Pharmacology

Pharmacology- study of drugs, derived from pharmakon meaning drug

Week 1: History and Basics of Pharmacology

History of Pharmacology

• Various diseases were treated by trial and error

• Important ones to know

  • Dioscorides (77 AD)- surgeon with Nero and student of Aristotle

    • compiled the first Materia medica

    • 6 volumes with over 600 plants

  • Publius Vegetius (5th century)- compilation of veterinary prescriptions

  • Paracelsus- clinical use of opium and a number of tinctures

    • “All substances are poisonous, there is none which is not a poison. Proper dose separates a poison from a remedy.”

  • William Withering- used foxglove plant extracts to treat “dropsy”- congestive heart failure

    • methylxanthines from coffee, tea, and other alkaloids were discovered

  • Merck Pelletier- isolated alkaloids from different plants

  • Rudolf Buchheim- first lab

    • published effects of several drugs and actions on living tissue

    • argued pharmacology was a separate discipline from doctors, pharmacy, and chemistry

  • John J Abel (1857-1938)- father of pharmacology in the USA

    • started the department of pharmacology of at UofM and at Johns Hopkins

Drug Discovery, Marketing, and Regulation

• preliminary studies

  • computer models, cell culture studies, testing on bacteria/fungi

• preclinical phase

  • tests on laboratory animals to determine safety and effectiveness of a drug

    • short term and long term toxicity studies

    • intermediate drug reactions, organ system damage, reproductive effects, teratogenicity and carcinogenicity

• submit INAD (investigational new animal drug) application to FDA

• if FDA approves, clinical trials can start on target species

• NADA filed (new animal drug application) once satisfactory results are obtained from clinical trials

• Drug marketing

  • purchased by veterinarians from company that manufactures (direct marketing)

  • from distributors or wholesalers

• once expired, other companies can apply to sell equivalent drug

Drug Regulation

• USDA and FDA two main agencies responsible for drug regulation

• certain drugs not allowed for use in food animal

• DEA (drug enforcement agency) oversees use of controlled substances

  • High abuse potential

  • Higher scheduling, higher abuse potential

  • Schedules I-V

    • Schedule I > Schedule V for abuse potential

Medical Pharmacology

• therapeutic goal- drug administered at correct concentration within target area of the body to achieve desired effect

  • within therapeutic range (concentration that produces desired effect with minimal to no side effects)

• Routes of administration

  • parenterally (other than intestinal)

    • ex: IM, IV, subq, etc

  • non-parenterally (intestinally)

    • oral route

• dosage forms: tablets, boluses, lozenges, capsules, powders, solutions, emulsions, and suspensions

  • solution- drugs dissolved in liquid, and will not settle if left standing

    • syrups: drugs dissolved in 85% syrup

    • elixirs: drugs dissolved in sweetened alcohol

    • tinctures: drugs dissolved in alcohol used for topical application

    
    

  • suspension- finely divided undissolved substance dispersed in water. Must shaken for uniform distribution of drug

  • emulsion- fine droplets of oil in water or water in oil

    • separates into layers when left standing and must be shaken before use

• injectable drugs

  • fastest method for drugs into bloodstream is intravenous (IV)

    • bolus administration

      • small volume of highly concentrated drug in single injection

    • intermittent therapy

      • diluted form of drug over 3-60 minutes through indwelling catheter

      • frequent for antibiotic administration

    • infusion of fluid

      • large volume of fluid containing electrolytes or amino acids over long periods of time

• IM injections

  • aqueous injection

    • absorbed rapidly and high blood concentrations are reached in 30 minutes

  • oily suspensions

    • absorbed more slowly than aqueous injection

  • injectable pellets

    • mixed drug with ingredient with limited absorption to delay absorption

  • tips of injection

    • drawback plunger so not in blood vessel when giving

    • needle should be deep in muscle layer and not in subq region

    • can be painful, especially oily suspensions

• Subcutaneous (subq) injections

  • effect observed faster than oral, but slower than IM

    • can also deposit pellet subq

• recommended dosages- amount of drug administered at one time to achieve desired effect (can be mg, g, ml, or cc)

  • loading dose

    • initial dose of drug that is given to get drug concentration up to therapeutic range within short amount of time

  • maintenance dose

    • dose of the drug that maintains or keeps drug within therapeutic range

  • total daily dose

    • dose of drug delivered in 24 hours

• dosage intervals

  • SID (semel in die or once daily), BID (bis in die, or twice daily), TID, QID

Responsibility of physician/veterinarian

• proper dosage selection

  • age, sex, clinical condition should be considered when selecting dosage

• administration of drugs

  • be aware of proper dosage, frequency, and duration of treatment for each drug prescribed

    • avoid combination if possible

• providing adequate information

• testing drugs for allergy when indicated

• proper storage and packaging

• maintenance of records

  • maintain patient record carefully, including dose administered

• security of controlled substances

• knowledge of incompatibilities

• welfare of patient/client is paramount

Week 2: Passage of Drugs across Membranes

Basic Terms

• Pharmacokinetics- branch of pharmacology that studies fate of pharmacological substances in the body

  • Absorption, distribution, metabolism, and elimination

  • what the body does to chemicals

• Pharmacodynamics- study of action or effects of drugs on living organisms

  • what chemicals do to the body

• 2 systems of circulation that can happen with a drug in the body

  • protein-bound form

  • free form in blood vessels

    • has several fates if free form

    • 1. fraction of drug can reach tissues to produce its effect

    • 2. it can be metabolized

    • 3. free form of the drug or its metabolite can be excreted

    • 4. drug can accumulate in the tissues

Structure and Function of Cell Membranes

• Cell membranes are lipid bilayers

  • phosphate head (polar) groups

  • cardon-hydrogen tails that are lipid (non-polar) groups

• for drugs to dissolve in membranes to pass through them, or be moved by transporters, receptors, channels and enzymes that are embedded

• 3 important functions of membranes

  • barrier, protects the cell

  • transport of chemicals and ions, essential for function of cell

  • separate various cell organelles

    • can be in nuclear membrane, mitochondria, etc.

Properties of Chemicals that Enable them to Cross Membranes

• movement of chemicals across membranes is facilitated by their inherent properties

• inherent properties can include

  • lipid solubility

  • charge/polarity

    • non-ionized state to cross membranes easily

  • size and shape

    • smaller the molecules, more readily they pass through the membrane

    • small pores on the cell

  • structural similarity to endogenous molecules

    • when drugs have some structural similarity to endogenous chemicals

      • can pass through membrane by fooling channel proteins to accept them by looking like other chemicals

Processes by Which Chemicals Cross Membranes

• Filtration

  • process by which transport of large volumes of water across a membrane with ions and chemicals

    • filtration like in kidneys

  • pressure gradient through cells by pores or channels

    • filter from high pressure to low pressure

  • factors that influence filtration are

    • size of molecule relative to the size of the pore

    • number of pores that are present

    • pressure gradient

• passive diffusion

  • chemical does not go through pores or around membranes, but dissolves in membrane to get across

  • chemicals have to lipophilic, non-ionized, and have small size

    • typically processes are dynamic and can go in either direction

    • net accumulation of chemical on one side of membrane depends on concentration gradient of the chemical

      • area of higher concentration to lower concentration

    • surface area of membrane will influence rate of diffusion

• factors that affect passive diffusion

  • lipid solubility

    • K=amount that dissolves in organic non-polar solvent/amount that dissolves in water

      • higher K value, more readily absorbed by the body

      • more readily absorbed drug if lipophilic

    • measure of lipid solubility by mixing equal volumes of non-polar solvent and water to test where the drug is absorbed more readily

  • ionization

    • drugs are more easily absorbed if they are non-ionized

    • most drugs are weak acid/bases that exist in an “associated form” and “dissociated form” (separated from H+)

  • lot of math with K, Ka, and conc of acidity based on log equations

    • if pH is less than pKA, (or Ka of 10^-pH), it will be completely non-ionized, which favors a greater absorption

    • in weak acids, associated form is non-ionized, dissociated form ionized

  • weak bases

    • amino group (R-NH2) that contrasts weak acids

    • associated form is ionized and dissociated form is non-ionized

    • Kb is calculated same way

      • Kb= [associated form][OH-]/[dissociated form]

    • weak bases remain in non-ionized form in alkaline environment

    • weak bases better absorbed in intestines

• Basic principles governing drug ionization and membranes

  • 1. concentrations of non-ionized and ionized forms of weak acids and bases is dependent on the pKa of the drug and the pH of the environment

  • 2. only non-ionized forms of the drug pass through lipid membranes by passive diffusion

    • concentration gradient of the non-ionized form determines the rate of movement of the drug across membrane

  • 3. at equilibrium, concentration of non-ionized form will be the same on both sides of a membrane that separates 2 aqueous compartments

    • concentration of ionized form will depend on pH on each side of the membrane

• based on the principles, properties of drug is important to determine the route of administration

  • will assess if drug will reach required concentration within body compartment to produce desired effect

    

• bottom line

  • most drugs are either weak acids or weak bases and their rate of diffusion across lipid membranes is determined by

    • degree of ionization (influenced by pH and pKa of drug)

    • lipid solubility of nonionized form

    • concentration gradient of nonionized form

  • only nonionized can cross membranes, so important to figure out how much ionizes based on environment pH and how that impacts what the drug works in

  • weakly acidic or basic drugs tend to concentrate on one side of a membrane when pH of fluids on either side are differing

• Ion trapping

  • trap a drug in an area based on the pH of the body system, which is useful for targeting specific areas of the body

    • ex: stomach ulcers can be treated with weak base that is easily ionized and trapped in high enough concentrations to produce effect

      • will not “escape” into bloodstream

Facilitated Diffusion

• carrier protein that binds to drug and transports it across membrane

• moves along concentration gradient

• distinct features

  • substrate-specific

  • carrier proteins are saturable at large concentrations of the drug

  • competitive process

Active Transport

• very similar to facilitated diffusion

  • competitive, saturable, substrate-specific

• moves against concentration gradient

  • requires ATP

• rate of movement starts fast and slow downs considerably due to carrier proteins saturation with drug

  • same with facilitated diffusion

  • opposite for passive diffusion

Pinocytosis

• drugs are taken into cell by endocytosis, which requires ATP

  • slow process

  • drug is engulfed by invagination of cell membrane and taken into cell

Week 3: Drug Absorption

General Considerations

• Drug absorption- transfer of drugs from the site of administration into the systemic circulation (like plasma)

  • fraction of drug enters system

    • amount of drug that is bioavailable

• rate and extent of absorption depended on factors:

  • blood flow to site of administration

  • nature of barriers to absorption

  • surface area

  • ionization state of the drug

  • lipophilicity of drug

  • carrier systems that are available to transport the drug

  • metabolism of drug at absorption site

• routes of drug administration

  • oral

  • sublingual

  • rectal

  • IV

  • SQ/SC (subcutaneous)

  • IM

  • inhalation

  • intraperitoneal (IP)

  • intrathecal

  • topical

Absorption of Drugs After Oral Administration

• Absorption of drugs from GI tract

  • GI mucosa acts as semipermeable barrier

  • differences in characteristics of GI tract lead to differences in drug absorption based on properties

• Oral Cavity

  • highly vascular, lined by stratified squamous epithelium

  • little to no appreciable absorption

• Stomach

  • large epithelial surface and rich blood supply

  • rate at which stomach empties determines length of time the drug remains in the stomach

    • factors influence absorption

      • properties of drug

        • degree of ionization

        • lipophilicity

      • binding of drug to food particles

      • surface area

      • blood flow

      • gastric emptying time

• Small Intestine

  • Largest GI surface area for absorption

  • lots of folds and very long area

    • lined with villi and microvilli

  • pH is 4-5 in duodenum, and becomes more alkaline further along tract (up to 8)

    • GI flora may inactivate certain drugs, reducing absorption

  • drug transport is usually slow compared to stomach

  • factors that influence absorption

    • properties of drug

    • binding of drug to food particles

    • surface area and motility

    • blood flow

  • factors favoring absorption of a weak acid from small intestine

    • large surface area

    • high blood flow

    • pH in blood favors ionized form

• Large intestine

  • no villi

  • rarely absorbed in large intestine, but technically possible

Fate of Drugs Administered Orally

• any drugs absorbed in oral cavity can reach blood circulation

  • stomach and intestines pass through portal vein and taken to liver

    • liver organized into hepatic lobules

      • each lobule has central vein surrounded by radiating cords of hepatocytes

      • between cords, sinusoids (large veins)

    • periphery of lobule, there is a branch of portal vein, hepatic artery, and bile duct

      • hepatocytes in liver can uptake and metabolize some of the drugs

      • first pass effect

      • metabolized fraction and free drugs can either be taken into vena cava by sinusoids or run through layers of hepatocytes and back to the GI tract for reabsorption

Absorption of Solid Dosage Forms

• oral drugs common for convenience and stability

• disintegrate into high surface area of GI tract

  • dissolution rate impacts drug absorption rate

• dissolution rate governed by drug properties

Absorption for Parenteral (non-GI) sites

• direct placement of drug into bloodstream ensures highest bioavailability

• rate of entry into capillaries is governed by

  • hydrophobicity of drug

  • rate of capillary blood flow

    • blood flow can be changed to area (vasoconstrictor/dilator) to impact length of action of drug

• slower absorption rate can be achieved by mixing drug with insoluble material, imbedding drug in matrix, etc.

  • for IV/IM/SQ: mixing insoluble salts, suspensions in non-aqueous vehicles, etc. can all achieve the same effect to get a slow release for hours/days/weeks

Parenteral Routes of Drug Administration

• IV route

  • 100% bioavailability

  • most preferred route of parenteral drug administration

    • easy to control dose and duration of action

  • only practical in clinical setting

• Intramuscular and subcutaneous

  • gain access through peripheral endothelium and lymphatic channels

  • perfusion important for drug absorption

• Inhalation

  • volatile agents like anesthetics or aerosols

  • 2 steps involved

    • ventilation to deliver drug to alveoli

      • amount of chemical in gaseous form in alveoli

    • absorption of drug into blood from alveoli

      • solubility

  • pass a few membranes in cells, such as pneumocytes

  • drug absorption favored in alveoli due to large surface area and high blood flow

    • few membranes to cross to reach blood compared to GI tract

  • impacted by lipophilicity, concentration of chemical in gaseous phase, solubility in plasma

• Topical, dermal, or percutaneous route

  • absorption of drugs in topic application generally happens through passive diffusion

    • epidermis is good barrier for topically applied agents

    • outer layer keratinized

      • only lipid-soluble agents easily absorbed

    • epidermis has limited blood supply, but can only reach blood supply reliably through a cuts or abrasions

      • no absorption through hair follicles

• Technically, also intra-arterial, intrathecal, and intraperitoneal, but all rarely used and only for specialized procedures

Week 4: Drug Distribution

Drug distribution general concepts

• movement of drugs and chemicals away from absorption into circulation and into extracellular space and cells

  • drug typically reaches tissues with high rate of perfusion first

    • heart, lungs, brain, liver, kidneys

  • then moves to lower perfusion rate

    • muscle and adipose tissue

• can move in blood in several ways

  • dissolved in plasma, bound proteins in plasma, attached to blood components (RBC or WBC)

• can also move by intercellular spaces to lymphatic vessels

• 3 compartments of body fluid

  • plasma

    • about 4% of total body weight

  • intercellular space (between cells)

    • about 16% of total body weight

  • intracellular space (within cells)

    • about 40% of total body weight

  • know how to do the math to calculate the total weight percentage per body fluid

  • plasma and intercellular fluid together makes extracellular fluid

Factors that influence drug distribution

• several factors influence drug distribution from site of administration

  • blood flow

  • composition and structure of vascular wall

  • accumulation of drugs in tissue

  • extent to which drugs are bound to plasma proteins

  • availability of membrane transport proteins to transfer drugs between fluid compartments

• blood flow

  • how much of drug is absorbed

  • how rapidly drug is absorbed

  • for highly soluble chemicals, blood flow to site of absorption may limit distribution

• composition and structure of vascular wall

  • sinusoids

    • discontinuous epithelium with holes in walls in which drug easily enters the tissues

      • incomplete basement membranes and intercellular gap

    • ex: spleen

  • density of capillaries in tissue determines how much drug enters tissue

  • blood brain barrier

    • formed by astrocytes and glial cells that surround capillaries

      • prevent most things/drugs from entering nervous tissue

    • not well developed in young animals

      • easier for drugs to reach CNS

      • why a lot of drugs not suitable for young

    • can be weakened with certain disease states

      • inflammation, meningitis

    • can also gain access to brain through active transport through choroid plexus

      • formation of cerebrospinal fluid

Accumulation of drugs in tissue

• accumulation of drugs in tissues influenced by

  • tissue perfusion

  • lipophilicity of drug

  • active transport of drug into tissue

  • binding of drug to tissue components

• either bind reversibly or irreversibly to tissue

  • works just as well for beneficial or toxic chemicals

  • effective for storage in body

• when drug accumulates, limits amount of drug distribution to other tissue

Plasma protein binding

• fraction of drug bound to plasma protein in circulation

  • amount dependent on affinity and structure of drug

• binding to plasma decreases amount free in circulation

  • decreases drug action

  • retains drug within blood vessel

• plasma binding favors absorption, but limits movement into tissue or extracellular space

  • limited by transport protein

• can bind to several proteins

  • albumin

    • most important and most abundant

    • 3 distinct classes of binding sites

      • high affinity for weak acids

      • Alpha1-acid glycoprotein for basic chemicals

  • lipoprotein

  • metal-binding proteins (transferrin)

  • transcortin

    • steroid drugs

• reversible binding

  • involves electrostatic forces, hydrogen bonding, hydrophobic interactions

  • important distribution mechanism

  • stores in blood temporarily to release slowly

  • important to consider for dosage if protein levels are low in body

Availability of membrane transport proteins

• transporters can influence distribution of drugs that enter cells by carrier-mediated processes

  • even if extensively bound to plasma proteins, movement is not reduced if actively transported

Drug redistribution

• drugs can redistribute to other tissues after distributed to initial tissues

• Thiopental that first moves to brain (heavily) for sedative affects

  • moves back into bloodstream and accumulates in adipose tissue so slow releasing after initial affect

    

• Role of placental barrier in drug distribution

  • placenta not very good barrier between fetus and maternal circulation

  • placenta slows drug movement, but does not prevent drug distribution to fetus

Apparent volume of distribution

• apparent volume of distribution (Vd)

  • hypothetical volume in which a dose of chemical would have to be placed to yield observed initial plasma concentration after IV injection

    • how well drug is distributed throughout body

    • larger the Vd, lower drug concentration in the body

      • means that most of the drug is in the plasma rather than in the tissue when Vd is high

      • when Vd is low, means that most of the drug is in tissue rather than in the plasma

  • Ratio of drug administered IV to maximum plasma concentration extrapolated to time zero (Cp0)

  • important for calculations of available drug with patients with free floating fluid

• physical volumes of body compartments into which drugs might be distributed