Ch. 1- Intro: The nature and development of drugs. Flashcards
Two principles that the student should remember
- all substances can be toxic and that chemicals in botanicals “nutraceuticals” are no different from chemicals in manufactured drugs except for the much greater proportion of impurities in botanicals.
- All dietary supplements and all therapies promoted as health enhancing should meet the same standards of efficacy and other drugs and medical therapies.
Xenobiotics
substances that are foreign to the body or to an ecological system.
Most drugs have weights between
100 and 1000
To achieve such selective binding, it appears that a molecule should in most cases be at least
100 MW in size
Even in the absence of an agonist, the receptor must still be in the active form sometimes. This is known as..
constitutive activity
Full agonists
maximize the Ra configuration of receptor
Partial agonists
Do not evoke a maximum response, no matter how high their concentration.
Intrinsic efficiency
Drugs such as partial agonist that still hold the Ri-D configuration are said to have low intrinsic efficiency.
A drug such as pindolol can do what?
If no full agonist is present, then it can act as an agonist
If full agonist is present, then it can act as an antagonist.
Think ** How it acts relative to what else is present.
When an antagonist blocks the effect of agonist
neutral antagonism
When a drug has a very high affinity for Ri-D configuration
Inverse agonists
Inert binding site
When binding of a drug to a nonregulatory molecule results in no detectable biological change in the function of the biological system
Prodrug
inactive drug that must be metabolized to active form in body
Fick’s Law of Diffusion
(C1-C2) x (Area * permeability coefficient) / (Thickness)
The more ionized a molecule that means more
water soluble
Weak acid
neutral molecule that breaks apart into an anion and a proton
Weak base
neutral molecule that can form into a cation
HH equation
log(prot/unprot)=pKa-pH
PKa pH relationship
The lower the pH relative to the PKa, the greater will be the fraction of drug in the protonated form.
Because the uncharged form is the more lipid soluble …
more of a basic drug will be in the lipid soluble form at alkaline pH because there will be less floating protons therefore the base will less likely to form a cation
easy version: acid = neutral molecule that can break into anion, so an acidic environment can prevent ion (charges formation) therefore more lipid soluble.
more of a acidic drug will be in the lipid soluble form at at acidic pH because there will be more protons to neutralize the anions formed.
easy version: base= neutral molecule that can form cation, so in basic or alkaline pH there are less protons for it to gain to become a cation therefore more lipid soluble
Weak acids are usually excreted faster in alkaline urine , why?
to be reabosorbed, the molecule must be lipid soluble. To be excreted, the molecule must be water soluble.
To be water soluble, the molecule must be charged.
To be charged, the weak acid must be in an environment where the molecule can lose protons. In an alkaline environment, there will be more OH- to capture the protons of the acid molecule, thus causing the molecule to become charged therefore the molecule will be charged and excreted faster.
Weak bases are usually excreted faster in acidic urine why?
A weak base is defined as a neutral molecule that can form a cation. For the base to be excreted, the base must be charged. For the base to gain a proton, it must be in an acidic environment to become a charged cation.
Three inorganic compounds discussed in class
Lithium Carbonate- neurological disorders
Silver nitrate-external antibiotic
Cisplatin-alkalizing treatment for cancer
Smallest molecule of drug is
Lithium chloride with a MW of 7
Liquid drugs discussed in class
ethanol , nicotine
Heparan comes from
bovine lungs and pigs intestines
The Lipinski rule of five
- MW is less than 500
- logP is less than 5
- Number of hydrogen donors in the molecule is less than 5 (amine, hydroxyl)
- Hydrogen acceptors of molecule are less than 10 (oxygen, nitrogen)
The more positive the logP, the more..
lipophilic
CNS drugs must have a ? logP value and why?
high, to cross BBB
logP values can be detected using
chromatography
What the body does to the molecule
Liberation
Absorption
Metabolism
Excretion
Four ways that drugs can be transported across biological barriers
- Aqueous diffusion- (passive)-small molecules
- Lipid diffusion- (passive, small lipophilic molecules
- Active transport-(active) for (peptides, glucose, amino acids) ((MDR1)) (MRP).
- Endocytosis and exocytosis- (active) B12, Neurotransmitters
Drug trial phases
P1: 20 -100 healthy volunteers to determine toxicity, etc, if adverse effects are seen in this phase, then participants with the disease participate in P1 trial. 63.2% move to phase 2.
P2: patients with the disease (100-200 people). 30.7% move to phase 3.
P3: similar to P2 but much larger sample. 58.1 percent move to new drug application.
Drugs from paper and drugs talked about in class
- Paclitaxel- chemo drug- isolated from the Pacific yew, Taxus brevifolia (fungus in the bark of the tree).
- Artemisinin- malaria-derived from A. annua.
- Ivermectin- targets nematodes-derived from Streptomyces avermitllis
