Test 1 Pharm: Module 1: Lecture Notes

Front 1

Van der Waals Bond

Back 1

Weak Bond Strength

Shifting electron density in areas of a moleculre, or in a molecule as a whole, results in the generation of transient positive or negative charges. These areas interact with transient areas of opposite charge on another molecules.

Front 2

Hydrogen Bond

Back 2

++ Bond Strength

Hydrogen atoms bound to nitrogen or oxygen become more positively polarized, allowing them to bond to more negatively polarized atoms such as oxygen, nitrogen, or sulfur.

Front 3

Ionic Bond

Back 3

+++ Bond Strength

Atoms with an excess of electrons (imparting an overall negative change on the atom) are attracted to atoms wiht a deficiency of electrons (imparting an overall positive charge on the atom).

Front 4

Covalent Bond

Back 4

++++ Bond Strength

Two bonding atoms share electrons.

Ex. Aspirin - cox enzyme binds and "kills" enzyme need to produce new protein to "reverse"

Front 5

Physiochemical Properties of Drugs

Back 5

* Bond Strength
* Lipophilicity - binds - like vs like
* Ionization
*Stereochemistry (enantiomers) - mirror images ex: citalopram & escitalopram
*Conformation - what happens when binding occurs

Front 6

Molecular Drug Receptor Interactions

Back 6

*Transmembrane - ion channel, linked to intracellular G protein, enzyme within cytosolic domain
*Intracellular
*Extracellular

Front 7

D+R = DR

Back 7

Drug + Receptor = Drug/Receptor Binding

Front 8

ED50

Back 8

ED50 = Therapeutic effect - 50% of pts have therapeutic effect

Front 9

TD50

Back 9

TD50 = Toxic dose = 50% of pts have toxicity (side effects)

Front 10

LD50

Back 10

LD50 = Lethal Dose = 50% have lethal effects

Front 11

Therapeutic Window

Back 11

Efficacy without unacceptable toxicity

TI = TD50/ED50

High TI = wide therapeutic window (Increase - optimal)
Low TI = small therapeutic window

Front 12

Agonists

Back 12

D+R = DR = DR*
What happens when D+R bind = Response

Full = elicits maximal response, stabilizes DR*
Partial & mixed agonist-antagonist = stabilizes DR and DR*
Inverse = inactivates free active receptors = stabilizes DR in the case of R* (natural state - inactivate R*)

Front 13

Antagonists

Back 13

*Inhibition of agonist activity - stabilization of DR; prevention of DR*
*Competitive - reversible binding, active site (competes with agonist)
*Noncompetitive - irreversible active site or allosteric site (binds to alternative site - not get DR*)
*Nonreceptor - chemical (agonist inactivation) and Physiologic (mediates opposite response of agonist)

Front 14

Full Agonist

Back 14

Activates receptor with maximal efficacy

Front 15

Partial Agonist

Back 15

Activates receptor but not with maximal efficacy

Front 16

Inverse Agonist

Back 16

Inactivates constitutively active receptor

Front 17

Competitive Antagonist

Back 17

Effects on Agonist Potency = YES
Effects on Agonist Efficacy = NO

Binds reversibly to active site of receptor; competes with agonist binding to this site

Front 18

Noncompetitive Active Site Antagonist

Back 18

Effects on Agonist Potency = NO
Effects on Agonist Efficacy = YES

Binds irreversibly to active site of receptor; prevents agonist binding to this site

Front 19

Noncompetitive allosteric antagonist

Back 19

Effects on Agonist Potency = NO
Effects on Agonist Efficacy = YES

Binds reversibly or irreversibly to site other than active site of receptor; prevents conformational change required for receptor activation by agonist

Front 20

Physiochemical Properties for Drug Transfer

Back 20

*Molecular size and shape
*Solubility at site of absorption - "pill in GI tract"
*Degree of ionization
*Relative lipid solubility of its ionized and non-ionized forms

Front 21

Biological Membranes

Back 21

*Hydrophobic lipid core
*Hydrophilic surface to aqueous extracellular and intracellular environments
*Drugs traverse the membrane through passive diffusion, facilitated diffusion - energy independent, active transport - energy dependent, and endocytosis

Front 22

Passive Diffusion

Back 22

Passive Diffusion is one way that drugs traverse the cell membrane. Needs to be small and hydrophobic.

Front 23

Facilitated Diffusion

Back 23

Facilitated Diffusion is one way that drugs traverse the cell membrane. It's energy independent - not need ATP - transporter carries.

Front 24

Active Transport

Back 24

Active Transport is one way that drugs traverse the cell membrane. It's energy dependent.

Front 25

Endocytosis

Back 25

Endocytosis is one way that drugs traverse the cell membrane. The drug attaches to the membrane and it's "eaten".

Front 26

Influence of pH

Back 26

*Most drugs - weak acids or weak bases in solutions
-nonionized molecules - lipid soluble
-ionized molecules - hydrophilic, difficulty penetrating
*Henderson-Hasselbalch equation= pKa = pH+log(HA/A-)
-pKa = pH at which 50% of the drug is ionized
*pH trapping
-determined by pKa and pH gradient across membrane
-weakly acidic drugs (ASA)
-Protonated in stomach (nonionized), deprotonated in plasma (ionized)

Front 27

Nonionized Molecules

Back 27

Lipid Soluble

Front 28

Ionized Molecules

Back 28

Hydrophilic, difficulty penetrating

Front 29

CNS Penetration - BBB

Back 29

BBB - tight junctions
*Prevention of passive diffusion - needs to be really small and hydrophobic
*Drugs penetrate CNS by:
1. Small and hydrophobic
2. Active Transport
3. Facilitated transport
4. Intrathecal (bypass)

Front 30

Absorption

Back 30

Absorption:
*Obstacles same as for invading microorganisms
*Rate at which and extent to which a drug leaves its site of administration
*Bioavailability
- extent to which a drug reaches systemic circulation
-"Fraction absorbed"
- Assumption - site of action is reached directly from systemic circulation.

Front 31

Factors that modify absorption

Back 31

*Concentration - higher concentration = greater the absorption
*Circulation at the site of absorption
-increase blood flow, local massage, local application of heat enhances absorption (with topical)
-decrease blood flow, vasoconstrictor agents, shock, or other disease factors slow absorption
*Drug solubility
-extent and rate of dissolution
*Surface area
-pulmonary alveolar epithelium, intestinal mucosa, & extensive application to skin

Front 32

Enteral (oral) Administration - Advantages

Back 32

*Most common method of administration
*Nonionized, lipophilic drugs favored
*Weak Acids for absorption from stomach
*Weak Bases for absorption from small intestine

*Advantages (safe, convenient, economical, painless, systemic infections less likely)

Front 33

Enteral (oral) Administration - Disadvantages

Back 33

*Disadvantages (absorption challenges - destruction in harsh GI environments, passage across GI tract epithelium, slow delivery compared to IV, first-pass metabolism -go through liver)

Front 34

Rectal Administration

Back 34

*When oral ingestion is not possible (vomiting, unconscious)
*~50% of the drug bypasses the liver (still have first pass)
*Erratic absorption
*Can cause irritation of the rectal mucosa

Front 35

Parenteral Administration - Advantages

Back 35

*IV, IM, SQ, IA, IT
*Rate of onset dependent of administration site and tissue vascularization
*Oil-based agents - give SQ or IM
*If given IV can ptt blood constituents or hemolyze erythrocytes
*Advantages
-Rapid delivery to site of action
-High bioavailability
-No hepatic first-pass effect
-No harsh GI environment

Front 36

Parenteral Administration - Disadvantages

Back 36

*Disadvantages
-Irreversible
-Administration technique
-Pain/fear
-Increased risk of infection

Front 37

Mucous Membranes Administration

Back 37

*SL, Ocular, pulmonary, nasal, rectal, urinary, reproductive tract (high vascularized)
*Dosage forms - liquid drops, rapidly dissolving tablets, aerosols, suppositories
*Advantages
-rapid delivery
-no hepatic first-pass effect
-no harsh GI environment
*Disadvantage - few drugs available to administer via this route

Front 38

Transdermal Administration - Advantages

Back 38

Advantages:
*Simple
*Convenient
*Painless
*No hepatic first-pass effect
*No harsh GI environment
*Continuous administration

Front 39

Transdermal Administration - Disadvantages

Back 39

Disadvantages:
*Requires drug with high lipophilicity
*Slow delivery to site of action
*Irritation

Front 40

SubQ Administration

Back 40

Advantage:
*Slow onset, may be used to administer oil-based drugs
Disadvantage:
*slow onset, small volumes

Front 41

Intramuscular Administration

Back 41

Advantage:
*Intermediate onset, may be used to administer oil-based drugs
Disadvantage:
*Can affect lab tests (Creatine Kinase), IM hemorrhage, painful

Front 42

IV Administration

Back 42

Advantage:
*Rapid Onset, controlled drug delivery
Disadvantage:
*Peak-related drug toxicity

Front 43

Intrathecal Administration

Back 43

Advantage:
*Bypasses BBB
Disadvantage:
*Infection, highly skilled personnel required

Front 44

Distribution

Back 44

*Drugs must reach target organ(s) in therapeutic concentrations
*Initial phase of distribution reflects regional blood flow
*Delivery of drug to muscle, most viscera, skin and fat is slower
*Cannot effectively measure tissue drug concentrations

Front 45

Distribution - Second Phase

Back 45

*Distribution to tissues
*Rapid distribution to interstitial compartment due to highly permeable nature of capillary endotheial membranes
*Restricted distribution
-Lipid-insoluble drugs that permeate membranes poorly
-Drugs binding plasma proteins

Front 46

Volume of Distribution

Back 46

Vd = Dose/(Drug)plasma
Volume of fluid required to contain the total amount of drug absorbed in the body at uniform concentrations equal to that in the plasma steady state
*Low Vd = retained within the vascular compartment
*High Vd = highly distributed into non-vascular compartments

Front 47

Metabolism

Back 47

*Liver, kidney, GI tract, lungs, skin, and other organs contribute
***Must be unbound in plasma***
*Generation of polar and/or hydrophilic inactive metabolites
*Biotransofrmation reactions (Phase 1 - oxidation/reduction, Phase 2- conjunction, hydrolysis)

Front 48

Metabolism: Phase 1: CYP450

Back 48

*95% of all oxidative reactions
*75% of all drugs
*Addition of hydroxyl group to drug
-rapid excretion into urine
-Drug+O2+NADPH+H+ ?Drug-OH+ H2O+NADP+
*If not excreted, undergoes Phase II

Front 49

Metabolism: Phase 1: CYP450

Back 49

*CYP450 3A4, 2D6, 2C19, 2C9, 2E1, 1A2
- enzyme family-subfamily-specific enzyme
-substrate specificity
*Alcohol dehydrogenase
-oxidizes alcohols to aldehyde derivatives
*MAO
-oxidizes amines

Front 50

Metabolism: Phase II

Back 50

*Substrates include drugs or drug metabolites
*Results in large polar conjunctions
*Common additions - glucuronate, sulfate, gluthathione, acetate (more polar)
*Excreted rapidly in the urine and feces
*Active metabolites possible
-active conjugate of morphine (morphine glucuronide) is a more potent analgesic

Front 51

Factors Affecting Metabolism
CYP450 Induction

Back 51

CYP450 Induction
*Increased transcription or translation
*Decreased degradation
*Induction by another drug or autoinduction

Front 52

Factors Affecting Metabolism
CYP450 Inhibition

Back 52

CYP450 Inhibition
*Incidental or deliberate
*Competitive inhibition
*Irreversible inhibition

Front 53

Factors Affecting Metabolism
Others

Back 53

*Genetics - "slow acetylator" phenotype
*Race and ethnicity - CYP450 2D6 is nonfunctional in 8% of caucasians
*Age and gender - lack of UPDGT in neonates
*Diet - grapefruit juice
*Disease-states - liver disease, cardiac disease

Front 54

Excretion

Back 54

*Either unchanged or as metabolites
*Excretory organs
-Lungs (elimination of polar compounds, anes. drugs)
-Renal (glomerular filtration, active tubular secretion)
-Feces (mainly unabsorbed orally administered drugs or drugs excreted via bile)

Front 55

Clinical Pharmacokinetics

Back 55

*Fundamental hypothesis: Pharmcologic or toxic response to a drug is related to the accessible concentration of the drug

*Three most important parameters:
-clearance
-volume of distribution (apparent space in the body available to contain the drug - inc Vol, inc distribution
-bioavailability (the fraction of drug absorbed into systemic circulation)

Front 56

Clearance

Back 56

*Measures the body's ability to eliminate drug
*Rate of elimination from the body relative to plasma drug concentration
*CL = (Metabolism + Excretion)/(Drug)plasma
*Clearance mechanisms include metabolism, excretion

Front 57

Clearance Kinetics

Back 57

*First-order Kinetics
-increase in plasma concentration = matched increase in clearance (metabolism/excretion)
-clearance mechanisms not saturated

*Zero-order kinetics
-increase in plasma concentration with no increase in clearance
-saturation kinetics

Front 58

Half-Life

Back 58

T 1/2 = time it takes for the plasma concentration to be reduced by 50%

T 1/2 = 0.693/k k=elimination rate constant

Factors affecting half-life
-Changes in Vd
-Changes in clearance

Front 59

Therapeutic Dosing

Back 59

*Potency vs Efficacy (eg atorvastatin/simvastatin)
*Bioavailability
*Vd
*Half-life
*Maintain Cmax (peak concentration) below toxic concentration
*Maintain Cmin (trough concentration) above minimum effective concentration
*Maintain Css (steady state) within therapeutic window

Front 60

Hypersensitivity I

Back 60

Classificiation: Immediate Type Hypersensitivity
Primary Triggers: Antigen binding IgE on mast cells
Primary Mediators: Histamine and serotonin
Examples of S/S: Hives, urticaria
Example of Drugs:PCN

Front 61

Hypersensitivity II

Back 61

Classification: Antibody-dep cellular cytotoxicity
Primary Triggers: IgG and complement binding cell-bound antigen
Primary Mediators:Neutrophils, macrophages, and NK cells
Examples of S/S: Hemolysis
Example of Drugs: Cefotetan

Front 62

Hypersensitivity III

Back 62

Classification: Immune-complex
Primary Triggers: IgG and complement binding soluble antigen
Primary Mediators:Neutrophils, macrophages, and NK cells; reactive oxygen species, chemokines
Examples of S/S: Cutaneous vasculitis
Example of Drugs: Mitomycin C

Front 63

Hypersensitivity IV

Back 63

Classification: Delayed-type hypersensitivity (cell-mediated)
Primary Triggers: Antigen in association with major histocompatibility complex (MHC) protein on the surface of antigen-presenting cells
Primary Mediators:Cytotoxic T lymphocytes, macrophages, and cytokines
Examples of S/S: Macular rashes and organ failure
Example of Drugs: Sulfamethoxazole