Week 1- Flashcards
Define the term “drug absorption”
Is the transfer of the drug from the site of administration to the circulation
Discuss the different factors related to the drug that modify drug absorption:
Molecular size- the SMALLER the molecular size, the FASTER is penetration through the pores
Lipid Solubility- the GREATER the lipid solubility, the GREATER is absorption
Degree of ionization- the HIGHER the ratio between N/I, the GREATER is absorption
Dissolution of drug in water- oral absorption of liquid drugs is faster than solid drugs
-oral absorption of solid drugs depends on their rate of dissolution
Concentration of drug at absorptive site- depends on the dose and concentration
-the higher the concentration the faster is absorption
Route of administration-
- sublingual and inhalation have a very rapid absorption
- intramuscular is slower than sublingual and inhalation
- subQ is SLOWER than intramuscular
- oral is usually SLOWER than injection
Discuss the different factors related to the animal that modify drug absorption
- Blood Flow
- Absorbing surface area
- Connective Tissue: decreases absorption
- Species
- individual
Discuss blood flow as a factor related to the animal
- Absorption of a drug from a particular site is related to blood flow to the site
- Increased blood flow increases drug absorption = “more blood, more drug”
- Drugs, physiological factors and disease can modify blood flow
- Heat or massage of intramuscular injection site increases blood flow and absorption
- Sympathetic stimulation increases blood flow to skeletal muscles
- Sympathetic stimulation decreases blood flow to the GI tract and subQ sites and skin
- Shock and edema decrease blood flow
Discuss the different factors affecting drug absorption from the GI tract
- the upper part of the small intestine is the main site of absorption for all drugs given ORALLY because of the extensive SA and rich blood supply
- therefore, the rate of absorption depends on the rate of gastric emptying
- drugs and disease can modify the rate of gastric emptying
- oral absorption of solid drugs depends on their rate of dissolution
- activity of the gut
- presence of other substances
- blood flow
- species
- individual
what are the different sources of drugs used clinically
- Natural (non-synthetic)- plant, animal, fungi, bacteria
- Semisynthetic
- Synthetic
What are the active ingredients of plant-derived drugs
- Alkaloids
- Glycosides
- Resins
- Gums
- Tannins
- Fixed oils
- Volatile oils
True or False - Alkaloids are basic nitrogenous substances that are insoluble in water
True
Characteristics of alkaloids
- End with -ine
- Their salts are soluble in water
- They can be precipitated by acids
What are glycosides
Sugars combined with other organic structures (aglycone or genin)
What are resins
they are substances formed by polymerization of volatile oils
What are gums
They are polysaccharides secreted by certain trees
examples are : Acacia, Tragacanth
What are tannins
They are non-nitrogenous plant constituents that produce an astringent effect - precipitate proteins
What are fixed oils, give examples
They are stable oils and they will NOT evaporate when exposed to air. Examples = cottonseed oil, castor oil, linseed oil
What are volatile oils, give examples
They are oils that WILL evaporate readily when exposed to air. Examples = peppermint oil, turpentine oil, oil of clove.
What are semisynthetic sources of drugs- give examples
They are from natural sources and chemically treated - examples= amoxicillin, apomorphine
What are synthetic sources of drugs- give examples
They are highly purified substances prepared synthetically. Examples = sulfonamides, furosemide, aspirin, acepromazine
What are the general routes of drug administration
Local Routes and Systemic Routes
Describe what local routes of drug admin is
Local routes are NOT absorbed into bloodstream. These include topical (ie. skin, eye)
Describe what systemic routes of drug admin is
Systemic routes are absorbed into bloodstream. There is ENTERAL = orally, PO, via tube feeding and PARENTERAL= any extra-oral or GI route, IV, IM, SQ, IP, IO, TM, inhalation
What are the advantages of systemic drug route Enteral route
- Convenient (give at home)
- Feeding tube is useful if non-compliant patient or multiple meds needed
- Infection at site not a concern
- Potential to decontaminate if needed- induce vomiting or gastric lavage in case of drug overdose/toxicity
What are the disadvantages of systemic drug admin enteral route
- Slower onset of action
- Inactivation by gastric pH, digestive enzymes, or rumen microflora
- Food or other drugs may affect absorption
- GI activity & intergrity
- Irritant drugs may cause GI upset
- Palatability
- Patient compliance
- Owner compliance
What are the advantages of systemic drug admin IV
- Rapid onset
- Less irritating than inj. into tissue
- Larger volumes can be given
What are the disadvantages of systemic drug admin IV
- Risk of complications
- Some drugs can irritate veins (phlebitis)
What are the advantages of systemic drug admin IM
- Rapidly absorbed
- Longer duration of action than IV route
- Suspensions can be given IM
What are the disadvantages of systemic drug admin IM
- Risk of tissue damage: irritants, hypertonic substances, acid/base drugs
- Administration site infection possible
What are the advantages of systemic drug admin SQ
- Slow but constant absorption
- Longer duration of action
- Can give at home in some cases (Insulin)
What are the disadvantages of systemic drug admin SQ
- Slow onset
- Irritating drugs cannot be used
- Admin site infection possible
What are the advantages of systemic drug admin Intraosseous
- Fluids flow as well as IV route: similar time to reach circulation as IV routes
- Rapid access from emergencies
- CPR drugs can be given IO
- Technically uncomplicated (with practice)
- Useful in neonates and tiny patients
What are the disdvantages of systemic drug admin Intraosseous
- Short-term use only
- Some drugs cannot be given IO
- Special equipment required
- Pain
What are therapeutic factors that affect route selection
- Onset of action
- Duration of action
- Site of action
- Adverse reactions
- Length of required tx
What are the drug factors that affect route selection
- Irritating properties
- Solubility
- pH
- Viscosity
What is the relative rate of onset of action of drug
IV or IO > Inhalation > Transmucosal > IM > SQ > Enteral
What are the different factors related to the animal that modify drug dosage or drug response
- Species, breed, individual
- Body weight, age, sex, temperament
- Idiosyncrasy
- Hypersensitivity
- Disease
- Tolerance
What are some species differences that modify drug dose/response
Anatomic- ability to vomit, rumen pH ~6.0, monogastric pH ~2-3
Physiologic- Cats lack salivary amylase, urine pH: Cats more acidic, dogs and horses more basic
Biochemical- Metabolic: cats deficient in certain drugs-metabolizing enzymes, presence of receptors, plasma protein binding
What are some breed differences that modify drug dose/response
- Herding breeds (collies, sheepdogs, etc.) sensitive to many drugs- Multidrug resistance (MDR-1) gene
- Brachycephalics (boxers, bulldogs, pugs, etc) sensitive to phenothiazines- increased vagal or parasympathetic tone
What is an idiosyncratic drug reaction
Individual drug sensitivity. Uncommon genetically determined and unpredictable. Not dose-dependent, can be serious and life threatening
What are some examples of idiosyncratic drug reactions
- Enrofloxacin: irreversible retinal damage and blindness in cats.
- Zonisamide: reversible neutopenia (low wbc)
What is drug hypersensitivity reaction
- Allergic drug reaction
- Drugs can act as antigens & haptens
- Prior exposure is necessary
What is drug tolerance
an unusual resistance to ordinary drug dose
What are the types of drug tolerance
- Natural Tolerance: ruminants tolerant to barbiturates
- Acquired tolerance: enzyme induction-> faster metabolism
increased excretion -> disease state or drug-drug interactions
receptor down-regulation -> chronic drug admin - Cross-Tolerance -> drugs in same classes
- Tachyphylaxis -> acute acquired tolerance
-no use in giving more of the same drug
-Different drug needed to achieve desired effect
When does drug accumulation occur?
Occurs when rate of elimination is slower than rate of absorption
Examples of drug accumulation
Renal insufficiency- can lead to cumulative drug effects - decrease drug excretion, may require dose-reduction
Adipose tissue stores- can lead to accumulation of lipophilic drugs. Increase drug re-distribution, slower drug excretion
What is drug-drug interactions
The administration of drugs concurrently or sequentially
What are the types of drug-drug interactions
- Summation (1+1=2) sum of the effects of the drugs
- Potentiation (1+1>2) intensification of effects, give another drug with DIFFERENT ACTION
- Synergism (1+1>2) exaggeration of effects, give another drug with SAME ACTION
- Antagonism (1+1<2) decreases effect of another drug
What are the factors related to the environment
- Ambient temperature: may alter active drug compounds
- Humidity: denaturing of compounds
- Oxygen: antibiotics used to tx anaerobic infections will not work well in oxygen rich environments
- Exposure to light: some drugs must be protected from direct light sources
Define drug disposition
study of the movement of drugs in the body across biologic membranes from the time of absorption until elimination
What are the 4 stages of drug disposition
- Absorption
- Distribution
- Biotransformation (metabolism)
- Excretion
Factors that affect disposition of the drug
- Biological cell membranes
- Concentration gradient
- Pump Mechanisms
- Site of admin
- Total body water
- Plasma protein binding
- Disease
What are the properties of biological cell membrane
- Phospholipid bilayer
- Membrane proteins and carbohydrates
- Cell Junctions
- Aqueous pores
What are the 4 mechanisms of transport
- Passive diffusion
- Facilitated diffusion
- Active Transport
- Pinocytosis
Does Passive Diffusion require energy?
No energy (ATP) is required for this process- movement down the conc. gradient
Majority of drugs move through the body via what mechanism of passive diffusion?
Simple diffusion- movement through lipid membrane
Does facilitated diffusion require energy?
No energy is required via facilitated diffusion - carrier mediated transport. Faster because there is a carrier to facilitate the transport of the drug
Discuss Active Transport
- Needs carrier and energy
- Carrier mediated transport : low to high concentration
Give an example of Primary Active Transport
Na+/K+ ATPase pump
Give an example of Secondary Active transport
Na+-dependent glucose transporter in renal tubules
What is Pinocytosis
A specific type of endocytosis where cell engulfs the drug molecules dissolved in water
Give a specific example of drug transport via pinocytosis
- Sequestration of aminoglycoside antibiotics (amikacin, gentamicin) in renal tubules
- Aminoglycocides can cause renal damage & can act as RENAL TOXINS
Properties of Passive Diffusion
- Moves down concentration gradient
- Requires no energy
- Substances can be moved in or out of cells
- MOST common form of transport
Properties of Facilitated Diffusion
- Moves down concentration gradient
- Requires a carrier
- Requires no energy
- Saturable
Properties of Active Transport
- Moves uphill from low to high concentration
- Requires energy (ATP)
- Symporters or antiporters
- Saturability
- Classified into primary or secondary
- Ex: Na/Glucose symporter in renal tubular cells
Properties of Pinocytosis
- Special type of endocytosis or “cell drinking”
- Drug dissolved in water
- Can be toxic ex: aminoglycosides in renal tubular cells
Factors affecting simple diffusion
- Concentration gradient
- Lipid Solubility
- Degree of drug ionization
True or False- Higher lipid solubility of the drug = faster crossing cell membranes
TRUE
What does the degree of ionization depend on?
- pH of the drug
- pKa of the drug
- pH of environment in vivo
Membranes are more permeable to what form of drugs
Non-ionized forms (lipid soluble and uncharged)
The rate of diffusion depends on what
the rate of diffusion depends on degree of ionization- non-ionized form of the drug: ionized form of the drug
= N/I
Define pKa
Equal to the pH of the medium at which the dissolved drug is 50% ionized and 50% non-ionized
What property would not favor transport via passive diffusion
Mostly ionized (should be non-ionized)
define the term absorption of drugs
the transfer of the drug from the site of administration to the systemic circulation
What is the main site of absorption for enterally admin drugs
the upper part of the small intestine
Why is the upper part of the small intestine the main site of absorption for enterally admin drugs
- Extensive SA
- Rich blood supply
What is rate-limiting step for oral absorption
Dissolution- b/c drugs given orally must disintegrate before they can dissolve and must dissolve before they can be absorbed
What is the first-pass effect
- Drugs absorbed from GIT and distribute first to the liver for metabolism
- Some drugs will be metabolized before distribution to other tissues
- Drugs with high first-pass metabolism have less distribution
Define distribution of drugs
The transport of drugs from the plasma to the tissue (site of action, site of storage, site of metabolism, site of excretion)
What factors affect drug distribution related to the drug
- Plasma protein binding
2. Affinity for certain tissues
What factors affect drug distribution related to the animal
- Plasma protein binding
2. Tissue barriers
What proteins do acidic drugs bind to
mainly albumin
What proteins do basic drugs bind to
mainly to acid alpha-glycoproteins and glycoproteins
What drugs can bind to globulins
hormones, steroids
True or False - plasma protein binding is generally reversible
TRUE
True or False - Only free/unbound drug is biologically active?
TRUE
What is plasma half life
is a measure of how long the drug stays around in the blood stream.
T or F - the bound form of a drug is biologically active
False- the bound form is biologically INACTIVE
What can happen if drugs bind to the same site
- This can result in displacement of one of the rugs which will INCREASE the amount of free drug in circulation.
- This is one way in which a drug may cause potentiation of another drug and can lead to toxicity.
- Binding can be modified by disease
- Also varies between species
True or false - the rate of tissue perfusion relative to the mass of the tissue will affect distribution of drug to that tissue
TRUE
What are the factors that can alter blood flow
- Physiologic factors: Stress
- Drugs: Epinephrine (vasoconstriction) Acepromazine (vasodilation)
- Disease: Cirrhosis of the liver (reduced hepatic blood flow), Ischemia/blood clot, Renal failure (reduced kidney blood flow)
What parts of the body have unique barriers?
- Brain (BBB)
- Eye (blood-ocular or blood-aqueous barrier)
- Testicles
- Placental
- Mammary gland
- Prostate
- Synovial joints
What are the properties of the BBB
- Comprised of tight capillary endothelial junctions
- Further sealed off by glial cells
- active transport mechanisms for removal of organic acids or bases
- Constant flow of CSF into venous drainage (flushing)
Factors affecting the BBB
- Age: younger animals have greater drug movement across the BBB than other animals due to incomplete and developing BBB
- Physiological factors: Inflammation, allergic reactions, severe hypotension or hypoxia, organic solvents, heavy metals.
Define redistribution of drugs
the movement of drugs from the tissues back to the bloodstream, and sometimes to other tissues
What are the key points to remember for the redistribution of drugs
- Drugs don’t ONLY go to the intended site of action
- Drugs usually have to return to the blood stream to get to the liver/kidney for metabolism/excretion (this is a form of redistribution
Name an example of redistribution
-THIOPENTAL - an IV anesthetic induction drug and it is highly lipophilic. Goes to brain and adipose tissue. Due to its highly lipophilic properties some of the drug in the brain will redistribute to the adipose.
True or False- More highly lipophilic drugs will not distribute and redistribute more readily
False- they will distribute and redistribute more readily
How does Inflammation affect the BBB, give ex (Distribution pp, slide #15
ex- meningitis -> increased drug movement across the BBB due to increased permeability
How does anaphylaxis affect the BBB
It increases drug movement from distribution of tight tell junction
Why can tetracycline be an undesirable drug
it binds to calcium in skeletal tissues which can lead to bone changes or tooth discoloration
Define excretion of drugs
the removal or clearance of the drug from the body
What is the most important route of drug excretion
Renal (kidney)
Renal excretion is dependent on what 3 factors
- Glomerular filtration rate (GRF)
- Active tubular secretion
- Passive tubular reabsorption
What is the major factor that affects total renal excretion
Urine pH modifiers - enhance either excretion of weak acids or weak bases
What is the second most important organ for excretion of drugs
The LIVER
Drugs excreted in bile are either what
Unchanged or glucuronides
Does enterohepatic recirculation prolong the half-life of a drug?
Yes it does
What can you use to reduce enterohepatic recirculation of ingested toxins
Activated charcoal
what are two other routes of drug excretion
Feces and milk.
what route of drug excretion have higher amts of basic drugs being excreted due to ion trapping
Milk excretion
How will IV fluid therapy affect GFR
It will enhance tubular flow (reduce reabsorption so increase excretion)
T/F acidification of urine pH enhances renal excretion of weak basic drugs
True
What can you administer that will enhance excretion of a weak basic drug
Ammonium chloride
T/F alkalinization of the urine pH enhances renal excretion of weak acidic drugs
TRUE
What would you give a patient to increase urine pH?
Sodium bicarbonate
Define pharmacodynamics
The study of the effects of drugs and their mechanism of action in the body.
What does pharmacokinetics describe
What the animal does to the drug
What does pharmacodynamics describe
What the drug does to the animal
What effect will the drug have following admin?
- Targets for drug action
- Drug-receptor interactions
- Quantification of drug response
Targets for drug action have what two interactions
- Physical interaction
2. Biological interaction
What are the physical interactions - non-specific effects
- Osmotic diuretics
- Antacids that act by direct neutralization of acid in the GI tract
- Radioactive iodine (I-131)
What are the non-receptor interactions
- Enzymes: analogues that COMPETE with a real substrate for binding to the enzyme
- False substrates abnormal (often inactive) metabolites are produced
- Carrier proteins: require transport proteins
Describe receptor interactions
Specific recognition sites for endogenous chemical messengers
- > Ligand-gated ION CHANNELS(ionotropic receptors)
- > G-protein coupled (metabotropic receptors)
- > Kinase linked receptors
- > Nuclear receptors (transcription factor receptors)
What is Type 1: Ligand-gated ion channels (ionotropic)
- Groups of 4 or 5 proteins embedded in the cell membrane forming a pore
- Binding of drug allows/prevents ions such as Ca2+, Na+, K+ from passing through
What is Type 2: G-Protein Coupled (metabotropic)
- Also called 7TM (seven transmembrane) receptors
- Transduce an extracellular signal to intracellular one
What are examples of slow secretory and smooth muscle functions (seconds)
- Muscarinic Ach receptors
- Histamine receptors
Describe Gs protein receptor coupled pathway
- Couples to adenylate cyclase causing and increase in cAMP
- Increased cAMP activates kinase A which phosphorylates cellular constituents.
Describe Gi/o protein receptor coupled pathway
- Couples negatively to adenylate cyclase causing decrease in cAMP
- Increases outward K+ conductance and close Ca2+ and K+ channels
Describe Gq protein receptor coupled pathway
- Couples to phospholipase C-beta (PLC-beta)
- Increasing IP3 which increases Ca2+ release from SER
Define tolerance (under receptors slide 21)
Gradual decrease in responsiveness to a drug when given repeatedly over days to months
Define tachyphylaxis
Acute tolerance developing over a short period of time, sometimes involves depletion of stored mediator.
What are the four drug-receptor interactions
- Agonist
- Antagonist
- Inverse agonist
- Mixed agonist-antagonist
Define agonist
Mimics the effect of an endogenous ligand
-Affinity and efficacy
Define antagonist
Binds to the same receptor and prevents an agonist form
-Inhibits the effects of the receptor
Is competitive antagonism reversible
Yes= concentration-dependent binding
-Can compete for binding site with an agonist
Define reverse Agonist
Binds to the same receptor site and produces the opposite effect as agonist ex: beta-carboline
Explain mixed agonist-antagonist
- binds to > 1 receptor
- Acts as an agonist on one receptor and as an antagonist on other types of receptors.
- ex: butorphanol acts as an agonist at k opioid receptors and as an antagonist at u opioid receptors
Define efficacy
The maximal effect a drug can have (e=1 full)
-Partial agonist may never be able to achieve full efficacy (ceiling effect)
What is effective concentration (EC50)
- 50% of maximal response in vitro
- Relates to the concentration of the drug at the site
What is effective dose (ED50)
- Desired effect in 50% of the population
- Relates to the dose given to individuals and observed effect
- Toxic effect or dose that causes death (Lethal dose/LD50)
Define narrow therapeutic index
means that the dose required to cause death is close to the dose required to have a therapeutic effect
Define wide therapeutic index
means that the dose required to cause death is much higher than the dose required to have a therapeutic effect
T/F The larger the therapeutic index the wider the safety of the drug
TRUE
