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.
Inverse agonists
Bind to receptor molecules that are in an activated state in absence of a ligand (basal activation). Thus, inverse agonists decrease the basal activation level of a receptor by stabilizing its inactive form
Dose requirements for partial vs full agonists
If there are spare receptors (usually there are), the partial agonist needs to interact with more receptors to achieve the maximum cellular response. Thus, the partial agonists requires a higher dose than the full agonist.
Competitive antagonists
Bind to the site normally occupied by the agonist, thereby reducing the number of receptors available for agonist binding.
Noncompetitive antagonists
Bind to a different ligand-binding site on the receptor (allosteric site) resulting in a conformational change of the receptor that leads to reduced or no agonist binding.
Pharmacodynamics vs pharmacokinetics
PD- what drug does to body
PK- ADME
Type A ADR
Side effect
Dose, related, predictable reaction to a drug
Type B ADR
Non-dose related, unexpected ADR (idiosyncratic reaction)
Allergic reactions, carcinogenic and teratogenic effects
PK vs PD DDI
PK- ADME of drug
PD-agonist/antagonist interactions
Kefauver-Harris amendments of 1962
Drugs must be safe and effective
To have the desired composition, herbal products must
be grown under appropriate conditions, must be the appropriate age before harvest, and must contain the appropriate plant part.
Persons with hormone-sensitive cancers should not use
DHEA
The FDA regulates dietary substances as
food
Do dietary supplements have to undergo premarket safety and efficacy testing?
No
Black cohosh
Has been described as having antiosteoporosis, antiviral, antitumor, antioxidant, and antiangiogenic activities. May relieve menstrual cramps, hot flashes, sweating
AE- liver toxicity, skin reactions
Little evidence
Cranberry (vaccinium macrocarpon)
Believed to enhance the urines ability to prevent bacteria from adhering to urinary tract cells.
Some clinical evidence
Echinacea
Anti-inflammatory, antibacterial activity
May assist in wond healing by stabilizing hyaluronic acid
Prevention and treatment of the common cold
AE- rare, mild
No efficacy in cold treatment
Flax
Bowel stimulation, Omega-3 supplementation, hyperlipidemia, atherosclerosis, GI disturbances, SLE, RA, local inflammation
No AE
Positive effect of flaxseed on CV health, breast cancer, prostate cancer, lupus, and arthritis
Decreases LDL, decreases BP
Garcinia gummi-gutta
Weight loss, appetite stimulation, bowel complaints, intestinal parasites, rheumatism
Serotonin syndrome if on other serotonergic agenets
No efficacy
Ginger
N/V, fever, GI, diarrhea, dysmenorrhea, arthritis, diabetes, anticoagulant
No AE
Ginger is effective in treating nausea and reduced pain in dysmenorrhea
Green Tea
educe CV risk, Reduce risk of cancers, diuresis, dysuria, mild diarrhea, reduced risk of osteoporosis, HA, CNS stimulant, weight loss
Toxicities are caffeine related (flatulence, abdominal bloating, insomnia, restlessness, tremor, HA)
Significantly reduces systolic BP, total cholesterol, and LDL
Produces modest, but significant reductions in BMI
Horehound
Expectorant, dyspepsia symptoms
No AE
No evidence
Ivy leaf
Inflammatory bronchial diseases
Expectorant, antitussive
AE- GI, cannot use with opiate antitussives
Clinical trials- safe and effective adjunct in treating inflammatory lung diseases
Turmeric
Dry, flaky skin, skin sores and wounds, indigestion, dyspepsia, digestive aid
AE- abdominal pain, constipation, nausea, vertigo, itching
Clinical trials- Lowers LDL and TG, pain reduction in arthritis, improves ulcerative colitis
Dietary fish
Should be increased to 2 servings/week to decrease risk of CV disease.
This should be lifelong
Omega 3 in diet
Fish, flaxseed, nuts such as walnuts
Glucosamine/ Chondroitin
G- Available as HCL salt or sulfate (obtained from shellfish)
C- made from bovine or shark cartilage
Vegetarians need to be made aware of vegetarian formulations
Coenzyme Q10
Used to treat HF, HTN, angina, diabetes, cancer
AE- GI, mild
Patients on warfarin may have increased INR or PT
Dehydroepiandrosterone
Used in depression, arthritis, cancer, and as a performance enhancer.
AE- acne, oily skin, voice deepening, weight gain, menstrual changes, gynecomastia, insomnia
Vitamin E and Vitamin A
May provide protection against CV disease in dietary food. Increased risk at pharmacologic doses.
Factors limiting the vitamin D conversion process
Dark skin, distance from equator, atmospheric pollution, sunscreen, increased hours spent indoors, obesity
Active Vitamin D
1,25-hydroxyD3
Excipient
An inert substance that is used to constitute the final dosage form to ensure adequate delivery of the drug
Enthalpy
Heat content
As a temp increases, the enthalpy increases proportionally
Substances can undergo a phase change or change of state
Solubility
The # of mL of solvent needed to dissolve 1 g of solute
Liquids tend to assume a _____shape
spherical
A volume with the minimum surface area and least free energy
Surface free energy
The work required to increase the surface area A of the liquid by 1 unit area
Newtonian substances
Liquids that behave according to viscosity eqn
Crystalline solids
Ice or NaCl
Are arranged in fixed geometric patterns and exhibit definitive shape
Amorphous solids
Show a lower degree of order and have randomly arranged units. Wider range of nondistinct melting points. Isotropic
Colloid
Type of chemical mixture in which one substance is dispersed evenly throughout another
Suspension
2-phase coarse dispersion system that is composed of insoluble solid material dispersed in an oily or aqueous liquid medium.
Emulsion
Thermodynamically unstable heterogenous system that consists of at least one immiscible liquid that is intimately dispersed in another to form droplets.
Shelf life
Time lapsed to maintain 90% of the drug at a specific temperature or pH
Suspensions follow ______ kinetics
zero-order
Sublingual/buccal absorption
thin mucus membranes cause a low barrier to systemic entry.
High vascularity allows a high-concentration gradient.
Paracellular absorption
Only low molecular weight and highly hydrophilic compounds are absorbed paracellularly (between cells). This is due to tight junctions between the cells that limit abs
Transcellular abs
Across the epithelial cells
Occurs as either passive diffusion, carrier-mediated transport, or pinocytosis
Passive diffusion
Most common mech of abs
Diffuse from a region of high concentration (gastric fluids) to low (blood circulation)
Pinocytosis
plays a very small role in drug transport. In pinocytosis, molecules or carrier packets are engulfed by a cell. The cell membrane encloses the molecule. It then fuses again, forming a vesicle that detaches and moves to the cell interior, where it releases its contents. Liposomes are examples of drugs that enter cells by pinocytosis.
Enteric coated
Designed to minimize exposure to the acidic pH of the stomach
Diluents
Provide bulk in tablet and accurate dosing of drug
Binders
Bind powders together to aid in granulation and compression
Lubricants
Prevent adherence of granules and powders to tablet punches and dies; aid smooth ejection of tablets
Polymers
Modulates drug dissolution from tablet
Vd
The theoretical volume that would occur if the drug were allowed to completely distribute throughout the body w/o elimination
First order elimination
A constant percentage of drug eliminated per unit time
