MedChem Flashcards
Most drugs are
weak acids or weak bases
The acid-base properties of drugs influence their
ADME, compatibility with other drugs in solution.
An acidic drug like aspirin donates a
proton on ionization to generate a conjugate base
A basic drug like acetaminophen accepts a
proton to generate a conjugate acid
Resonance stabilization of the conjugate base of an acidic drug ________ acidity
enhances
Delocalization of electrons from the nitrogen atom of a basic drug ________ basicity
decreases
Example- arylamines (acid pka 4-5; less basic than alkylamines (pka 9-11)
Amphoteric drug
Contain both acidic and basic functional groups
Drugs with nitrogen-containing heterocycles are
basic because the lone pair of electrons on the nitrogen is readily available to serve as a proton acceptor.
The nitrogen atom in pyrrole does not contribute to basicity of drug molecules because
the lone pair of electrons on the nitrogen contributes to the aromatic sextet and thus is not available to accept a proton.
Six membered nitrogen containing heteroaromatics (such as pyridine) are
weak bases because only one of the nitrogen lone pairs of electrons contributes to the aromatic sextet. Thus, an unshared pair of electrons is available to serve as a proton acceptor
PKa
relative acid strength
Indicates the relative acid-base strength of organic functional groups. Cannot be used to determine whether a given drug molecule is acidic or basic. It can be used to calculate the percent of ionized and unionized forms of drugs at a given PH using the henderson-hasselbalch eqn.
The PKa contributes to the
relative water solubility which is important in abs and excretion
Highly polar drugs with low lipophilicity (heparin) is a candidate for IV because
it poorly penetrates biological membranes through passive diffusion
Log P
Partition coefficient
The ratio between the fraction of the drug unionized that dissolves in an organic phase (octanol) and the fraction that distributes in an aqueous phase (water)
Used to estimate the ability of a drug to cross biological membranes (distribution)
Drugs with _____ Log P values cross biological membranes more easily and are rapidly absorbed in the GI tract.
High
pH-partition theory
Relates the effect of a biological compartments pH and a drugs pKa to the extent the drug is ionized or unionized and its resulting ADME.
If the pKa of a weakly acidic drug is > than the pH of the environment, the drug exists primarily in an unionized state, which facilitates absorption.
If the pKa of a weakly acidic drug is < the pH of the environment, the drug exists in the ionized state, limiting abs
If the pKa of a basic drug is > the pH of the environment, the drug will exist in the ionized state, which limits abs
If the pKa of a basic drug is < the pH of the environment, the drug will exist in the unionized state, promoting abs
Covalent bond
Strongest drug-receptor interaction. Sharing of electrons between an atom from the drug and an atom from the receptor. Covalent bonding is irreversible and leads to destruction of the receptor.
Ionic bond
Salt bridge
Type of electrostatic interaction that occurs between oppositely charged functional groups on the drug and receptor
Ionic bond
Salt bridge
Type of electrostatic interaction that occurs between oppositely charged functional groups on the drug and receptor
Hydrogen bond
Electrostatic interaction in which a hydrogen atom serves as a bridge between two electronegative atoms, one from drug and the other from receptor
Hydrophobic interaction
Van der Waals forces or London forces
Occurs between nonpolar regions of the drug and the receptor. The drug must be close to the receptor for this to occur.
Occupancy theory
The binding of a drug (agonist) to its receptor results in a conformational change in the receptor that initiates a response
Rate theory
Number of drug-receptor interactions per unit time determines the magnitude of response
Induced fit theory
A receptor undergoes conformational change near a drug molecule to allow effective binding of the drug to the receptor.
Macromolecular perturbation theory
Combines the rate and induced fit theory. 2 confirmational changes occur
Activation-aggregation theory
Receptors are always in a state of dynamic equilibrium between active and inactive states. Explains the activity of inverse agonists.
Decomposition of drugs through oxidation may be prevented by the following:
Packing the drug under an inert gas atmosphere to exclude oxygen
Packaging the drug in amber-colored containers to exclude light
Adding chelating agents to remove metal ions
Adding antioxidants
Pharmacophore
A set of structural features in a molecule that is recognized at a receptor site and is responsible for the molecules biological activity.
Can include ionizable groups, H bond donors or acceptors, lipophilic features, aromatic ring systems
Structure-activity relationship (SAR) studies
May include homologation ( increasing/decreasing length of alkyl chains), chain branching, ring-chain transformations, functional group modifications, and bioisosteric replacement
Drugs that act without specific molecular targets
Buffers (antacids)
Gaseous and volatile general anesthetics
Osmotic diuretics or laxatives
Groups of approved biologics
Monoclonal antibodies and antibody constructs
Hormones and growth factors
Enzymes
Major classes of receptor superfamilies
Receptor-operated channels (nicotinic ACh channel)
Receptor-operated enzymes (epidermal growth factor receptor)
G-protein coupled receptor (a1-adrenergic receptor)
DNA-linked receptors
G-protein coupled receptors
Have a transmembrane protein with extracellular and intracellular domains. The intracellular domain is coupled with G-proteins, which facilitate signal transduction after stimulation of the receptor by second-messenger pathways. The drug binding domain lies within one of the transmembrane domains.
Full agonists
Bind to receptors and produce a molecular response (conformational change ) that results in maximum tissue response
Competitive agonist
Bind to receptors without initiating a molecular response. Their effect is produced by denying endogenous agonists access to the receptor.
Partial agonist
Bind to receptors and produce a molecular response, but even at high concentrations, the max response is not achieved. Thus, the maximum tissue response of a partial agonist is less than that of a full agonist. Partial agonists can compete with full agonists and can thus act as antagonists to full agonists.
