Pharmacology basics Flashcards
Pharmacology is
the study of the interactions between a drug and organism (body, enzyme, etc)
Pharmacodynamics is
the study of how a drug affects the organism (biochemical, physiological, and molecular effects)
Pharmacokinetics is
the study of how the organism affects the drug
What is included within pharmacodynamics? (5 things)
Site of Action
Mechanism of Action
Receptor Binding
Postreceptor Effects
Chemical Interactions
What can pharmacodynamics be affected by? (3 things)
Disease or Disorder
Age
Drug–Drug interactions
In regard to pharmacodynamics, what are the three receptor subtypes?
Enzymes
Ion Channels
Membrane receptors
When drugs bind, what kind of chemical interactions can they go through? Which one do we like, and which do we typically avoid? (four things).
Electrostatic interactions are what we prefer (it occurs with intermolecular forces, always will have van Der Waals, hydrogen bonding prominent)
Hydrophobic interactions
Covalent bonds – typically avoid; intramolecular force; irreversible, can be problematic, shuts down receptor; certain bonds can cause DNA mutations
Stereospecific interactions (enantiomers) r, s, e, z
Some receptors are specific, some are not - this could lead to bad side effects with stereoisomers
The drug acts as a what to the receptor?
Ligand
What were the three drug properties discussed in class? What do we want in a drug?
Affinity – how well the drug binds to the receptor
Efficacy – how well the drug produces its desired effect
Potency – term used to compare the relative affinity of competing drugs
–
We want a drug to have high affinity, and high specificity.
What are the categories of drugs? (2)
Agonists – bind and activate receptors
Antagonists – bind, but do not activate receptors
Drugs can bind in two ways to a receptor. What two ways are those?
Competitive – bind reversibly
Non-competitive – either binds irreversibly or binds to create allosteric effects that diminish an agonist’s ability to bind to a different receptor.
What is pharmacokinetics, and how does concentration come in to play? What does us help us understand?
The study of the absorption, distribution, metabolism, and excretion of drugs from the body.
Concentration affects the ability of the drug to give its desired effect
Helps to better understand the following:
Drug administration
Therapeutic dosing
Time intervals between drug dosing
Toxic dosing
Adding what to a drug stops it from being oxidized without adding much weight or changing properties?
Fluorine
What methods of administration are available? Which is not very efficient? Which is the fastest? Which bypasses first pass effect?
Enteral (oral) – through the intestines; not very efficient, lose a lot of drug
Parenteral – other than the intestine (four below)
Intramuscular
Subcutaneous
Intravenously – fastest; bypass first pass effect
Inhalation
Absorption rate determines what?
Time to maximal concentration at the receptor to produce peak effect.
What is bioavailability?
how much of the administered drug is actually absorbed. (typically used for oral administration)
What are the 8 factors affecting bioavailability?
Molecular weight of the drug
Drug formulation
Drug stability (especially pH sensitivity)
First pass metabolism (typically in the liver)
Blood flow
Gastric emptying (food slows this process)
Intestinal motility
Drug interactions
What is distribution?
Effectiveness of the movement of the drug throughout the body
What are the 6 things distribution is influenced by?
Blood
Total body water
Extracellular fluids
Lymphatic fluids
Cerebrospinal fluids
Protein-binding
What do drug solubility properties help us determine?
help determine ability of drug to be distributed to the desired receptor site.
What must be done to a drug to make it more soluble? Can it be too soluble?
The drug has to be more ionized; can’t be too soluble, otherwise it will have a hard time crossing membranes.
What is metabolism, and what does it do? What does it have the potential to do?
Breakdown of drugs into metabolites
Prodrugs – convert from inactive form to active form
Typically inactivates the drug ahead of excretion
Has the potential to lead to the formation of toxic metabolites
What are two common processes of metabolism? Which is MORE common?
Hydrolysis (esters, amides, and nitriles) – typically in pancreas, etc
REDOX reactions (Cytochrome P450 enzymes in the liver) – most common
What is excretion?
Removal of the drug and its metabolites from the body
What is the purpose of excretion?
Helps to prevent toxic buildup of the drug in the body
What are the four main routes of excretion?
Kidneys (majority of drugs)
Feces (unabsorbed drug or metabolites from bile)
Lungs (inhaled anesthetic drugs)
Sweat (not very common)
Where does the majority of metabolism take place? How about excretion?
Liver - metabolizes most
Kidney - excretes most
When do most drugs fail?
During the discovery phase of drug development
What % of drugs fail in clinical testing?
~90%
What is the ratio of drugs that make it to market vs those that don’t?
1:10,000
What are the 8 steps of drug development in order, with time frame?
Target validation (1.5 years)
Compound screening (1.5 years)
Lead optimization (1.5 years)
Pre-clinical test (1 year)
Phase I (1.5 years)
Phase II (2.5 years)
Phase III (2.5 years)
Approval to launch (1.5 years)
What is done during drug development: Target validation
Disease models
Target identification
Target validation
What is done during drug development: Compound Screening
Visual screening
HTS
What is done during drug development: Pre-Clinical testing & Lead optimization
SAR
Drug like properties
Solubility
Permeability
ADME
Plasma PK
Efficacy
Toxicity
What is done during drug development: Phase I
PK
Dose escalation
Toxicity
What is done during drug development: Phase II/III
Dose
Efficacy
Toxicity
What are the two areas in drug development that most drugs fail?
Target validation & Phase II (ADME/Efficacy)
What is lipinski rule of 5?
describes drug potential for a new chemical entity (NCE)
Used as a tool to measure a NCE’s potential bioavailability
10:500:5 (less than 10 hydrogen bond acceptors, less than 500 MW, cLogP less than 5)
What is Lipinski rule of 5 based on?
Hydrogen bond donors (typically amines and alcohols)
Hydrogen bond acceptors (total number of N, O, and F)
Molecular weight (MW) = 500 or less**
Calculated Partition Coefficient (cLogP)
If a rule within Lipinski rule of 5 is violated, what does it typically (but not always) mean?
Violation of more than one “rule” predicts a NCE (new chemical entity) is non-orally available/probably won’t be good drug
What is cLogP?
measure/ratio of solubility of drug in oil vs water (octenol & water)
What does a cLogP of less than 5 mean?
Crosses membranes easily
What functional groups are linked to increased toxicity due to metabolites?
Aromatic anilines
Nitroaromatics
Aliphatic halides
Polycyclic aromatic hydrocarbons
Thiophenes
What is drug efficacy directly related to?
Concentration of the drug at its site of action
What should be considered when deciding concentration of a drug?
Drug concentration must be high enough to elicit the desired effect, but not too high to cause negative effects.
Drugs must cross membranes throughout the entirety of ADME. What does that look like?
Absorption – enter into blood stream
Distribution – contact with receptor
Metabolism – leave receptor and move to liver (or other metabolism site)
Excretion – passage to kidneys for removal
What drugs might use passive transport? How about active transport?
Passive - small, uncharged drug
Active - large, charged drug
What is passive diffusion?
Transport across a membrane from area of high concentration to area of low concentration (requires no energy)
What drugs use passive diffusion?
Low molecular weight drugs have an easier time crossing membranes
What is passive diffusion dependent on? (in regard to absorption of drugs)
Absorption of drugs into the bloodstream is dependent on the acid/base properties of the drug and the pH at the site of absorption
What is active transport?
Transport of a drug across a concentration gradient. Uses energy
What does active transport require?
Requires the aid of membrane-bound proteins to recognize the drug for transport. Requires energy.
What is influx?
Transport into the cell
What is efflux?
Transport out of the cell
What happens in active transport with high drug concentrations?
Transport plateaus due to a limited number of transport proteins available. This can lead to competition with structurally similar compounds.
What is drug transport and distribution affected by?
Size & charge of the drug molecule.
What size is considered a small drug?
<50 Da (bulk flow/passive transport; Pelphrey said they can be interchangeable)
What size is considered a lipophilic drug?
50-500 Da (Passive transport)
What size of a charged drug would require active transport?
> 50 Da
