Kunze Midterm #1 Flashcards
ADME and membranes
ADME properties of most drugs depends on the ability of the drug to pass through membranes via diffusion. Only the unionized form of the drug can pass through the membrane via simple diffusion. Charged and/or uncharged forms of the drug can pass through membranes via influx and efflux transporters. Example is amino acids and simple sugars which require transporters. P-gp is main efflux transporter
Absorption
net diffusion of a drug through the intestinal epithelium into the portal blood. Dependent on dissolution, lipid solubility, ionization state (pKa) and transporters systemic bioavailability: amount of drug that makes it into the systemic circulation
Distribution
drugs are distributed into various compartments in the body where the find targets that include receptors and metabolic enzymes. Targets can be extracellular or intracellular. Usually have to pass through additional membrane to reach these targets. Remember that potassium is high in the cell and sodium is low in the cell, but pH is the same inside and outside the cell.
Metabolism
metabolic enzymes are usually located in the hepatocytes. Metabolism creates more polar and less active metabolites that are readily excreted, and thus controls the rate at which drug is cleared from the body.
Excretion
Largely excreted as metabolites and/or unchanged by the kidneys. Renal clearance depends on the reabsorption of the drug from the filtrate which depends on the ionization state of the drug in the tubule.
Ionization of drugs
ionization depends on the functional groups pKa value and the pH of the aqueous phase. Some pH values: blood and intracellular fluid pH = 7.4; urine pH = 5-8 (7 is normal); GI tract pH = 1-7 (stomach is 1; intestine is 3-7); CSF pH = 7.3 Henderson-Hasselbach: pKa = pH - log([conjugate base]/[conjugate acid]). When pH = pKa the ratio of conjugate base to conjugate acid is 1:1.
Carboxylic Acids
OH –> O- and H+ pKa = 4-5 conjugate acid is OH (neutral )and conjugate base is O- (charged) At pH 7.4 majority of drug is conjugate base. At pH 7.4 majority of drug is conjugate base. At pH < 4 majority of drug in conjugate acid
Absorbed in duodenum because pH favors the uncharged form of the drug.
Aromatic Amines
NH3 + –> NH2 pKa 4-5 conjugate acid is NH3 + (charged) and conjugate base is NH2 (uncharged) At pH 7.4 majority of drug is in the conjugate base which is uncharged. Absorbed in ileum which is more distal and more basic.
Electron withdrawing groups trends in pka
electron withdrawing groups tend to lower pKa values, and electron donating groups tend to raise pKa values
Weak acids
Weak acids are considered to be pKa 2-5 or so and strong acids have pKa less than 2 and are always ionized in the body
Membranes and passive diffusion
When a membrane separates compartments of different pH the total concentration of an ionizable drug will be different in each compartment while the concentrations of the unionized species will be the same due to passive diffusion.
logP
logP is the partition coefficient that is a quantitative measure of lipophilicity. Compares the solubility of the unionized form in octanol to that in water. Therefore, logP is measured for only the non-ionized species. Equal solubility in both phases gives a P=1 and a logP=0. LogP values are independent of pH.
logD
logD is the partition coefficient that is a quantitative measure of the ration of total drug in each phase. For non-ionizable drugs then logP and logD are the same. For ionizable drugs logD is dependent on pH of the aqueous phase. = [drug octanol]/([HA water] + [A- water])
trends of logP and logD
- LogD for weak acids (conjugate acid is neutral) decreases as pH increases 2. logD for weak bases (conjugate acid is charged) increases as pH increases 3. pKa, logP and logD are related. If you know any two values you can calculate the third. 4. Increasing logP and/or logD confers better absorption 5. Increasing logP and/or logD confers worse percentage of drug excreted unchanged
Lipinski’s rules
Used to guide the development of new drugs that would be orally active An orally active drug has no more than one violation of the following criteria 1. Not more than 5 hydrogen bond donors 2. Not more than 10 hydrogen bond acceptors 3. A molecular weight less than 500 grams/mole 4. An octanol-water partition coefficient, log P, not greater than 5.
Stereospecific
when one isomer has a property and the other one does not
Stereoselective
when the isomers have a common biological property but different magnitude of effect
enantiomers
used when the molecule has only two possible isomers (one chiral center)
Diastereoisomers
Present when the molecule has multiple chiral centers, and the total number of possible isomers becomes 2^n where n is the number of chiral centers. Each isomer will have one enantiomer and it is the inversion of that isomer. Example an S,S isomer’s enantiomer will be R,R. These isomers have identical properties in an achiral environment but act differently as drugs due to the three-dimensional structures of receptors. The remaining isomers will be diastereoisomers. These differ in chemical properties as well as in biological activities.
Stereochemistry Example: warfarin
Older drug that initially was given as a racemic mixture. pKa = 5, logP = 3.5 stereoselective inhibition of vitamin K epoxide reductase, the S enantiomer is 3 times more potent than the R enantiomer. Development of the single S enantiomer was attempted but failed to improve outcomes
Stereochemistry Example: fluoxetine
pKa = 9 and logP = 3.5 Unknown stereochemistry, so the drug is always given as a racemate. Metabolites through CYP catalyzed N-demethylation reactions Absorption occurs in ileum due to pKa. Efforts to develop and market the enantiomers failed
Stereochemistry Example: ofloxacin
fluoroquinolone antibiotic that inhibits topoisomerase S enantiomer is much more active than the R enantiomer and is marketed as a separate drug, Levofloxacin. Because with levofloxacin we give a lower fluoroquinolone dose because of its higher potency, it presumably has lower probability for tendon rupture. Molecule is zwitter-ionic and is therefore always in a charged state, though bioavailability is good. Therefore, must be absorbed through transporters.
Stereochemistry Example: Omeprazole
PPI’s all have an unique chiral center at a sulphur atom. The lowest priority group will be the lone electron pair and the sulphur does not undergo racemization. Controversial whether the S enantiomer, Nexium, has any benefit over the racemate. Unstable in the stomach so they are formulated for release in the intestine and require transportation through the blood stream back to the stomach where the irreversibly inhibit proton pumps
Stereochemistry Example: Ibuprofen
Weak carboxylic acid. S enantiomer is the active form however efforts to develop the single enantiomer to improve potency were discontinued when it was realized that an acyl-CoA racemase converts the R enantiomer to the S enantiomer.
Things to worry about when isomeric drugs are compared
- different ADME properties are almost always observed since transporter, metabolic enzyme and albumin are 2. complex 3D structures and interact stereoselecively and stereospecifically 3. different pharmacology at receptors (one isomer may be an agonist and the other may be an antagonist) different off-target effects and side effects
Enzymes as targets
many drugs are competitive inhibitors that are structurally similar to the endogenous substrate. Goal is to develop drugs with increased affinity (lower IC50), and have minimal off target effects
Reversible inhibitors Example
Statin drugs
Endogenous reaction of HMG-CoA
HMG-CoA and NADPH form mevalonate and CoASH which is catalyzed by HMG-CoA reductase. This is the rate limiting step in the formation of cholesterol.
Statin mechanism
Inhibition of HMG-CoA reductase by statins decreases LDL and increases HDL Statins: reversible and bind tightly to competitively inhibit HMG-CoA reductase. Statins must enter the cell to bind the enzyme active site. The affinity for HMG-CoA for the enzyme is much poorer than the inhibitor.
Statin structure
all of the statins must have a similar lactone ring as is found on the endogenous HMG-CoA. The ring must be open to bind to the enzyme. Type 2 compounds (all but simvastatin and compactin) contain a para-fluoro phenyl group which associates with an arginine side chain.
Statin side effect
rhabdomyolysis
Statin availability
Only 15% of the drug is systemically available but the metabolites are active so it appears that about 70% of the drug is available.
Irreversible inhibitors Example
Acetylcholine esterase and Sarin
ACh
ACh is a neurotransmitter released from the presynaptic neuron and binds to postsynaptic receptors that control calcium and secondarily chloride channels. ACh is a quaternary ammonium compound that is always charged Two receptors for ACh: nicotinic (nAChR) and muscarinic (mAChR)
ACHE
ACHE is an esterase that controls the intensity and duration of action of ACh. Many drugs, insecticides and nerve gases inhibit ACHE which potentiates the ACh effect. 1. ACHE reversibly forms an acyl intermediate to form acetic acid 2. Neostigmine binds to ACHE to form a carbamyl intermediate which is slowly reversed back to an active ACHE. Considered pseudo-irreversible because the reaction takes so long to restore activity to ACHE 3. Sarin gas irreversibly binds to ACHE and cannot undergo hydrolysis to reform the ACHE. Sarin gas contains a phosphorous group that is a chiral center, and which cannot be hydrolyzed. 4. Botulinum toxin: prevents release of ACh from granules in presynaptic cells
Extracellular receptor: muscarine receptor
muscarine: quaternary nitrogen that is always positively charged. pKa is around 9 (S)-nicotine: contains two basic ionizable groups (pyridine pKa around 5) and an alkylamine (pKa around 9). pKa is around 5. mAChR: 5 types of muscarinic receptors, all are GPCR. M1, M3 and M5 control intracellular free calcium concentrations via the phophoinisitol pathway. M2 and M4 inhibit the formation of the second messenger, cAMP. The quantity and distribution of the receptor types depends on the nerve of interest.
Chantix
used for smoking cessation, but has issues with bizarre behavior. Agonist of the nAChR which is a Na/Ca channel.
Succinyl choline
anesthesia that is a depolarizing neuromuscular blocking agent that initially depolarizes. It is an ACh mimic that is an antagonist because it doesn’t allow ACh to bind. Structure forms two ACh
Methanocholine
agonist of mAChR. Diagnostic for bronchial hypersensitivity in asthma. The (S) enantiomer is the more potent. Structurally contains an quaternary ammonium group that is always charged.
atropine
antagonist of mAChR. (S) enantiomer is 120 times more potent.
Ki and EC50
Ki is the affinity of the of the inhibitor for the compound. Lower Ki means more affinity for the compound. IC50 is the inhibitory concentration to inhibit 50% of the compound. Lower concentrations mean the drug is more potent for the compound
Intracellular receptors
Steroids easily enter the cell and exert their effects by translocating receptor complexes to bind to regulatory regions of DNA called response elements. Binding to a response element can either activate transcription or inhibit transcription.
Glucocorticoids
- subclass of steroid hormones that modulates metabolic, cardiovascular, immune and behavioral functions. 2. GR: glucocorticoid receptor which is part of a large macromolecule. When glucocorticoid binds, GR undergoes a change in conformation and dissociates from the regulatory macromolecule and is hyperphosphorylated. 3. Activated GR translocates to the nucleus where it binds as a homodimer directly to DNA promoter regions at a glucocorticoid response element (GRE) leading to transcriptional induction or repression. 4. Synthetic is dexamethasone. Endogenous is cortisol.
Mineralcorticoids
Bind to a receptor in the kidney tubule called the mineralcorticoid response element (MRE) which causes upregulation of the synthesis of the basolateral Na/K pump. This causes conservation of sodium, secretion of potassium, increased water retention and therefore increased blood pressure. Aldosterone is a endogenous agonist.
General side effects of intracellular molecules
General side effect of any glucocorticoid, mineralcorticoid or steroid for that matter is that receptors are no specific but are somewhat selective, and thus have off-target effects.
Aliphatic Amine
Pka 1
pKa 2
pKa 3
pKa 4
