Veterinary Pharmacology

Pharmacokinetics

• Describes what the body does to drugs

• It's the complex sequence of events after drug administration

• The body has an effect on the drug after administration

• A drug must reach the desired area and accumulate in fluid or tissue at the required concentration to be effective

• Drugs must be given at fixed intervals to maintain concentration and counteract breakdown/excretion

• A loading dose is a high initial dose for rapid effectiveness

• A maintenance dose is a reduced dose to maintain concentration by replacing lost amount

• Steady state is when drug accumulation equals drug elimination

• Therapeutic drug level is the range of drug concentration that is effective without being too toxic or ineffective

• Therapeutic index is the difference between minimum and maximum effective doses

• Drugs with close maximum and minimum effective doses have a narrow therapeutic index

• Therapeutic drug monitoring involves measuring drug levels in blood, urine, or CSF to assess therapeutic levels

• Several factors influence drug concentrations:

  • Rate of absorption
  • Amount of drug absorbed
  • Drug distribution
  • Drug metabolism or biotransformation
  • Rate and route of excretion

Routes of Administration

• Routes of administration are influenced by the:
  • Available form of the drug
  • Properties of the drug (irritating?)
  • Desired speed of onset
  • Patient behavior
  • Condition being treated

Oral Route

• Many common drugs are given orally, which is suited for at-home use

• Drugs can be administered directly in the mouth, via nasogastric tube, or orogastric tube

• Oral drugs are absorbed more slowly than injected ones

• Absorption rates depend on:

  • Species (ruminants vs. simple stomachs)
  • Stomach pH
  • Stomach fill
  • GI motility
  • Drug solubility

• Oral administration generally produces a longer-lasting effect than injections

Parenteral Route

• Parenteral routes involve any drug administered by injection
• Types of parenteral injections:
  • Intravenous (IV)
  • Intramuscular (IM)
  • Subcutaneous (SQ/SC)
  • Intradermal (ID)
  • Intraperitoneal (IP)
  • Intraarterial (IA)
  • Intraarticular
  • Intracardiac (IC)
  • Intramedullary
  • Epidural/subdural

IV - Intravenous

• Intravenous drugs generally have the fastest effect; irritating drugs are often given IV because of dilution

• IV drugs must be given slowly to avoid adverse reactions

• With few exceptions, cloudy, thick, or opaque substances should not be given IV

• Exceptions to this rule include: Propofol, pink or blue euthanasia solutions, Legend®

• Drugs meant for IV injection can be very irritating outside the vein, could leading to tissue necrosis

IM - Intramuscular

• IM injections typically have a slower onset but longer duration than IV
• Water-based drugs can have a fast onset with IM
• Depot forms can have a very long duration, and are sometimes suspended in oil
• Not a good choice for irritating drugs
• Aspirate before injection to prevent inadvertent IV injection

SQ - Subcutaneous

• SQ injections have a slower onset but slightly longer duration than IV
• Irritating or hypertonic solutions should not be given this route; may cause necrotic plaque
• Avoid quantities that would cause dissection between skin and underlying tissues
• Hyaluronidase may be added added to speed absorption

ID - Intradermal

• Used for tuberculosis and allergy testing

IP - Intraperitoneal

• Used to deliver drugs to the abdominal cavity
• Usually used when other routes are unavailable, especially in small or exotic pets

IA - Intraarterial

• Usually inadvertent
• In horses, inadvertent injection of sedative into the carotid artery (instead of jugular) can result in seizures or death

IA - Intraarticular

• Used to treat inflammatory conditions in the joint
  • Antibiotics
  • Corticosteroids
  • Hyaluronic acid
  • Stem cells
• Must use sterile technique

IC - Intracardiac

• Infrequently used for cardiopulmonary resuscitation or euthanasia

Intramedullary

• Substances are injected into the medullary cavity of a long bone
• Most frequently done in exotic or pediatric patients for rehydration when IV isn't available

Epidural/Subdural

• AKA intrathecal, where medicine is given by IV into the spinal canal
• Used most frequently for anesthesia and pain control in veterinary medicine via spinal canal

Inhalation

• Medications are administered in inspired air by converting liquid form of drig to a gas via nebulizer or vaporizer
• Often use:
  • Inhaled anesthetics
  • Bronchodilator
  • Antibiotics

Topical

• Includes skin-transdermal and mucosa-sublingual, rectal, mammary glands, uterus, eyes, and ears
• May be affected by drug vehicle or carrier:
  • Dimethyl sulfoxide (DMSO) is an organic solvent for this

Drug Absorption

• The degree to which a drug is absorbed and reaches general circulation bioavailability

• Bioavailability is demonstrated by blood level curve and influenced by

  • Manufacturing and the Mechanism of absorption
  • simple passive diffusion vs active transport

• pH/ionization/solubility of the drug

• Absorptive surface area and blood supply

• Drugs absorbed through passive transport via diffusion from high to low concentration use no energy

• Drugs absorbed through active transport from lower to higher concentration use energy

  • This includes sodium, potassium, and other electrolytes

• Drugs may be absorbed by pinocytosis; Drug is invaginated to form a vesicle that breaks off in the cell interior

• Rate of absorption depends on fat or water solubility, size/shape, and degree of ionization

• Drugs can pass through cell membranes if they are nonionized

  • Acidic drugs do not ionize well in acidic environments, so they're absorbed readily
  • Mildly alkaline drugs become ionized and trapped in acidic environments

• Increased absorptive surface area increases the absorption rate

• Villi of the small intestine maximize surface area

• Drugs given IM have faster absorption than SQ because of higher blood flow, reduced by

  • Poor Circulation and can increase from Increased blood flow of fight/flight response

• May be increased with heat and massage

• Solubility is directly proportional to nonionization

  • Lipid-soluble/nonionized drugs are absorbed more quickly

• Lipid partition coefficient= the degree of lipid solubility

• Rate of absorption may also depend on formulation

• Depot and spansule drugs have binding agents for a sustained release

• Orally given drugs depend on Gl tract condition and interactions with other drugs or foods

  • Milk or dairy products reduce tetracycline absorption

First-Pass Effect

• This involves substances absorbed by the Gl tract into the hepatic portal venous system, which delivers the drug to the liver before entering general circulation
• The liver's enzymes remove toxins and dangerous substances
• Drugs may be metabolized in the liver to forms which may make the drug less active/inactive
• Those prone to first-pass effect are not recommended for oral administration

Drug Distribution

• Carries drug from absorption to action site:
  • Site->plasma->interstitial fluid->into cells->bind with cellular receptors->action
• Distribution depends on:
  • Tissue perfusion
  • Temperature, vasoconstriction and vasodilation
  • Concentration gradient
  • Degree of protein binding
  • Lipid-soluble drugs move into tissue and may be bound

Barriers to distribution:

• Placenta
• Prostrate
• Eye
• Brain (the blood-brain barrier)

Plasma Protein Binding:

• Some drugs bind to plasma protein too large to enter the capillary's endothelium
• Bound circulating drugs are inactive, and only the unbound/free drug exerts its effects
• Animals who are HYPOproteinemic may require lower doses/suffer toxicity
• Some drugs, like cefovecin, bind protein to create a depot effect, releasing the drug into the tissues over an extended time

P-glycoprotein:

• P-glycoprotein is an active transport pump in the intestinal wall, liver and blood-brain barrier

• Its purpose is to actively pump drugs back into circulation for excretion

• P-glycoprotein defect/ MDR1 gene defect

• Exists at the blood-brain-barrier in collies, Old English sheepdogs, Australian shepherds and results in increased ivermectin toxicity

• Reptiles: renal portal system distributes toxic drug levels to the kidney if the drug is given in the posterior 1/3 of the body

Biotransformation

• Metabolism is the body's ability to change the chemistry of the drug to eliminate it

• It mainly occurs in the liver

• Enzymes make the drug water soluble for excretion in the urine

• An altered drug is a metabolite

• Most metabolites are inactive, though some are active

• Some lipid-soluble drugs are eliminated in the bile

• Four chemical reactions controlled by microsomal enzymes of the liver are

1. Oxidation- loss of electrons
2. Reduction- gain of electrons
3. Hydrolysis- splitting of the drug molecule with the addition of a water molecule
4. Conjugation- addition of a glucuronic acid to make it more water soluble

Special cases:

• Cats have limited ability to form glucuronic acid, leading to metabolizing difficulties with aspirin, barbiturates and narcotics
• Young animals have not fully formed liver enzyme systems
• Older animals have decreased ability to form liver enzymes
• Malnourished animals have decreased raw enzyme production

Drug Excretion

• Most drugs are metabolized by the liver then eliminated through the kidneys

• May excreted by mammary glands, bile, lungs, GI/salivary glands or skin

• Route of excretion must be considered when drugs are selected

• The liver excretes drugs by incorporating them into bile, then they either are:

• Excreted as feces

• Reabsorbed from small intestine

• Orally given drugs that are not absorbed may be eliminated in the feces

• Drugs may convert to to gas and be eliminated via the lungs

• May pass from blood into milk, which must be considered for nursing offspring/people consuming the milk

Renal Excretion

• Involves two mechanisms:
• Glomerular filtration is where the glomerulus removes metabolites out of blood into glomerular filtrate
• Tubular secretion is when kidney tubules secrete metabolites out of capillaries into filtrate
• If a nephron is not functioning well, toxic drug levels may accumulate

Half-Life

• T ½ = time required for a drug in the body to be reduced by one half
• Drug residue quantities of drug remaining in animal products that may have human safety implications
• People may be allergic to the drug
• Prolonged exposure may result in resistant bacterial strains
• Residues may cause cancer
• Food Animal Residue Avoidance Database (FARAD) repository of residue avoidance information and withholding times for meat/milk

Pharmacodynamics

• Study of how a drug affects the body

• Drug molecule combines with components to alter cell function

• The drug and receptor must interact exactly like a lock and key

  • Affinity-a drugs tendency to binds with receptors
  • Agonist- a drug with high affinity and efficacy
  • Partial agonist-a drug with less adffinity and efficiency
  • Antagonist- a drug that blocks others from combining receptors

• Dose response curve correlates increased drug amounts effect

• As the amount of a drug increases in the body, and the drug reaches a given plateau, it shows its maximum effect

• No drug has a single effect so some doses may exert unintended ones

• Drug potency is the amount of drug needed to produce a desired response

• Efficacy is the degree to which the drug produces the desired response

• Therapeutic index is the relationship between the drug's ability to produce a desired response and tendency to produce toxic effects Therapeutic index = LD50/ED50

• LD50 the dose at which the drug is lethal to 50% of the animals treated

• ED50 the dose at which the drug has the desired effect in 50% of the patients

• Adverse drug reaction is any undesirable result from the drug itself, its quality/purity or the dose

• Can manifest dermatitis, anaphylactic shock, and photosensitivity

Drug Interactions

• Altered pharmacologic response to a drug caused by a second
  • Pharmacokinetic interaction is when the level of one drug is affected by presence of another
  • Pharmacodynamic interaction is when the effect of one drug is altered by another
  • Pharmaceutic interaction is when a physical/chemical reaction occurs from mixing drugs (diazepam precipitates when mixed)

Pharmacology questions for veterinary medicine, focusing on drug concentration, administration routes, therapeutic monitoring, and biotransformation. Key aspects include P-glycoprotein defects and peak/trough level monitoring. The questions also tests the understanding of how conditions like hypoalbuminemia affect drug dosage in animals.