Flashcards in Exam 1 Terminology Deck (174):
Factors Related to the Animal
4. Body Condition
8. Idiosyncratic drug reactions
Idiosyncratic drug reactions
Unpredictable abnormal reaction. Not dose-dependent and can occur on first exposure.
An acute form of tolerance, sometimes involves depletion of stored mediator
Factors Related to the Drug
1. Route of administration
2. Timing of administration
4. Drug-drug interactions
5. Pharmacokinetic effects
Drug A + Drug B = A + B
Two drugs have additive effects
Drug A + Drug B > A + B
Two drugs have greater efficacy when combined
Drug A + Drug B > A + B
One drug increases the availability or efficacy of another
Drug A + Drug B
The drugs chemically react to each other causing inactivation of one or the other drug (in vivo or vitro)
The drugs work differently and have opposing physiologic effects that cancel each other out
One drug reduces the concentration of the other drug at its site of action by interfering with its ADME processes
One drug binds to a receptor and prevents the other drug from having its normal activity at that receptor
Acidifying the urine ...
... increases excretion of weak bases
Alkalinizing the urine ...
... increases the excretion of weak acids
Factors related to the environment
1. Ambient temperature
5. Contact surfaces
Study of movement of drugs across biological membranes in the body from the time of absorption until elimination
Movement with a concentration gradient
Diffusion through intercellular aqueous channels. Specialized intercellular junctions.
Diffusion through lipid membranes and aqueous protein channels in the cell membrane
Lipid/water partition coefficient
The relative solubility of a drug in lipid as compared to water. The higher the lipid solubility, the faster it crosses cell membranes
A measure of the diffusional mobility of a particular molecule. Molecular size, molecular conformation, degree of ionization.
The pKa of a weak acid or base determines in what pH the substance will be ionized (unable to cross lipid membrane or non-ionized (mobile across lipid membrane)
pKa = pH
The drug is 50% ionized and 50% non-ionized
Acidic drugs are ...
... ionized in basic environments
Basic drugs are ...
... ionized in acidic environments
When a drug ionizes and then is unable to cross back over the membrane
Movement with a concentration gradient. No energy required. Movement can be from inside to outside the cell or other way around.
Facilitated diffusion. Transfer of substances across the membrane involves attachment to a specific macromolecular "carrier". May or may not be specific. The carrier system is saturable.
Facilitated diffusion. Transport across the membrane involves opening of ion channel proteins
Carrier-mediated transport. Saturable, selective. Movement against concentration gradient. It does require energy.
Primary active transport
Energy directly from ATP. Na+/K+ ATPase
Secondary active transport
Stored energy in the Na+ electrochemical gradient generated by using ATP
Secondary active transport, where two substances move together into a cell
Secondary active transport, where one substance is exchanged for another
P-glycoprotein (P-gp) system
Specific form of active transport in which the transporter is an efflux pump. This protein is an expression of the ABCB-1 gene (formerly called the MDR-1 gene) and will remove substances from specific cells.
A specific type of endocytosis. Drugs bind to the surface of the membrane that then invaginates and interiorizes the drug. It does require energy (ATP).
Weak acids are ...
... absorbed from an acidic environment and sequestered in an alkaline medium
Weak bases are ...
... absorbed from an alkaline environment and sequestered in the acid medium
Movement of the drug from the site of administration into the blood
Routes of administation
IV, IM, PO, SC, IP, Inhalation, dermal
Factors affecting absorption - related to the drug
1. Molecular size
2. Disintegration and dissolution
3. Lipid solubility
4. Degree of ionization
5. Concentration at the absorptive site
6. Route of administration
Factors affecting absorption
- related to the animal
1. Blood flow
2. Absorbing surface area
3. Connective tissue
5. Individual variation
6. Fasted vs. fed
Enteral (or alimentary)
Routes of administration typically given oral (PO), rectal or sublingual
Physical dispersion of a solid dosage from. Affected by exicpients, compaction pressure, enteric coatins, capsules, homegeneity
Drug molecules enter the solution. Solubility can be affected by particle size/surface area, binding, local pH, buffers, boundary layers.
DISSOLUTION IS OFTEN THE RATE LIMITING STEP CONTROLLING ABSORPTION!
Drug is intended to reach the blood stream. If a drug is not given IV then it must undergo absorption to get from the site of administration to the blood stream.
Transfer of drugs from the bloodstream to tissues around the body
Factors Affecting Distribution
1. Physicochemical properties of the drug
2. Concentration gradient between blood and tissue
3. Ratio of blood flow to tissue mass
4. Affinity of the drug for tissue constituents
5. Physiological determinants
6. Tissue barriers
7. Plasma protein binding
Of the drug itself will determine how much and how fast it will cross membranes
Of the body is fluid
When a drug is plasma protein bound it is considered to be ...
Acidic drugs typically bind to ...
Basic drugs typically bind to ...
B-globulins and glycoproteins.
The chemical alteration of the drug by different body tissues. (Also called biotransformation)
The process of making a drug inactive and easier to excrete
When a prodrug is converted to an active metabolite
inactive substance. Drugs needs to be metabolized into an active state before it can have its desired effect.
When an active drug is converted to an active metabolite, or a non-toxic substance can be converted to a toxic metabolite.
Cytochrome P450 (CYP450)
Attached to SER, also known as the mixed function oxidase system. A non-specific enzyme that catalyzes Phase 1 reactions in hepatocytes.
Phase 1 Reactions (Non-synthetic)
Involve the addition or loss of an electron, often can produce more reactive metabolites that then may have a phase II reaction. Such as oxidation, reduction, and hydrolysis.
Phase II (Synthetic)
A molecule (endogenous substance, parent drug, or metabolite) with a reaction group conjugates with a substituent group rendering a final metabolite that is typically inactive and water soluble (polar)
Is the most common reaction and is microsomal (the others are non-microsomal). Cats are deficient.
Factors Affecting Liver Metabolism
3. Individual variation
4. Route of administration
5. Plasma protein binding
6. Body temperature
7. Liver disease
Drugs that increase synthesis, decrease degradation, and/or activate pre-existing compounds. Only microsomal enzymes are induced. Can lead to tolerance or drug-drug interactions.
Ex: Phenobarbital, rifampin, and Kale
Drugs that inhibit the liver production or certain metabolic enzymes.
Ex: Chloramphenicol, cimetidine, ketoconazole, and Grapefruit Juice.
Removal of the drug (and metabolites) from the body
Is comprised of glomerular filtration, active tubular secretion, and tubular reabsorption. The combination of these processes is termed "total renal excretion" of a drug
This is a passive process that depends on systemic blood pressure and renal blood flow. Molecular size, charge and protein binding are factors that significantly affect a drugs likelihood of being filtered
Active tubular secretion
in the proximal convoluted tubule active secretion occurs. Drugs are moved against a concentration gradient, energy dependent, ionized drugs are moved, insensitive to protein binding, saturability and inhibition.
Organic Cation Transporters (OCTs)
Secretion of organic bases.
Endogenous: choline, dopamine
Drugs: Cimetidine, procainamide, nicotine
Organic Anion Transporters (OATs)
Secretion of organic acids
Endogenous: Uric acid
Drug: Penicillin, thiazide diuretics, loop diuretics
Passive diffusion occurs in the proximal and distal convoluted tubules. Lipid soluble, non-ionized drugs have the greatest chance of moving back into ciruclation
Acidification of urine
With ammonium chloride or methionine will cause weak basic drugs to be ionized and enhance their excretion
Alkalinization of urine
With sodium bicarbonate or potassium citrate will cause weak acids to be ionized and enhance their excretion
Factors Affecting Renal Excretion
1. Age of patient (lower in neonates)
2. Heart/Kidney/Liver disease
3. Urine pH
4. Drug factors
Typically an active transport of drugs and/or conjugates from the hepatic sinusoids to the bile canaliculi
Any drugs excreted in the bile and not reabsorbed will be eliminated in the feces. Drugs that are given orally but not absorbed will be excreted in the feces. Some drugs will move from plasma into the GIT and be excreted in the feces.
Excretion in milk/eggs
Concerned about drug residues. Concerned about route of administration (e.g. systemic vs intramammary), ion trapping (some weak basic drugs will be ion trapped in milk), witholding times for drug therapy, maximal allowable residue levels.
Using mathematical models to quantitate the time course of drug absorption and disposition in man and animals
The Rate of ADME
How fast the mass (dose) of a drug change per unit time (mg/min)
The Extent of ADME
How much the mass (dose) of a drug changes in total.
Dosage of Regimen
- Dosage and route of administration
- Frequency of administration
- Duration of administration
Amount of drug given to an individual (mg)
A "recipe" for how much to give (mg/kg)
a collection of tissues that have similar pharmacokinetics
One compartment model
Considers the body as consisting of a single homogenous compartment. Volume of compartment is the volume of distribution (Vd)
Two compartments. (1) Central compartment into which the drug is added and from which it is cleared. (2) a second compartment to which the drug is distributes.
Non-compartmental (stochastic) models
This is the primary method. Involve using statistical analysis of large numbers of actual animal data (time plasma concentration curves).
Mean Residue Time
Most useful non-compartmental model. Describes the length of drug persistence in the body.
When drug follows zero-order kinetics (such as when saturation has occurred - sometimes called dose dependent pharmacokinetics)
This system estimates pharmacokinetcs by looking at populations. Mathematical techniques allow studies of large numbers of animals with less individual sampling. This can allow for development of parameters for a drug that would apply to all breeds, ages, gender etc.
This uses pharmacokinetc data in multiple species to try to predict the behavior of a drug in a species for which this information is unknown (scaling based on size and metabolism)
Area under the curve
A measure of drug exposure
The fraction of the given dose which finds it way into the systemic circulation
Different formations of the same drug are bioequivalent when they are absorbed to a similar extent and similar rate.
When the AUC, Cmax and Tmax are similar.
Half Life (t1/2)
The time required for the plasma drug concentration to decrease by one-half (or 50%)
The AMOUNT of drug eliminated per unit time is fixed, regardless of plasma concentration. Half life will be different depending on the starting amount.
The PROPORTION of drug eliminated per unit time is fixed. The rate of elimination changes at a constant rate.
Commonly used values as for most clinical purposes 97% of the drug being gone means it is essentially eliminated.
(Apparent) Volume of Distribution
The volume of a drug would occupy if it was evenly distributed at the same concentration as in plasma (L/kg)
Volume cleared of the drug per unit time (mL/min/kg)
A very low Vd
Suggests that the drug is not being distributed to all of the tissues. Remain mostly in the plasma.
A very high Vd (> 1 L/kg)
suggests that the drug is distributing preferentially to tissue and may even be sequestered somewhere. Somewhere outside of the blood stream.
Total Body Clearance (CLb)
The volume of distribution of drug in the body cleared of the drug per unit time (mL/min/kg). Takes into account both metabolism and excretion.
As Vd increases
t1/2 gets longer
As Vd decreases
t1/2 gets shorter
As CLb increases
t1/2 gets shorter
As CLb decreases
t1/2 gets longer
Plasma Concentration at Steady State (Cpss)
the concentration at which the amount of drug going in (repeated dosing or CRI) is equal to the amount going out (clearnace CLb)
the effects of drugs and their mechanisms of action within the body. What the drug does to the animal
What we want to see the drug perform
Which are secondary to the intended effect and may be good or bad
Which are unintended and unwanted, thick includes NOT producing a desired clinical effect. The study of monitoring of adverse effects is called pharmacovigilance.
Responses to a drug that are harmful to the health or life of the animal
Targets for drug action
Can be physical interaction or biological interaction
Are considered non-specific effects such as:
1. osmotic diuretics
3. radioactive iodine
these molecules move through the body dragging water with them by osmosis until they are excreted.
Direct neutralizers; given orally they directly interact with acid in the GIT. A form of physiologic antagonism
Iodine is actively concentrated in the thyroid and the radiation will destroy all tissue within 2-3 mm causing focal, controlled destruction.
Biological Interaction: Non-receptor - Ion Channels
Blocking of ion channels can occur by the drug molecules physically obstructing the channel to impair ion movement. The drug may also modulate the opening and/or closing of the channel.
Biological Interaction: Non-receptor - Enzymes
Drugs can be analogs that compete with the real substrate for binding to the enzyme and thus blocking the enzyme from doing its job.
Drugs can also be false substrates which will interact with the enzyme and lead to the formation of abnormal metabolites.
Biological Interaction: Non-receptor - Carrier Proteins
Some small polar molecules cannot cross cell membranes and get carried in and out by carrier proteins. Drugs may alter this movement either preventing re-uptake of a molecule which increases its level in the synapse or preventing output of a molecule to decrease its levels.
Biological Interaction: Receptors (signal transductions)
Specific recognition sites for (a ligand) endogenous chemical messengers. Can be:
1. Ligand gated ion channels
2. G-protein coupled
3. Kinase linked receptors
4. Nuclear receptors
Ligand-gated ion channels
Ionotropic receptors. Groups of proteins embedded in the cell membrane forming a pore. Something had to bind to the receptor to cause a change in shape or 'opening' of a channel that allows a large influx of ions.
drugs can bind to these to active them (agonist) or prevent them from opening (antagonist)
GTP-binding Protein (G-protein) coupled receptors
Also known as 7TM for crossing the membrane back and forth seven times. Transduce an extracellular signal to an intracellular one. These are common receptor types for secretory and smooth muscle functions.
Responses can be either excitatory OR inhibitory, depending on the subtype of the receptor.
G-protein subtype: couples to adenylyl cyclase which increases formation of cAMP, which activates protein kinase A, which phosphorylates cellular constituents.
G-protein subtype: couples negatively to adenylyl cyclase, so decreases cAMP formation. It can also close ion channels.
G-protein subtype: couples to phospholipase CB (CBeta) which alters regulation of intracellular calcium and phosphorylation
Direct activation of enzymes. Extracellular receptor, protein has an intracellular portion with enzymatic activity (kinase domain). Phosphorylation and activation of proteins which then activates effectors.
Intracellular; AKA Transcription factor receptors. Receptors are actually located in the cytoplasm but after the ligand binds the receptor they translocate to the nucleus of the cell and bind to a response element within the DNA to initiate specific gene transcription.
Endogenous neurotransmitter often bind to more than one type of receptor. Ex: Adrenergic receptors (alpha & beta) - same signaling molecule can then cause different effects or have different affinity in different tissues or species.
Increase in the number of receptors, resulting in an increase in the effect of the drug
Receptor Down Regulation
Decrease in the number of receptors an therefore a reduction in effect
Gradual decrease in responsiveness to a drug when given repeatedly over days to months
Anything that binds to a recognition site
Mimics the effect of an endogenous ligand
Binds to the receptor to elicit a maximal response
Will bind to the receptor but not cause as much effect as a full agonist, it does prevent anything else from binding to the receptor while it is "docked" there. Lower efficacy.
When the ligand has exerted its maximal effect - that point will generally be at a lower level of efficacy for a partial agonist compared to a full agonist.
Reverse (inverse) agonist)
Will bind to the receptor and cause the opposite effect as the endogenous ligand would
Or neutral agonist. Binds to the receptor but (in theory) does nothing on its own, however it prevents an agonist from binding and thus blocks effect of the receptor.
when the antagonist binds to the same receptor as the ligand, usually a transient bond, and so if both antagonist and agonist are present they will "compete" for the binding.
adding more agonist cannot reduce the effect of antagonism. Usually from an irreversible bond. Or antagonist is binding somewhere other than the receptor site to alter the binding of normal ligand at the receptor.
Acts as an agonist at one type of receptor and as an antagonist on another type
1. Chemical antagonism
2. Pharmacokinetic antagonism
3. Physiological antagonism
two drugs directly interact and chemically inactivate each other
A drug alters ADME of another drug and reduces its effect
Drugs have opposite effects that cancel each other out, but work through different receptors or pathways
Quantification of Drug Response: Efficacy
The maximal effect a drug can have (e=1 is a full effect). A partial agonist may never be able to achieve full efficacy (ceiling effect)
Quantification of Drug Response: Potency
A comparison of the concentration of two drugs needed to induce the same magnitude effect. A partial agonist could be more potent.
Quantification of Drug Response: Slope
Linear in the ~20-80% range
Maximal effect (ceiling)
Point at which increasing concentration does not yield greater response
Effective Concentration 50% (EC50)
This is the concentration at which a drug produces 50% of its maximal effect. Only applies in vitro.
Effective Dose 50% (ED50)
Dose that produces a result (usually the desired effect) in 50% of animals. Typically in vivo.
The therapeutic index is the ratio of LD50 to ED50
A ratio used to evaluate the safety of a drug
Narrow Therapeutic Index
(small number, close to 1) means that the dose required to cause death is close to the dose required to have a therapeutic effect
Wide Therapeutic Index
(often many time higher) means that the dose required to cause death is much higher than the dose required to have a therapeutic effect
Standard Safety Margin
is a more conservative measure. It looks at the dose required to produce a therapeutic effect in ALL animals relative to the dose required to produce a hazardous effect.
Quantification of Drug Response: Onset of action
the time required after drug administration for a response to be observed. Also called latent period
Quantification of Drug Response: Duration of action
the length of time that a drug is effective (from onset of action until termination of action)
A specific formulation of an active substance(s) and has a claim for efficacy and safety at a certain dose
Includes active ingredients as well as excipients, substances the impact ADME, flavors, etc.
At X dose the produce is effective for Y disease.
Why is a veterinary drug different from a list of active ingredients?
A veterinary drug contains active ingredients in a specific formulation as well as excipients that would not be included in a list of active ingredients.
Must be safe and effective for intended use. Must be manufactured, processed, packaged to maintain drug quality and efficacy. Must be registered with USDA.
Product must be safe for its intended use. Product must be safe for target animal it will be used in. FDA and product registration holder negotiate wording on label and leaflet.
Specific quantity of medication per kg.
Quantity of medication for a range of body weights.
Max safe dose