Week 1 Pharmacodynamics and pharmacokinetic Flashcards
Pharmacodynamics
Pharmacodynamics
Defined as “ The actions of a drug on the body”
“What does the drug do to the body? ”
Describes a drug’s molecular, biochemical, and physiologic effects or actions occurring by binding to specialized target macromolecules (receptors) on or in the cell.
Drug-receptor complex
Starts biological molecular activities by signal transduction
Magnitude of cellular response: proportional to the number of drug-receptor complex
More drug binding to receptor more physiological receptor
Transmembrane ligand-gated(subtance/drug-gated) Ion Channels
Regulates cellular access of soluble ions (Na++, K+)
Ligand-binding area is on the cell membrane
Key feature: downregulation of receptors
Receptors may be internalized within the cell, making them unavailable for further agonist interaction ability to hide within the cell, leading to no more binding in the cell
G-Protein-Coupled Receptors
Generate intracellular second messengers to initiate cellular cascade for intracellular effect.
Has ability to amplify signal intensity and duration
Example: Alpha- and beta- adrenergic receptors; hormone receptors
When hormone or drug bind the receptor, it changes the receptor shape, leading it to interaction to G protein (GTP to GDP), alpha and other attaches itself to acti adenyly cyclase
Enzyme-linked Receptor(insulin receptor or growth factor receptor)
Increase intracellular enzyme activity (tyrosine kinase) -> ^ autophosphorylation
Last for minutes to hrs
Has ability to amplify signal intensity and duration
Ex: Growth factor and insulin receptor
Intracellular receptors
Cytoplasmic receptors,
Respond to lipid soluble ligand molecules
Drug attaches to receptor -> Moves into nucleus -> initiates DNA transcription -> mRNA -> specific proteins -> biologic effects
The effect of drugs or endogenous ligands that activate intracellular receptors takes hours to days to occur.
Ex: steroid and thyroid hormones
Initial small signal gets amplified in the signal pathways (Signal Cascade Effect)
Need only a fraction of the total receptors for a specific ligand to be occupied to elicit a maximal response.
Some receptors are “spare”
About 99% of insulin receptors are “spare,”
Provides an immense functional reserve that ensures that adequate amounts of glucose enter the cell.
Only about 5% to 10% of the total β-adrenoceptors in the heart are spare.
Little functional reserve exists in the failing heart, because most receptors must be occupied to obtain maximum contractility.
Down regulation
Reduced synthesis of new receptors
Usually happens with repeated exposure to an agonist
Sequestration or Internalization
Sequestration or Internalization
Degradation of preexisting receptors through endocytosis
Usually happens with repeated exposure to agonist
Up-regulation of receptors
Receptor reserves are inserted into the membrane, increasing the number of receptors available.
Usually happens with repeated exposure of a receptor to an antagonist
Can make cells more sensitive to agonists and/or more resistant to effects of the antagonist.
Desensitization or Tachyphylaxis
A rapid decrease in response (effects of medication) to chronic, repeated exposure to agonist over a short time period , (Could occur at the initial dose)
Etiologies
Downregulation or sequestration of receptors
Exhaustion of secondary messengers
^ metabolic degradation of the medications
Tolerance
A slow decrease in response to chronic, repeated exposure to agonist
Seen in chronic opioid users: Target receptors are reduced -> higher dose is needed to have same benefit
Potency
requires less amount to produce therapeutic effect
A measure of the amount of drug necessary to produce a given effect.
Indicated as half maximal effective concentration (EC50)
The concentration of drug producing 50% of the maximum effect
Efficacy
The magnitude of response when a drug interacts with a receptor
Dependent on the number of drug–receptor complexes and the intrinsic activity of the drug
The relative ability of agonist to fully or partially activate receptors
Maximal efficacy of a drug (Emax)
Occurs when the drug occupies all receptors (generally meds have a maximum dose because after taking a certain amount, it is found that no matter how much more you take will not increase the efficacy of the drug)
No increase in response to higher concentrations of drug
Intrinsic activity of drugs
A measure of the ability of a drug in producing a change in cellular activity when it binds to the receptors
Determines its ability to fully or partially activate the receptors.
Drugs may be categorized according to their intrinsic activity and resulting Emax values
Affinity
A measure of the tightness with which a drug binds to the receptor
Higher affinity -> Higher potency
Ligands
: endogenous hormones or neurotransmitters (ex: adrenalines: norepinephrine, epinephrine)
Bind to the specific receptors that results in physiological response
synthetic ligands
Drugs: synthetic ligands (i.e thyroid meds, bind to thyroid sites)
Receptors:
Protein molecules
Located on the organs of our body ( inside the cell or on its membrane)
Bind to specific ligands: Causes physiological responses in our body
Full Agonists
Produce a maximal biologic response(Same Emax) that mimics the response to the endogenous ligand that is supposed to bind to the receptor
Eg:
Phenylephrine is a full agonist at α1-adrenoceptors
Produces the same Emax as the endogenous ligand, norepinephrine
Partial Agonists
Cannot produce the same Emax as a full agonist even when all the receptors are occupied
May function as antagonist when given with full agonist
Compete for receptors with full agonist
Emax of a full agonist would decrease until it reached the Emax of the partial agonist.
Competitive reversible Antagonist
Characteristic shift of the agonist dose–response curve to the right (increased EC50 ) without affecting Emax
Eg: Terazosin (compete with natural neurotransmitter , epinephrine at α1-adrenoceptors)
Requires more epinephrine given to get the same result when given with terazosin since terazosin also competes to binding site (competitive reversib le antagonist - but removable when have enough agonist)
Competitive Irreversible Antagonist
Competes for the same sites of the receptors with agonist
Binding is not reversible
Permanently reduce the number of receptors available to the agonist
Causes a downward shift of the Emax, with no change EC50 values
Addition of more agonist does not overcome the effect of irreversible antagonists.
Competitive irreversible antagonist will not come off of the recetpro
Allosteric (Noncompetitive) antagonist
Binds to a site (allosteric site) other than the agonist-binding site and prevents receptor activation by agonist
Irreversible binding
Causes a downward shift of the Emax of an agonist, with no change in the EC50 value.
Competitive reversible antagonists reduce agonist potency (increase EC50)
Competitive irreversible antagonist and noncompetitive antagonists (allosteric antagonist) reduce agonist efficacy (decrease Emax).
Effective Dose (ED 50)
Effective Dose (ED 50):the dose of a drug that produces, on average, a specified all-or-none response in 50% of a test population
Toxic Dose (TD50):t
Toxic Dose (TD50):the dose required to produce a particular toxic effect in 50% of a test population
Lethal Dose (LD 50):
Lethal Dose (LD 50): the dose required to kill 50% of a test subject population
Therapeutic Index
Therapeutic Index
Determined using drug trials and accumulated clinical experience
Reveal a range of effective doses and a different (sometimes overlapping) range of toxic doses
High TI values are required for most drugs
Some drugs with low therapeutic indices are routinely used to treat serious diseases
When the risk of experiencing adverse effects is not as great as the risk of leaving the disease untreated
First pass effect
phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemic circulation. It is the fraction of drug lost during the process of absorption which is generally related to the liver and gut wall
What is Pharmacokinetics?
What the body does to the drug?
Absorption: how the drug gets into the body
Distribution: where the drug goes to in the body
Metabolism: how the body chemically modifies the drug
Excretion: how the body gets rid of the drug
Absorption
Site: gut to plasma
bio availability
factors: drug characterisitcs, blood flow, cell membrane
Distribution
sites: plasma to tissue volume of distribution phases: 1) blood flow from site of adminstration 2) delivery of drug into tissues at site of drug actiob
Biotransformation (Metabolism)
Site: liver
enzyme inhibition/induction
first pass effect
phase1: oxydation cytochrome P450
phase2: glucuronidation
Elimination
Site: kidney
clearance, halflife, steady state, linear/nonlinear kinetics
4 ways of Absorption from GI tract
Passive Transport:
Passive diffusion,
Facilitated diffusion
Active Transport: requires energy
Endocytosis: large molecule transport
Strong acid or base
Completely dissociate in water Completely polarized (Ionized or charged) in water
Weak acid or base
Partially dissociate in water Partially polarized (Ionized or charged)) in water
Passive diffusion
No energy expenditure by cell
Movement through the concentration gradient: move from high concentration to low concentration
Ficks Law: “The greater the distance and the larger the molecule, the slower the diffusion rate”
Majority of drugs are absorbed by passive diffusion
Facilitated Diffusion
Movement through the concentration gradient
Does not require energy
Process that uses drug transporter protein
Facilitate the passage of large molecules
Drug transporters undergo conformational changes
Allow the passage of drugs or endogenous molecules into inside of cells.
Can be saturated
May be inhibited by compounds that compete for the drug transporter (transporter in use, unable to transport others)
Active Transport
Protein molecules act as transporters across cell membrane
Large molecules can enter the cells via this process
Molecule from lower concentration to high concentration, uses ATP - energy to bring large molecules into high concentration area
Selective permeability of cell membrane: Ability to differentiate between different types of molecules
Requires energy expenditure
Absorption_Endocytosis
Used to transport drugs of exceptionally large molecular size
Involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug-filled vesicle.
Vitamin B12 is transported across the gut wall by endocytosis
Factors Affecting Absorption
pH of the environment where drug is in
Blood flow to the absorption site
Expression of P-glycoprotein (Drug transporter molecules)\
Total surface area available for absorption
Contact time at the absorption surface
pH of the environment where drug is in
Blood flow to the absorption site
Expression of P-glycoprotein
Total surface area available for absorption
Contact time at the absorption surface
Pharmacokinetic vs Pharmacodynamics
Pharmacokinetic interactions
ADME properties of the drug is altered by the precipitants
Pharmacodynamic Interactions
The activity of the object drugs at its side of action is altered by the precipitant
Distribution
Altered distribution pattern of the drug by affecting the protein-binding capacity of the drug (Object drug)
Precipitant drug may displace the drug (Object drug) from it’s binding site
Increases the amount of free, circulating drug
May lead to toxicity
Usually transient because free drug is subject to metabolism
Clinically significant drug displacement interactions occur when:
Drugs are > 90% protein bound and
Narrow therapeutic index
Excretion
Acidification or alkalinization of urine
Urine pH determines the ionization state of the excreted molecule
Ionized molecules become trapped in urine and are excreted
Weak acidic medication is combined with alkaline urine in kidney, like weak basic medication is combined with acidic urine in kidney, ionized molecule become trapped and unable to reutn back to the bloodstream/become reabsorbed
How does high fat food affect drug absorption?
Increase absoprption rate of lipophilic drugs
How does diary product affect drug absorption?
bioavalibility of tetracyclin and fluoroquinolone antibodies
How does orange, tomato, grapefruit juice: alkaline urine affect drug absorption?
bioavalibilty of weak base drugs P450 interaction with grapefruit juices
How does Rich in Vit K affect drug absorption?
opposte the anti coagulartory efficacy of warfarin
How does rich in tyramine affect drug absorption?
what food is rich in tyramine?
(aged cheese, dry type summer sausage, pepperoni, salami)
precipitate a hypertensive crisis in patient with MAO inhibitors
MAOI increase breakdown and absorption of tyramine
How does acacia- fiber suppliement affect drug absorption?
slows or reduce absoprtion of amoxicillin
doses should be separated by 4 hours
How does St. John’s wort affect drugs?
induces CYP3A4, 2E1, 2C19
clinically signifi ant interaction with immunosupressant, hypoglucemics, anti inflammatory agents, antimicrobial agents, anti migraine medication, oral contraceptives, cardiovascular agents, antivirtals, CNS, GI, respiraotry agents,
GI transit time (GI Motility) delayed by
High fat meals
Solid foods: The presence of food in the stomach both dilutes the drug and slows gastric emptying. Therefore, a drug taken with a meal is generally absorbed more slowly
Diarrhea : Drug moves through the GI tract very fast. Lower absorption
Bioavailability:
The % of the drug that reaches the systemic circulation
Depends upon the route of administration and ability to pass through membranes or barriers in the body
IV = 100% bioavailability
PO = Variable
calculated based on AUC
Area Under Curve(AUC):Represents the total exposure to a drug that the body receives.
First pass metabolism ( First pass effect)
A phenomenon in which a drug gets metabolized at a specific location in the body
Results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation.
Affects efficacy of the drug, may require higher dose?
Often associated with the liver, as this is a major site of drug metabolism.
Also occur in the lungs, vasculature, gastrointestinal tract, and other metabolically active tissues in the body
Crucial to the proper administration and maintenance of pharmacological therapy.
Factors Affecting Bioavailability
First-Pass metabolism
Solubility of the drugs
Chemical instability transportation
Nature of the drug formulation
For a drug to be readily absorbed, it needs to be what?
Very hydrophilic drugs: Poorly absorbed because of the inability to cross lipid-rich cell membranes.
Extremely lipophilic drugs: Poorly absorbed, because they are insoluble in aqueous body fluids
For a drug to be readily absorbed
Must be largely lipophilic
Yet have some solubility in aqueous solutions.
This is one reason why many drugs are either weak acids or weak bases.
Expression of P-glycoprotein
Transmembrane drug transporter protein:
Function as efflux pump, pumping its substrates from inside to outside the cell.
Affects the plasma and tissue concentrations of the drugs and ultimately the final effects.
Known as multidrug resistance protein 1 (encoded by MDR1)
High expression of this protein pump reduces absorption
Stomach and Duodenum have what kind of pH
acidic pH
Weak acid drug with more non-ionization
Become more nonionized when pH is decrease
Better absorption
Due to thick mucus in the stomach, poor absorption even if weak acid meds
Ileum’s pH is
: Alkaline pH
Weak base drug becomes more nonionized
Absorption
: how the drug gets into the body
Distribution
: where the drug goes to in the body
Metabolism
: how the body chemically modifies the drug
Excretion
: how the body gets rid of the drug
What are the two phases of biotransformation and what do they do
Phase 1: Oxidation, hydrosis or reduction
Drug changed to form a more polar or water-soluble compound
Involves Cytochrome P450 (CYP) system
Phase 2: Conjugation (Glucuronidation)
Adds a conjugate (glucuronide and others) to the parent drug or phase 1 metabolized drug to increase water- solubility and enhance excretion.
What is Phase 1 of biotransformation in the liver?
Oxidation, hydrosis or reduction
Drug changed to form a more polar or water-soluble compound
Involves Cytochrome P450 (CYP) system
What is Phase 2 of biotransformation in the liver?
Conjugation (Glucuronidation)
Adds a conjugate (glucuronide and others) to the parent drug or phase 1 metabolized drug to increase water- solubility and enhance excretion.
Cytochrome P 450 (CYP ) enzymes in Phase I
A protein superfamily of heme-containing isoenzymes located in most cells.
Primarily in the liver and GI tract- where its converted into forms that can be excreted
Considerable genetic variability
Poor metabolizer vs rapid metabolizer
May alter drug efficacy and the risk of side effects
What are the three types of P450 enzymes
substrate, inducer, or inhibitor
What is a substrate
Drugs utilize CYP enzymes for normal metabolization
Drugs are metabolized by using the enzyme
There may be some inducer to increase the process of the enzyme activity, but CYP2D6 doesnt have inducer
What is a Inducer?
- increase elimination of
Drugs that stimulates the production of enzyme available to metabolize certain drugs
Will increase metabolism of certain drugs
Could result in less efficacy of certain drugs
Ex: Rifampin (Inducer) for HIV protease inhibitor
Enzyme induction and inhibition are the basis of metabolically-mediated drug-drug interactions
If takes drugs that are inducers the drug that is taken will be excreted out faster
It taken 2 drugs, a common substrate and a inducer, the dosage may need to be increased to provide the same effect
What is a Inhibitor
- slow down elimination of
Drugs that inhibit the production of an enzyme and thereby decreases the metabolism of certain drugs.
Will slow down elimination of certain drugs
Could result in increased concentration of certain drugs
Could result in adverse effects of certain drugs
Ex: Omeprazole (Inhibitor) for Warfarin
Polymorphism
: The presence of genetic variances in single gene that result in the different phenotypes.
What is biotransformation?
(drug metabolism) - usually happens in liver, its elimination of drug
Necessary steps for change of drugs into water-soluble forms to be easily excreted.
Active form of drug to inactive form through metabolism to be excreted by kidney or in bile.
The kidney cannot efficiently excrete lipophilic drugs - usually passes the cell membrane of kidneys very well leading to reabsoprtion in distal convulented tubules
Waterphilic gets excreted faster
Primarily occurs in the liver: Phase I and II Reaction
what is Pharmacogenomics
Relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions)
The study of how genes affect a person’s response to drugs
To develop effective, safe medications and doses that will be tailored to a person’s genetic makeup
What are 3 factors that affects Distribution
Cardiac output/local blood flow to the area of action
Capillary permeability- how well the medication can go through capillary tells ho far the medication can go through tissue
Degree of binding of the drug to plasma proteins or tissue proteins
What are the 3 Plasma proteins:
Albumin, Globulin, Fibrinogen
What does Albumin do?
The most abundant / Made by the liver
Transport vehicles for fatty acids and steroid hormones (Binding protein)
Bind to various substances
The most significant contributor to the osmotic pressure of blood
Holds water inside blood vessle, and draw the volume from outside the wall into the wall
What does Globulin do?
The gamma globulins
Involved in immunity
Known as an antibodies or immunoglobulins.
Alpha, beta globulins :
Transport iron, lipids, and the fat-soluble vitamins A, D, E, and K to the cells
Contribute to osmotic pressure
What is Fibrinogen?
Essential for blood clotting
What is Volume of Distribution (Vd)?
Hypothetical volume
Defined as the fluid volume that is required to contain entire drug in the body at the same concentration measured in the plasma
Reflects the extent to which the drug is present in extravascular tissues but not in plasma.
Vd = dose / plasma concentration
It can be expressed as liters or indexed to body mass in L/kg.
What does a drug with high Vd mean?
Leave the plasma and enter the extravascular compartments of the body
High Vd -> More distribution to other tissue
A higher dose of a drug is required to achieve a given plasma concentration.
What does a drug with low Vd mean?
Remains in the plasma
(Low Vd -> Less distribution to other tissue)
A lower dose of a drug is required to achieve a given plasma concentration.
What are the effect of Vd on drug half life?
A drug with a high Vd
Most of drugs in the extra-plasma space ->Not readily available for elimination.
So it takes longer time to be eliminated -> Half-life is longer
What is Cmax?
: The highest drug concentration in the body
What is tmax?
: Time at which the highest concentration occurs
What is T1/2 (Half Life) ?
T1/2 (Half Life) : Time taken to remove the half of the current concentration of the drug from the body
What is AUC: (Area Under the Curve)?
Represents the total exposure to a drug that the body receives. AUC shows how high the concentration [C] of the drug gets, as well as how quickly it is excreted
Between lipophilic drugs and waterphili drugs, which gets excreted faster via kidney?
waterphilic
Elimination can happen which 2 ways?
By excretion of an unmetabolized drug in its intact form by kidney
or
By metabolic biotransformation followed by excretion
What organs take part in excretion?
By several organs: Kidneys, GI tract (feces and biles), lungs, skin, mammary glands, sweat glands, salivary glands.
What are the steps to renal excretion?
Glomerular filtration
Proximal tubular secretion - water soluble medication gets excreted with energy, non polarized, lipid soluble drugs goes via passive diffusion
Distal tubular reabsorption - most of the nonpolizated will get back into capillary nephron
At the end, excretion have the ionized, lipid insoluble drug into urine (water soluable)
What is Total Clearance (CL total )?
Represents the capacity for drug elimination by various organs
The volume of plasma cleared of a medication per unit of time (ml/min or L/hr)
defined as the volume of plasma cleared of a drug over a specified time period
Drug’s half life is used as a measure of drug clearance
Elimination kinetics play an essential role in drug clearance.
What is First - order kinetics (linear kinetics) (exponential decrease)
Most drugs gets eliminated through this kinetics
A constant proportion of drug (%) is eliminated per unit of time
Absolute amount of drug eliminated is different
Rate of elimination is directly proportional to the concentration of drug
As the concentration of the drug drops, the rate of elimination of the drug will drop
What is Zero-order (Non-linear elimination ) kinetics ?
Rate of drug elimination is independent of the concentration of the drugs
Absolute amount of drugs eliminated is the same per unit of time but not a proportion of drug.
Phenytoin or ethanol or warfarin, aspirin
Half-life ( T½)
Time required for the drug concentration to be reduced by 50 %
Useful for estimating excretion rates and steady-state concentrations for any specific drug
Clinically relevant when determining the most efficient yet safest dosing schedule to achieve an optimal therapeutic effect
The clinical significance of half-life tends to arise in situations involving drug toxicity.
Renal impairment
Hepatic impairment
What is a Steady-state concentration (Css)
A dynamic equilibrium in which drug concentrations consistently stay within therapeutic limits for long periods.
Rate of elimination = rate of administration
Occurs when the amount of a drug being absorbed is the same amount that’s being cleared from the body when the drug is given continuously or repeatedly.
Reaching a steady-state concentration is generally necessary for efficacy of drugs
What is a drug’s half life used to measure?
Drug’s half life is used as a measure of drug clearance
