Pharmacology Concepts

• Pharmacokinetics explains how drugs are absorbed in the body
• Pharmacodynamics explains how the drugs affect the body

Pharmacokinetics

• Knowing where drugs are absorbed in the body is crucial
• Factors that can affect drug absorption need to be identified
• Drug distribution involves protein-binding, free drug forms, and displacement
• The liver's role in drug metabolism involves the CYP450 system
• Drug excretion pathways include renal and biliary routes
• First Pass Effect must be understood to determine the pathways
• Liver and renal dysfunction can impact drug dosing and scheduling depending on the assessment findings
• Key pharmacotherapy terms include toxic concentration, therapeutic range, lethal dose, effective dose, onset, and duration of action

Pharmacodynamics

• Therapeutic Index needs to be calculated to ensure drug safety
• Factors impacting the body's responses to drugs need to be recognized
• Drug efficacy and potency should be compared
• The differences between antagonists and agonists needs to be understood

Diphenhydramine (Benadryl)

• Diphenhydramine is an older antihistamine
• Diphenhydramine blocks inflammatory mediator histamine from binding with H1 receptors on mast cells, smooth muscle, and endothelial cells to target intended cells
• The "blocking” prevents many of the signs and symptoms of inflammation related to histamine release
• It is important to think of people with hay fever, pollen allergies, allergic reactions to bee venom
• Histamine release causes vessel vasodilation and increased vessel permeability
• Runny nose and watery eyes in hay fever represent vasodilation and permeability
• It is important to think of the symptoms with histamine
• Histamine is a neurotransmitter in the brain that helps keep people awake and is also produced by WBCs on organs in mucosal membranes

Opioid Side Effects

• Opioids side effects happen because morphine binds to NON-targeted cells
• Respiratory depression is a life-threatening side effect
• Other side effects: confusion, euphoria, decreased blood pressure (hypotension), bradycardia, itching, urinary retention, and constipation

Absorption of Drugs

• Drugs are transmitted from location of administration (GI tract, muscle, skin) to bloodstream
• Most common routes are enteral (through GI tract) and parenteral (by injection)
• Drug absorption is determined by drug's physicochemical properties, formulation, and route
• Drugs must be in a solution to be absorbed regardless of the route of administration
• Solid forms of a drug must be able to disintegrate
• Drugs must cross permeable cell membranes to reach systemic circulation, unless given IV
• Drugs can cross cell membranes through passive diffusion, active transport or pinocytosis (rarely used)
• Proteins embedded in the cell's plasma membrane function as receptors
• Receptors help transport molecules across the membrane

Absorption - Passive Diffusion

• Drugs diffuse across a cell membrane from a region of high concentration to low concentration
• Most drugs are absorbed from the stomach and small intestine through passive diffusion
• Diffusion rate is directly proportional to the gradient, lipid solubility, size, degree of ionization, and the area of absorption surface
• Small, non-ioinized, and lipid-soluble molecules move via passive diffusion
• Drugs exist as ionized (water-soluble) and non-ionized (lipid-soluble) forms based on ionization
• Most drugs = weak organic acids or bases, existing in both non-ionized and ionized forms
• Non-ionized form is lipid soluble (lipophilic) and diffuses easily across cell membranes
• Ionized form has low lipid solubility (hydrophilic) and high electrical resistance
• The Henderson-Hasselbalch equation can calculate percentages of a drug that is ionized and non-ionized in the stomach

Factors Affecting Drug Absorption

• Drug formulation: liquid formulations absorb faster than tablets or capsules
• Dose: high doses lead to fast absorption and rapid onset of action
• Route of administration: IV drugs lead to very rapid absorption and onset of action
• Size of drug molecule: large molecules lead to low absorption
• Surface area of absorption site: large surface areas lead to fast absorption
• Digestive motility: may speed up or slow down the absorption depending on the drug
• Blood flow: great blood flow leads to fast absorption
• Lipid solubility of drug: lipid soluble formulations are absorbed faster than water-soluble
• Degree of ionization of drug: charge of a molecule/drug depends on the pH of the environment and whether or not that drug is a weak acid or a weak base
• Non-ionized form is usually lipid soluble (lipophilic), and diffuses readily across cell membranes
• pH of local environment and whether or not the drug is weak acid or a weak base
• Most absorption occurs in the small intestine because of size area and permeable membranes
• Drug-drug/food-drug interactions impact absorption
• Calcium, iron, and magnesium can delay absorption of Tetracyclines
• High-dietary supplement/herbal product-drug interactions can delay absorption
• Fatty foods can slow stomach motility and therefore delay absorption

Routes of Administration

• IV route allows drugs to start working fastest in the body, no membranes
• Greater blood flow, greater lipid solubility, higher doses, larger surface areas = accelerated absorption
• Larger molecules have a harder time (slower) being absorbed

Distribution of Medications

• Distribution is the transport of drugs throughout the body
• Blood flow to body tissues is the main factor determining distribution
• Kidney, brain, GI tract and skeletal muscles receive the largest supply of blood
• After administration and absorption, drugs are initially present in plasma and may be partly bound to plasma proteins
• Drugs may gain access to interstitial fluid and intracellular water as well
• Blood-brain barrier: consists of cerebral capillaries, and endothelial cells that have overlapping "tight” junctions restricting passive diffusion
• The capillaries also have a basement membrane with astrocytes that serve as blockages to drug entry into the CNS
• Low molecule weight or lipid-soluble drugs can cross the blood-brain barrier but are restricted by CNS proteins

Hypoperfusion

• Pay attention to which organ gets the most blood to ID patient with hypoperfusion/hemorrhaging
• No blood means no oxygen/nutrients which means minimal ATP production and non-performing cells
• Blood is made of plasma (water, blood proteins, nutrients, hormones, electrolytes) and cellular components (Buffy coat, red blood cells)

Distribution - Protein-Binding of Drugs

• After drugs are absorbed into the bloodstream, most are bound to plasma proteins
• Agents that are minimally protein bound penetrates tissue better than those that are highly bound, but the unbound drugs is excreted much faster
• Plasma proteins: albumin, lipoproteins, and alpha 1-glycoprotein
• Unbound fraction of the drug produces pharmacologic effects and can be metabolized and excreted

Warfarin

• The "fraction bound” of the anticoagulant warfarin is 97%
• 97% of warfarin in the blood is bound to plasma proteins
• The remaining 3% (the fraction unbound) is free to reach tissues to be metabolized and excreted

Displacement

• Competition for the same binding site on the plasma proteins may occur between two drugs
• Displacement of one drug increases concentrations & effects

Medication Metabolism

• Hepatic microsomal enzyme system (P450/CYP450 system) is a family of enzymes usually present in the endoplasmic reticulum of hepatocytes
• CYP450 enzymes inactivate drugs and accelerate drug excretion
• CYP450 enzymes can be induced or inhibited by many drugs resulting in drug interactions
• Interactions can enhance or reduce a drug’s actions in the body

Metabolism in the Liver

• Changes in the function of the hepatic microsomal enzymes can significantly affect drug metabolism
• Some drugs increase metabolic activity in the liver, called enzyme induction
• Phenobarbital increases liver synthesis of enzymes and needs higher doses as a result
• Certain patients have reduced hepatic enzyme activity, including infants and the elderly, making population more sensitive to specific drug therapy
• Patients with severe liver damage have decreased liver enzyme production, decreased drug metabolism, and increased risk of drug accumulation to toxic levels

Excretion of Medication

• Kidneys are the primary site of excretion
• Free drugs, water-soluble agents, electrolytes, and small molecules are easily filtered in the glomerulus
• Glomerulus is a cluster of capillaries around the end of a kidney tubule where waste products are filtered from the blood
• pH of filtrate can increase excretion: weak acids (aspirin) excreted faster when filtrate is alkaline, and weak basic drugs (diazepam) excreted faster when the filtrate is slightly acidic

Organ Dysfunction: Impaired Excretion or Metabolism

• Drug dosages and schedules may need to be altered in patients with organ dysfunction; likely decreased doses/frequencies
• Check the laboratory values to see how bad their organ disease is
• Serum Blood Urea Nitrogen (BUN) and creatinine for kidney issues
• Serum liver enzymes to assess liver function
• Consider alternative routes of delivery to bypass first-pass effect if there is dysfunction, such as sublingual, rectal, or parenteral

Creatinine

• Chemical waste molecule that is generated from muscle metabolism
• Produced from creatine, a molecule of major importance for energy production in muscles
• Approximately 2% of the body's creatine is converted to creatinine every day (steady rate)
• Damages kidneys result in lower creatinine levels in the urine and higher levels in the blood.
• Normal creatinine is < 1.3 and normal BUN is 5-20

Biliary Excretion

• Drugs are secreted into the bile and leave the body in feces
• Most bile is recycled by the body, circulates back to the liver via enterohepatic recirculation
• Drugs that undergo biliary excretion end up "going along for the ride” and are recirculated numerous times with the bile which prolongs effects
• Drugs recirculated are metabolized by the liver and excreted by the kidneys

Side Effects of Renal Damage

• Nephrotoxicity, kidney damage, and inflammation
• Fluid volume overload: edema, hypertension, crackles, jugular vein distention
• Electrolyte build-up: mostly a build-up issue because kidneys excrete the excesses
• Results in a build-up of potassium (hyperkalemia), phosphorus (hyperphosphatemia), and magnesium (hypermagnesemia)

Kidney Complications

• Hypocalcemia & osteoporosis (long term) result from kidney's loss of Vitamin D production which allows us to absorb calcium
• Uremia/Azotemia is build-up of waste products like Creatinine and blood urea nitrogen (BUN)
• Urine output down includes Obliguria (<400 mL urine/24 hours) and Anuria (<200 mL urine/24 hours)
• Metabolic Acidosis is waste products of body processes as Muscle breakdown, food breakdown, ATP production are acidic
• Kussmaul respirations: deep, labored respirations as body attempts to reduce CO2 blood concentrations to correct metabloic acidosis
• Proteinuria: protein in the urine means there is damage
• Anemia: kidneys make erythropoietin

Liver Damage Side Affects

• Jaundice results related to a bilirubin buildup
• Elevated liver enzymes: hepatocytes (liver cells)
• Normal ranges: ALT 10-130 U/L; AST 10-34 U/L; ALP 25-150 U/L; total bilirubin should be less than 1.0
• Symptoms such as: fatigue, N/V, abdominal pain/distention, and steatorrhea
• Fatty stools or diarrhea occur if liver can't make bile and clay-colored stools occur in the duodenum
• Liver Encephalopathy and Asterixis/liver flap results when liver processes/breaks down ammonia
• Liver inflammation (hepatitis) and/or enlargement (hepatomegaly)
• Liver clotting factors are lost due to liver damage
• Portal hypertension can occur

Drug Plasma

• The minimum effective concentration is the minimum amount of drug required to produce a therapeutic effect
• Plasma drug concentration is between the minimum effective concentration and the toxic concentration inside the therapeutic range
• Onset of drug action: time required to produce a therapeutic effect
• Peak plasma level: the highest concentration of the drug in the blood plasma
• Duration of drug action: amoun of time a drug maintains effect
• The half-life represents a drug's duration of action

Pharmacodynamics

• Pharmacodynamics: relationship between drug concentrations and the resulting effects on the body
• Concentrates on dose-response relationships with time, course, intensity and any adverse events
• For most drugs, the concentration determines site effect
• Other factors affect drug response: density of receptors or cell surface etc

Factors Influencing Drug Effects

• Gene translation and protein production
• The median effective dose or ED50 falls directly in the middle
• Used as the "standard dose” that should be monitored per patient given their therapeutic response
• A standard dose only predicts a therapeutic response for half the population

Nursing and Medication

• Nurses assess the patient's needs for medication and the resulting effects
• Factors assessed: monitor V.S., pain and anxiety levels, signs and symptoms, labs, and output

Lethal Dose Metrics

• Median Lethal dose (LD50) is used to assess the safety of a drug
• Determined in preclinical trials (animals)
• Cannot be determined in people because it represents a lethal dose in 50% of test animal groups
• Median Toxicity Dose (TD50) is the dose that will produce toxicity in 50% of groups of patients and cannot be tested in human because of lethality

Animal Testing

• Value may be extrapolated from animal safety data, and adverse effects in patient clinical trials
• Needed because medical lethal dose cannot be tested in humans

Therapeutic Index

• Therapeutic Index measures a drug's safety margin
• Higher the value/index = the safer
• ex: a drug with a TI of 10 safer than a drug with a TI of 2?
• A higher index also allows health workers to safely exceed maximum dosage limits

Drug Potency

• Drug potency: compared by the concentration at which 50% of the maximum effect
• Referred to as 50% effective concentration or EC50
• When two drugs are tested in the same individual, the drug with a lower EC50 should be considered more potent
• A lesser amount of a potent drug is needed to achieve compared to a less potent drug
• Drug potency is determined by the affinity of receptors in the body for the drug and the number of available receptors

Drug activity

• Determined by potency and efficacy

Medication Activation

• An Agonist activates a receptor to increase a response
• Ex: Salbutamol is a beta-2 agonist that when inhaled binds with beta-2 receptors in the lungs to cause bronchodilation
• Antagonists: drugs that bind to receptors without activating them and prevent the binding of other agonists
• Commonly called “blockers” and prevents increase

Norepinephrine

• A drug can produce more than one kind of biological response
• Norepinephrine (NE) acts as neurotransmitter (brain) and hormone (adrenal glands) to give a variety of reactions to the body
• Results can be bronchial relaxation, constricted arterial muscle, constriction and alertness