Day 1 (history + basics + receptor interactons)

3 principals of pharmacology

1. diseases have specific CAUSE for which there is a remedy

2. identifiable component of the natural remedy is responsible for efficacy

3. dose = degree of response

what is Phillipus Aurelous Theophratus (Paracelsus) most known for?

dose makes the poison

toxicon - primary toxic agent

Withering discovered the treatment of ______ (congestive heart disease) with the fox glove plant

Withering discovered ______ as the specific component responsible for the remedy— ACTIVE INGREDIENT

dropsy

digoxin

what was a big achievement of the 19th century?

the ability to isolate and synthesize pure organic chemicals (medicinal chemistry)

in the ____th century we now had the ability to isolate and synthesize pure organic chemicals

friedrich serturner was the first to isolate _______ from the _______ plant

— name comes from the greek God of dreams

Birth of ALKALOID pharmacology

19th

morphine poppy

__________ ______ classified drugs by their ACTION on organ functions rather than botanical origins

he is credited with the systematic exploration of experimental pharmacology of experimental pharmacological methods

used statistical analysis in experimentation

Rudolf Buchheim

who established the first department of pharmacology at the University of Dorpat (now Estonia)?

he was credited with the systematic exploration of experimental pharmacological methods (MOA + statistical analysis)

Rudolf bucheim

who acted both as a pharmacologist AND medicinal chemist studying the hypnotic effects of urea and nicotine blocking of cardiac vagal ganglia?

what did he isolate from toadstool Amantina Muscaria that mimics vagus stimulation on the heart ?

alkaloid muscarine

Who is known as the “Father of Pharmacology” known best for purifying epinephrine, pituitary hormones, and insulin?

John Jacob Abel

SEQ prominent figures of pharmacology and BRIEF synostosis of what they do?

1. Paracelsus = “dose makes the poison”

2. Withering = digoxin active ingredient

3. Serturner = morphine from poppy plant +alkaloid pharmacy

4. Bucheim = MOA + statistical analysis

5. Shcmeidenberg = pharmacologist + medicinal chemist

6. John Jacob Abel = father of American Pharmacology —> purification

Josef Von Mering + Fischer began

Rational Drug Design

What is another word for it? What does it imply?

structure-activity

you can improve drugs by changing their structure

what was the first true chemical designed based on the rational drug design?

hypnotic tranquilizers

diethyl barbituric acid or barbital

change in structure increased how well they worked

Pharmacology is the interactions of _______ with _______ systems to yield therapeutic or other beneficial effects

chemicals w/ biological systems

What are the 4 characteristics of pharmacologic agents?

1. intended for SPECIFIC purpose

2. prevent or treat illness

3. ADMINISTERED in an appropriate physical form

4. specific dosing REGIMENTS are required

interaction of chemicals with biological systems to yield adverse effects

toxicology

what is an example of an unintended adverse effect?

instead of decreasing blood pressure sildenafil citrate caused erection

it is now used for erectile dysfunction under the name viagra

study of biochemical and physiological effects of drugs and their mechanism of action

pharmacodynamics

study of the absorption, distribution, metabolism, and excretion of drugs (ADME)

pharmacokinetics

difference between pharmacokinetics and pharmacodynamics?

kinetics = how body effects drug

dynamics = how drug effects body

what’s another word for receptor?

drug target

a cellular macromolecular complex with which the drug interacts to elicit a cellular response

receptor

what exactly do drugs do if not create new responses?

alter the rate or magnitude of an already existing intrinsic cellular response

enhance or inhibit an existing cellular response

are all drugs ligands?

are all ligands drugs?

YES

NO

ligands are anything that binds to a receptor (internal or external)

drugs specifically refer to external molecules that bind to receptors

the response of a tissue to a drug or ligand is a function of the NUMBER of receptors bound to the drug

occupancy theory

what are the three principles of the occupancy theory

1. the site ON THE RECEPTOR where the drug binds is the binding site

2. concentration of drug/ligand is an important factor for the extent of receptor binding

3. need to reach a threshold of receptor occupancy by drug/ligand to see the effect in the tissue

we know that a single a single molecule of the active ingredient binding to a single receptor is not enough to cause a reaction due to which theory?

occupancy theory

what are the two different types of agonists that exist?

what different names do they go by?

what is the difference?

primary (orthosteric) and allosteric (allotopic)

primary = binds to same region on the receptor as endogenous ligand and mimic effect

allosteric = binds to a different region of the receptor to mimic the effect of the endogenous ligand

what is the difference between a competitive, noncompetitive, and functional

competitive - competes with agonist for the same or overlapping site on the receptor

noncompetitive- binds to an allosteric site on the receptor to change the shape of the binding site

functional - indirectly inhibit the effects of the agonist

what are the FOUR physical and chemical properties of drugs that effect its binding to its receptor?

• hydrophilicity

• ionization state (pka)

• conformation

• sterochemistry

which two drugs have significant differences in their effect based on which conformation the drug molecule is in?

Warfarin (anticoagulant) and Sotalol (anti-arrythmic)

what makes the S enantiomer 4 times more potent than the R enantiomer of Warfarin?

it has stronger interactions with vitamin K epoxide reductase (better able to inhibit vitamin K synthesis which allows for clotting)

can one enantiomer of a drug have a different therapeutic effect than the other? what is an example?

YES

l and d isomer of sotalol both block K+

but l can also act as a beta-adrenergic antagonist

which diastereomer of labetalol (anti-hypertensive) is a

• b1 antagonist + partial b2 agonist

• a1 antagonist + little b1 antagonist

• no adrenergic-blocking activity

• RR

• SR, SS

• RS

sequence of amino acids (peptide bonds)

C=O of one amino acid react with NH2 of another through dehydration

primary structure

form simple patterns from interactions between positively charged HYDROGEN atoms and negatively charged OXYGEN atoms on SAME polypeptide chain

secondary structure

interactions of amino acids that are relatively far apart using IONIC BONDS and covalent DISULFIDE links

tertiary

interactions between two or more independent protein SUBUNITS

quaternary

how can a receptor have both hydrophilic and hydrophobic segments? where would the drug bind for each?

hydrophobic segment would be found within the protein or lipid bilayer

hydrophilic segment would be found on the exterior of the protein

40-140 kcal

two bonding atoms that share eletrons

example: NH2—CH3

covalent

5-10 kcal

atoms with excess of electrons (impart negative charge on atom) are attracted to atoms with a deficiency of electron (positive charge on atom)

ionic bond

2-5 kcal = hydrogen bonds

H atoms bound to ___ or _____ and become more positively polarized allowing for them to be bonded to more negatively polarized atoms such as ___ ___ ___

O or N

SON

0.5kcal

shifting electron density in areas of a molecule results in the generation of transient positive or negative charges

these areas interact with transient areas of opposite charge on another molecule

van der walls

Imatinib is a drug that forms intermolecular interactions which receptor?

BCR-Abl Kinase

which bonds exist between imatinib and the amino acid residues of its target receptor (BCR-Abl kinase protein)?

vanderwalls and hydrogen bonds

how does imatinib work as an anti-cancer drug?

by binding to its target receptor (BCr-Abl kinase) it prevents the phosphorylation of a critical activation loop in the receptor protein

prevents catalytic activity

the drug binding to its receptor is influenced by

1. affinity

2. intrinsic activity

3. selectivity

4. number

briefly explain the difference between the following:

• affinity

• intrinsic activity

• selectivity

• number

affinity = how tightly a molecule is bound to its receptor

intrinsic activity= how effective the response is

selectivity = does the drug bind to other receptors

number= how many receptors are there to respond to the drug

a drug that is selective toward alpha 1 adrenergic receptors will only cause a response in what body system?

vascular

a drug that is selective toward alpha 2 adrenergic receptors will only cause a response in what body system?

presynaptic

a drug that is selective toward beta 1 adrenergic receptors will only cause a response in what body system?

heart

a drug that is selective toward beta 1 adrenergic receptors will only cause a response in what body system?

heart

a drug that is selective toward beta 2 adrenergic receptors will only cause a response in what body system?

smooth muscle

a drug that is selective toward beta 3 adrenergic receptors will only cause a response in what body system?

fat

which drug- receptor model states that the shape of the substrate and the confirmation of the active site are complimentary (like a puzzle)

lock and key model

Which model states that the binding of a drug to its receptor results in a conformational change that enhances the drug's affinity for the receptor?

induced fit model

not perfect fit at first but once the drug is bound interaction become stronger