Week 1 Pharmacodynamics and pharmacokinetic

Question 1

Pharmacodynamics

Answer 1

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.

Question 2

Drug-receptor complex

Answer 2

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

Question 3

Transmembrane ligand-gated(subtance/drug-gated) Ion Channels

Answer 3

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

Question 4

G-Protein-Coupled Receptors

Answer 4

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

Question 5

Enzyme-linked Receptor(insulin receptor or growth factor receptor)

Answer 5

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

Question 6

Intracellular receptors

Answer 6

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

Question 7

Initial small signal gets amplified in the signal pathways (Signal Cascade Effect)

Answer 7

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.

Question 8

Down regulation

Answer 8

Reduced synthesis of new receptors

Usually happens with repeated exposure to an agonist

Question 9

Sequestration or Internalization

Answer 9

Sequestration or Internalization
Degradation of preexisting receptors through endocytosis
Usually happens with repeated exposure to agonist

Question 10

Up-regulation of receptors

Answer 10

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.

Question 11

Desensitization or Tachyphylaxis

Answer 11

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

Question 12

Tolerance

Answer 12

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

Question 13

Potency

Answer 13

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

Question 14

Efficacy

Answer 14

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

Question 15

Maximal efficacy of a drug (Emax)

Answer 15

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

Question 16

Intrinsic activity of drugs

Answer 16

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

Question 17

Affinity

Answer 17

A measure of the tightness with which a drug binds to the receptor
Higher affinity -> Higher potency

Question 18

Ligands

Answer 18

: endogenous hormones or neurotransmitters (ex: adrenalines: norepinephrine, epinephrine)
Bind to the specific receptors that results in physiological response

Question 19

synthetic ligands

Answer 19

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

Question 20

Full Agonists

Answer 20

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

Question 21

Partial Agonists

Answer 21

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.

Question 22

Competitive reversible Antagonist

Answer 22

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)

Question 23

Competitive Irreversible Antagonist

Answer 23

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

Question 24

Allosteric (Noncompetitive) antagonist

Answer 24

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).

Question 25

Effective Dose (ED 50)

Answer 25

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

Question 26

Toxic Dose (TD50):t

Answer 26

Toxic Dose (TD50):the dose required to produce a particular toxic effect in 50% of a test population

Question 27

Lethal Dose (LD 50):

Answer 27

Lethal Dose (LD 50): the dose required to kill 50% of a test subject population

Question 28

Therapeutic Index

Answer 28

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

Question 29

First pass effect

Answer 29

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

Question 30

What is Pharmacokinetics?

Answer 30

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

Question 31

Absorption

Answer 31

Site: gut to plasma bio availability factors: drug characterisitcs, blood flow, cell membrane

Question 32

Distribution

Answer 32

``` 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 ```

Question 33

Biotransformation (Metabolism)

Answer 33

Site: liver enzyme inhibition/induction first pass effect phase1: oxydation cytochrome P450 phase2: glucuronidation

Question 34

Elimination

Answer 34

Site: kidney | clearance, halflife, steady state, linear/nonlinear kinetics

Question 35

4 ways of Absorption from GI tract

Answer 35

Passive Transport: Passive diffusion, Facilitated diffusion Active Transport: requires energy Endocytosis: large molecule transport

Question 36

Strong acid or base

Answer 36

``` Completely dissociate in water Completely polarized (Ionized or charged) in water ```

Question 37

Weak acid or base

Answer 37

``` Partially dissociate in water Partially polarized (Ionized or charged)) in water ```

Question 38

Passive diffusion

Answer 38

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

Question 39

Facilitated Diffusion

Answer 39

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)

Question 40

Active Transport

Answer 40

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

Question 41

Absorption_Endocytosis

Answer 41

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

Question 42

Factors Affecting Absorption

Answer 42

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

Question 43

Pharmacokinetic vs Pharmacodynamics

Answer 43

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

Question 44

Distribution

Answer 44

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

Question 45

Excretion

Answer 45

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

Question 46

How does high fat food affect drug absorption?

Answer 46

Increase absoprption rate of lipophilic drugs

Question 47

How does diary product affect drug absorption?

Answer 47

bioavalibility of tetracyclin and fluoroquinolone antibodies

Question 48

How does orange, tomato, grapefruit juice: alkaline urine affect drug absorption?

Answer 48

bioavalibilty of weak base drugs P450 interaction with grapefruit juices

Question 49

How does Rich in Vit K affect drug absorption?

Answer 49

opposte the anti coagulartory efficacy of warfarin

Question 50

How does rich in tyramine affect drug absorption? | what food is rich in tyramine?

Answer 50

(aged cheese, dry type summer sausage, pepperoni, salami) precipitate a hypertensive crisis in patient with MAO inhibitors MAOI increase breakdown and absorption of tyramine

Question 51

How does acacia- fiber suppliement affect drug absorption?

Answer 51

slows or reduce absoprtion of amoxicillin | doses should be separated by 4 hours

Question 52

How does St. John's wort affect drugs?

Answer 52

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,

Question 53

GI transit time (GI Motility) delayed by

Answer 53

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

Question 54

Bioavailability:

Answer 54

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.

Question 55

First pass metabolism ( First pass effect)

Answer 55

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.

Question 56

Factors Affecting Bioavailability

Answer 56

First-Pass metabolism Solubility of the drugs Chemical instability transportation Nature of the drug formulation

Question 57

For a drug to be readily absorbed, it needs to be what?

Answer 57

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.

Question 58

Expression of P-glycoprotein | Transmembrane drug transporter protein:

Answer 58

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

Question 59

Stomach and Duodenum have what kind of pH

Answer 59

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

Question 60

Ileum's pH is

Answer 60

: Alkaline pH | Weak base drug becomes more nonionized

Question 61

Absorption

Answer 61

: how the drug gets into the body

Question 62

Distribution

Answer 62

: where the drug goes to in the body

Question 63

Metabolism

Answer 63

: how the body chemically modifies the drug

Question 64

Excretion

Answer 64

: how the body gets rid of the drug

Question 65

What are the two phases of biotransformation and what do they do

Answer 65

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.

Question 66

What is Phase 1 of biotransformation in the liver?

Answer 66

Oxidation, hydrosis or reduction Drug changed to form a more polar or water-soluble compound Involves Cytochrome P450 (CYP) system

Question 67

What is Phase 2 of biotransformation in the liver?

Answer 67

Conjugation (Glucuronidation) Adds a conjugate (glucuronide and others) to the parent drug or phase 1 metabolized drug to increase water- solubility and enhance excretion.

Question 68

Cytochrome P 450 (CYP ) enzymes in Phase I

Answer 68

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

Question 69

What are the three types of P450 enzymes

Answer 69

substrate, inducer, or inhibitor

Question 70

What is a substrate

Answer 70

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

Question 71

What is a Inducer?

Answer 71

- 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

Question 72

What is a Inhibitor

Answer 72

- 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​

Question 73

Polymorphism

Answer 73

​: The presence of genetic variances in single gene that result in the different phenotypes.

Question 74

What is biotransformation?

Answer 74

(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

Question 75

what is Pharmacogenomics

Answer 75

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

Question 76

What are 3 factors that affects Distribution

Answer 76

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

Question 77

What are the 3 Plasma proteins:

Answer 77

Albumin, Globulin, Fibrinogen

Question 78

What does Albumin do?

Answer 78

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

Question 79

What does Globulin do?

Answer 79

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

Question 80

What is Fibrinogen?

Answer 80

Essential for blood clotting

Question 81

What is Volume of Distribution (Vd)?

Answer 81

Be used to determine the size of a loading dose in order to quickly reach the required therapeutic plasma concentration - 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.

Question 82

What does a drug with high Vd mean?

Answer 82

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.

Question 83

What does a drug with low Vd mean?

Answer 83

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.

Question 84

What are the effect of Vd on drug half life?

Answer 84

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

Question 85

What is Cmax?

Answer 85

: The highest drug concentration in the body

Question 86

What is tmax?

Answer 86

: Time at which the highest concentration occurs

Question 87

What is T1/2 (Half Life) ?

Answer 87

T1/2 (Half Life) : Time taken to remove the half of the current concentration of the drug from the body

Question 88

What is AUC: (Area Under the Curve)?

Answer 88

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

Question 89

Between lipophilic drugs and waterphili drugs, which gets excreted faster via kidney?

Answer 89

waterphilic

Question 90

Elimination can happen which 2 ways?

Answer 90

By excretion of an unmetabolized drug in its intact form by kidney or By metabolic biotransformation followed by excretion

Question 91

What organs take part in excretion?

Answer 91

By several organs: Kidneys, GI tract (feces and biles), lungs, skin, mammary glands, sweat glands, salivary glands.

Question 92

What are the steps to renal excretion?

Answer 92

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)

Question 93

What is Total Clearance (CL total )?

Answer 93

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.

Question 94

What is First - order kinetics (linear kinetics) (exponential decrease)

Answer 94

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

Question 95

What is Zero-order (Non-linear elimination ) kinetics ?

Answer 95

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

Question 96

Half-life ( T½)

Answer 96

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

Question 97

What is a Steady-state concentration (Css)

Answer 97

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

Question 98

What is a drug's half life used to measure?

Answer 98

Drug’s half life is used as a measure of drug clearance