliva, sweat, and breast milk."

Creatinine Clearance (CLcr) and Blood Urea Nitrogen (BUN)

"Common blood tests used to determine renal function. Creatinine is a metabolic by-product of
muscle that is excreted by the kidneys. The creatinine clearance test compares the level of creatinine
in the urine with the level of creatinine in the blood. Varies with age and gender."

Glomerular Filtration Rate (GFR)

(Expensive and not commonly used)

"The best test to measure kidney function levels and stage kidney disease. Normal results range from
90 to 120 mL/min/1.73m2"
"Decreased drug dose is usually required in patients with renal dysfunction. (Caused either by age
or as a result of kidney disorders)."
"Creatinine clearance needs to be determined to establish appropriate drug dosage for these
patients. Decreased creatinine clearance requires decreased dosage."

Pharmacodynamics
"the study of the way drugs affect the body. Drug response can cause a primary or secondary
physiological effect or both.
- Primary effect is desirable
- Secondary effect may be desirable or undesirable"

Dose Response
"The relationship between the minimal versus the maximal amount of drug dose needed to produce
the desire drug response."

Maximal Efficacy
"Maximum drug effect"

Onset of Action
"The time it takes to reach the minimum effective concentration (MEC) after a drug is administered."

Peak Action
"Occurs when the drug reaches its highest blood or plasma concentration."

Duration of Action
"The length of time the drug has a pharmacologic effect."

Nonspecific Drugs
"Drugs that affect various sites and have properties of nonspecificity. (Drugs that evoke a variety of
responses throughout the body have a nonspecific response)."

Nonselective Drugs
"Drugs that affect various receptors or have properties of non-selectivity."

Categories of Drug Action (Four)

1. "Stimulation or Depression
- Stimulation increases gland secretions
- Depression reduces cell activity and function of a specific organ
2. Replacement
- Replace essential body compounds
3. Inhibition or killing of organisms
- Inhibit or kill/bacterial cell growth
Active Absorption
"Requires a carrier such as an enzyme or protein to move the drug against a concentration gradient.
(Active absorption requires energy). "

Pinocytosis
"The process by which cells carry a drug across their membrane by engulfing the drug particles."

GI Membrane

*"Drugs that are lipid soluble and non-ionized are absorbed faster than water-soluble and ionized
drugs."
..."is composed mostly of lipid and protein. Drugs that are lipid soluble pass rapidly through the
membrane. Water-soluble drugs need either enzyme or protein carriers to pass through the
membrane. Large particles pass through the cell membrane if they are non-ionized, (neither + or -
charged). Aspirin is a weak acid drug that easily passes through the stomach lining due to less
ionization."

"Blood flow, pain, stress, hunger, fasting, food, pH vasoconstrictor drugs or disease affect drug
absorption"
-"Solid, hot or fatty foods slow gastric emptying allowing the drug to remain in the system longer.
-Exercise increases peripheral blood flow thus decreasing visceral blood flow. "

First-pass effect (Hepatic first pass)

*Most drugs given orally are affected by first-pass metabolism

"The process in which the drug passes to the liver first. (Some drugs do not go directly into the
systemic circulation following oral absorption, instead they pass from the intestinal lumen to the liver
via the portal vein). "

Bioavailability

*"(Bioavailability may be altered by drug form, route of administration, GI mucosa and motility, food
and other drugs and changes in liver metabolism caused by liver dysfunction or inadequate hepatic
blood flow.)"
"(A subcategory of absorption). The percentage of the administered drug dose that reaches the
systemic circulation. Bioavailability for:
Oral route is always less than 100%
IV route always 100%"

Distribution
"The process by which the drug becomes available to body fluids and body tissues. (Influenced by
blood flow, the drug's affinity to the tissue and the protein-binding effect. Drugs with a larger volume
of drug distribution have a longer half-life and stay in the body longer."

Protein-binding Effect

"(Drug dose is prescribed according to the percentage in which the drug binds to protein).
** To avoid drug toxicity, the protein-binding percentage of all drugs administered to a patient must
be checked. "
"A drug's efficiency may be affected by the degree to which it binds to the proteins within blood
plasma. The less bound a drug is, the more efficiently it can transverse cell membranes or diffuse.
Common blood proteins that drugs bind to are albumin, lipoprotein, glycoprotein and globulins."

Free Drugs
"Drug not bound to proteins (Active and can cause a pharmacologic response)."

Blood Brain Barrier (BBB)

** "During pregnancy, both lipid-soluble and lipid-insoluble drugs are able to cross the placental
barrier. Lactation/breast milk effects too."
"Semipermeable membrane in the CNS that protects the brain from foreign substances. Highly lipid-
soluble drugs are able to cross the BBB. Drugs that are not bound to proteins and are not lipid soluble
are not able to cross the BBB, thus inhibiting distribution."

Metabolism (Biotransforms)
"The process by which the body inactivates or biotransforms drugs. Liver is primary site for
metabolism. (Liver disease inhibits the liver's metabolism enzymes leading to increased drug
accumulation leading to toxicity)."

Time-response Curve
"Evaluates three parameters of drug action:
1. The onset of drug action
2. Peak action
3. Duration of action"

Receptor Therapy

*"The activity of many drugs is determined by the ability of the drug to bind to a specific receptor.
Most receptors are proteins found within cell membranes. Drug-binding sites are primarily on
proteins, glycoproteins, proteolipids and enzymes."
"Drugs act through receptors by binding to the receptor to produce (initiate) a response or to block
(prevent) a response."

Receptor Families (Four)

1. "Kinase-linked receptors
2. Ligand-gated Ion Channels
3. G protein-coupled receptor systems
4. Nuclear receptors"

Ligand-binding Domain
"The site on the receptor at which drugs bind."

1. Kinase-linked Receptors
"The ligand-binding domain for drug binding is on the cell surface. The drug activates the enzyme
(inside the cell), and a response is initiated"
2. Ligand-gated Ion Channels
"The channel spans the cell membrane and the channel opens to allow for the flow of ions into and
out of the cell. Primarily sodium and calcium."

4. Irritation
- Mechanism or irritation, ie. laxatives increase peristalsis by irritating the inner wall of the colon. "

Therapeutic Index (TI)

*Drugs with a low therapeutic index have a narrow margin of safety.

"Estimates the margin of safety of a drug through the use of a ratio that measure the effective
(therapeutic) dose (ED) in 50% of people (ED50) and the lethal dose (LD) in 50% of people (LD50). The
closer the ration is to 1, the greater the danger of toxicity. TI = LD50 divided by ED50"

Therapeutic Range (Therapeutic Window)

"The level of drug between the minimum effective concentration in the plasma for obtaining desired
drug action and the minimum toxic concentration (the toxic effect). "

Peak and Trough Drug Levels

1. "Peak drug level is the plasma concentration of drug at a specific time. Indicate the rate of
absorption of a drug.

2. Trough Drug Level is the lowest plasma concentration of a drug. Indicate the rate of elimination of a
drug. Trough levels are drawn immediately before the next dose of drug is given, regardless of route
of administration. "

Loading Dose
"When an immediate drug response is needed, a large initial dose of the drug is given to achieve a
rapid minimum effective concentration in the plasma."

Side Effects
"Physiologic effects not related to desired drug effects. May be desirable or undesirable."

Adverse Reactions
"More severe than side effects; unintended and occur at normal doses. Can be mild to severe."

Toxic Effects (Toxicity)

"Can be identified by monitoring the plasma (serum) therapeutic range of the drug. When the drug
level exceeds the therapeutic range, toxic effects are likely to occur from overdosing or drug
accumulation."

Pharmacogenetics
"The scientific study of how the effect of a drug action varies from a predicted drug response because
of genetic factor or hereditary influence. " Genetics can influence metabolism of certain drugs.
Tolerance
"Refers to a decreased responsiveness over the course of therapy.

Tachyphylaxis
"Refers to a rapid decrease in response to the drug. Tachyphylaxis is an acute tolerance."

Placebo Effect
"A psychological benefit from a compound that may not have the chemical structure of a drug effect."