Sample questions-Ph. chemistry I-Spring semester 2023-2024.pdf

PHAR206 Final Exam – Sample Questions 1- Describe the process of drug absorption subsequent to administering an oral dosage form? The journey of a drug from an oral dosage form to reaching the bloodstream involves several sequen...

PHAR206 Final Exam – Sample Questions 1- Describe the process of drug absorption subsequent to administering an oral dosage form? The journey of a drug from an oral dosage form to reaching the bloodstream involves several sequential steps aimed at achieving optimal bioavailability. The initial phase involves disintegration of the dosage form, enabling the release of the active ingredient. The drug transforms from coarse particles to finely dissolved particles and eventually reaches a molecular state, ensuring each molecule is fully dissolved and available. Subsequently, the drug traverses the biological membrane, typically a bimolecular lipid layer, to facilitate absorption. 2- Does the pH-gradient remain consistent throughout the gastrointestinal tract (GIT) from the oral cavity to the colon? No, there is a substantial variation in pH throughout the GIT. The oral cavity typically maintains a pH of around 7, but this sharply drops to a highly acidic pH of 1-3 in the stomach. As digestion progresses through the gastric environment, the pH gradually starts to increase and becomes more alkaline. Consequently, the pH in the duodenum measures around 5.5, rises to 7 in the small intestine, and eventually the colon exhibits a notably basic pH of 8. 3- Could you describe the general characteristics of the passive diffusion mechanism? − Passive diffusion constitutes roughly 95% of drug absorption within the gastrointestinal tract. − It involves the movement of drug molecules from areas of higher concentration in the gastrointestinal lumen to regions of lower concentration within the blood vessels. Thus, the primary driving force behind passive diffusion is the existing concentration gradient. − Molecules existing in non-ionized or neutral states exhibit higher permeability compared to their ionic counterparts. 4- According to the pH-Partition Theory, what parameters are considered determinants affecting the extent of drug absorption across biological membranes? The pH-Partition Theory attributes the extent of drug absorption across biological membranes to the interplay among three key parameters: the dissociation constant of the drug, its lipid solubility, 1 and the pH of the fluid at the absorption site. These factors collectively govern the absorption extent from a solution. 5- Considering the passive diffusion mechanism, what pH conditions are preferable for optimal absorption of basic and acidic drugs? For basic drug molecules, the optimal condition for passive diffusion across the biological membrane occurs at higher pH values. At these levels, a higher proportion of the drug exists in the unionized form, facilitating passage across the biological membrane. Conversely, at lower pH levels, the percentage of the ionized form increases, hindering its ability to traverse the biological membrane. The opposite holds true for acidic drugs. 6- The aspirin is an acidic drug, with a pKa value of 3.5. What is the anticipated site of absorption for aspirin and the rationale behind this prediction? And is it preferred to be taken after meal or before meal? The predicted site of absorption for aspirin, an acidic drug with a pKa value of 3.5, is the stomach. This is primarily due to the stomach's pH range of 1-3, which allows aspirin to predominantly exist in its unionized form. Given that the stomach's pH is lower than the drug's pKa (acidic in an acidic environment), aspirin tends to be more available in its non-ionized form, facilitating its absorption. Thus it should be taken after meal because taking it after a meal prolongs its stay in the stomach, optimizing its absorption at the intended site 7- Which one of the following figures represents the passive diffusion and the one represents the active (carrier mediated) transport? (A) (B) Figure (A) illustrates passive diffusion. In this depiction, as the drug concentration rises, the absorption rate also increases in a consistent and linear relationship. In contrast, the figure (B) representing active (carrier mediated) transport showcases a distinct pattern. Initially, the rate of absorption escalates with increasing drug concentration until reaching a saturation phase. Beyond 2 this point, despite further increases in drug concentration, the absorption rate stabilizes, indicating a maximum capacity for absorption through this mechanism. 8- In pharmaceutical terms, what does the Partition Coefficient (Log P) value signify, and what does a higher Log P value indicate regarding a drug's properties? The LogP serves as a guide to determine the lipid solubility or lipophilic nature of a drug. A higher LogP value indicates the higher lipid solubility of the drug, signifying increased lipophilicity. 9- When aiming to improve the oral bioavailability of a drug through design or modification, what characteristics regarding lipophilicity and hydrophilicity are preferred? The optimal goal is to strike a balance between the drug's lipophilicity and hydrophilicity. It's favorable for the drug to possess hydrophilic properties for rapid dissolution, while also exhibiting adequate lipophilic characteristics to facilitate its passage across biological membranes. 10- Enalapril is an example of a prodrug (In active) form, defines a prodrug, and how does the enalapril convert into its active form? Enalaprilat Enalapril Prodrugs are modified derivatives of drug molecules designed to undergo enzymatic or chemical changes within the body, leading to the release of the active parent drug responsible for the desired pharmacological effect. In the case of enalapril, enzymatic hydrolysis of its ester bond by esterase enzymes found in the liver, bloodstream, and cells converts it into the active form, a carboxylic acid. 11- What is the purpose of drug metabolism, and which reactions are involved in Phase I and Phase II metabolism? Drug metabolism serves to convert lipid-soluble compounds into water-soluble forms, aiding their easier excretion from the body through various processes. Phase I metabolism involves mild 3 reactions like oxidation, reduction, dealkylation, and hydroxylation. Phase II metabolism includes conjugation reactions. 12- In the metabolism of paracetamol depicted in the figure, which metabolite is regarded as the most toxic, and what attributes contribute to its heightened toxicity? The most toxic metabolite in the metabolism of paracetamol is NAPQI. This metabolite contains a quinone-imine aromatic ring, forming a potent nucleophile with negative charges. NAPQI's strong binding affinity with proteins and nucleic acids contributes to its heightened toxicity. 13- What defines the Lipinski Rule of 5, and what are the parameters it includes? The Lipinski Rule of 5 serves as a guideline to differentiate between drug-like and non-drug-like molecules, providing insights into their potential success or failure as drugs. It consists of parameters such as a molecular mass less than 500 Dalton, high lipophilicity (LogP less than 5), fewer than 5 hydrogen bond donors, fewer than 10 hydrogen bond acceptors, and a molar refractivity ranging between 40-130. 14- What does bioisosterism entail, and what are the primary objectives behind using this strategy in drug design? Bioisosterism refers to the substitution of one atom or group of atoms in a parent compound with another having similar electronic and steric configurations. This strategy is employed in drug design to facilitate the creation of new compounds for various purposes: enhancing patent positions, replacing metabolically unstable moieties, seeking more favorable receptor interactions, and crafting improved pharmacodynamic profiles. 15- What substitutes serve as optimal isosteres for the following functional groups: phenyl ring, carboxylic acid, ester, and methyl groups? The optimal isosteres for these functional groups are the pyridine ring for phenyl rings, tetrazole ring for carboxylic acids, amide for ester bonds, and fluorine for the methyl group. 4  16- Why do ester-containing drug molecules exhibit high in vivo lability and low metabolic stability? How can their metabolic stability be enhanced through chemical modification? Ester-containing drug molecules demonstrate high in vivo lability due to the ubiquitous presence of esterases found in blood, liver, kidneys, and various organs. To improve the metabolic stability of ester-containing drugs, bioisosteric substitution of the ester group with an amide bond has been extensively explored. The amide bond is considerably more resilient against degradation by esterase enzymes, thereby enhancing the molecule's metabolic stability. 17- Why is the preference for having multiple drugs covering a broad spectrum of lipophilicity and hydrophilicity profiles crucial in both clinical and pharmaceutical research, particularly concerning excretion sites and patient cases? Hydrophilic drugs are typically excreted via the kidneys, whereas lipophilic drugs are eliminated through the liver. Hence, patients with renal failure should avoid hydrophilic drugs, whereas those with liver failure should steer clear of lipophilic medications. Having a range of drugs with varied lipophilicity and hydrophilicity profiles allows for tailored prescriptions that account for specific excretion pathways, ensuring safer administration in patients with organ-specific complications. 18- Why is the replacement of the para-methyl group in celecoxib with fluorine considered an optimal chemical modification, and why is fluorine considered an ideal biostere? Fluorine is deemed an optimal biostere for methyl due to the C–F bond's greater resistance to direct attack by cytochrome P450 (CYP) oxidases compared to the CH3-C bond. This increased stability makes the C–F bond less susceptible to metabolic degradation. Additionally, fluorine atoms positioned para to phenyl rings prevent metabolic hydroxylation, contributing to enhanced metabolic stability when replacing the p-methyl group in celecoxib with fluorine. 5  19- What advantages of replacing phenyl ring with pyridine? the replacement of phenyl ring with pyridine ring usually leads to enhance solubility and decrease the toxicity due to preventing the forming of toxic metabolites. Also, the pyridine ring is less susciptable for the metabolic attack especially for CYP450 because the pyridine ring less electron density than phenyl ring due to the electron withdrawing effect of nitrogen conpaired to carbon atom. 20- Why does substituting the R group at the ortho position of -NH- significantly enhance lipophilicity in the following structure? The replacement of the R with fluorine at the ortho position leads to the formation of a hydrogen bond between -NH- and fluorine. This interaction results in the masking of hydrogen bonds that the -NH- would typically form with water. Consequently, the structure loses one hydrogen bonding site with water, leading to an increase in lipophilicity. 21- The Pka value of -OH functional group here is similar to pka value of carboxylic acid due to what? 6 Due to the electron withdrawing effect of the two Fluorine atoms. 22- What actions are controlled by the sympathetic and parasympathetic nervous systems within the autonomic nervous system? The sympathetic nervous system activates the fight-or-flight response in situations of threat or perceived danger. Conversely, the parasympathetic nervous system restores the body to a state of calmness. 23- What serves as the natural neurotransmitter of the parasympathetic nervous system? The natural neurotransmitter of the parasympathetic nervous system is acetylcholine 24- What is the term used to describe chemical compounds that induce stimulation of the parasympathetic nervous system? The chemical compounds that cause stimulation of the parasympathetic nervous system are termed cholinomimetic or parasympathomimetic agents. 25- What targets should be considered in designing a new drug intended to act as cholinomimetic agents? 7 The newly designed drugs should aim to function as agonists that directly act on cholinergic receptors or act as inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine. 26- Why is acetylcholine considered a poor therapeutic agent for treating an imbalance in parasympathetic tone? Acetylcholine's nonselective actions, affecting all cholinergic receptor sites, can lead to serious consequences due to its lack of specificity. Additionally, as a quaternary ammonium salt, acetylcholine poorly crosses biological membranes, resulting in low bioavailability regardless of the administration route. Moreover, its ester functional group undergoes rapid hydrolysis in the acidic conditions of the gastrointestinal tract and by plasma esterases, leading to a short half-life and further limited bioavailability. 27- What physical forces and conformational requirements can be extracted from the model of the following muscarinic Acetylcholine receptor? The model emphasizes the importance of muscarinic agonists possessing an ester functional group and a quaternary ammonium group separated by two carbons for optimal fitting within the receptor's binding site. It showcases the necessity for an ionic interaction between the positively charged quaternary nitrogen of acetylcholine and an anionic site on the receptor. Additionally, the model highlights the essential hydrogen bond formation between the ester oxygen of acetylcholine and a hydroxyl group contributed by the esteratic site of the receptor. 28- What is the physiological mechanism responsible for terminating the action of acetylcholine after binding with its receptor and completing its action? 8 The physiological mechanism for terminating the action of acetylcholine involves hydrolysis by the acetylcholine esterase enzyme. The acetylcholine is hydrolyzed into choline and acetic acid. 29- What steps are involved in the hydrolysis of Acetylcholine (ACh) by the acetylcholine esterase enzyme? The mechanism of Ach hydrolysis involves two sequential steps: acylation, followed by deacylation. 30- How can the following synthesis pathway be completed to synthesize acetylcholine? The chemical structure suitable to complete the synthesis pathway is OH-CH2-CH2-Halogen, such as Cl, Br, or I. However, fluorine (F) is not a suitable because it not good leaving group so could not be applied. Therefore, the applicable reactants that can be used are OH-CH2-CH2- Cl, OH-CH2-CH2-Br, or OH-CH2-CH2-I. 31- Based on the previous question, why couldn't we obtain (CH3)3N-CH2-CH2-Cl, with the OH replacing, as both carbons adjacent to chloride and OH are strong electrophiles and could attract the nucleophile (nitrogen atom)? Answer: The explanation is that chloride (a halogen) is a good leaving group, while OH is not a good leaving group. Therefore, the OH group cannot be easily replaced, whereas the Cl can be readily replaced. 32- In the synthesis of Pilocarpine, which reagents are employed to convert the carboxylic acid (-COOH) to acyl chloride (-COCl)? The reagents that can be used to convert carboxylic acid to acyl chloride are SOCl2, PCl3, or PCl5. 9  33- What are the Structure-Activity Relationships (SAR) associated with achieving muscarinic activity based on the structure of acetylcholine? It has been determined that compounds exhibiting appreciable muscarinic activity possess a positive charge on the nitrogen atom, typically in the form of a quaternary ammonium. Inactivity is observed when all three methyl groups on the nitrogen are replaced by larger alkyl groups or smaller substituents leads to decrease the activity. Furthermore, altering the ethylene bridge to longer or shorter bridges results in diminished activity. 34- How can you explain the resistance of carbacol (carbamylcholine) to acid hydrolysis compared to acetylcholine? The carbonyl carbon (-CO-) in carbacol (carbamylcholine) is less electrophilic due to the electron- donating effects of the adjacent -NH2 group. This results in carbamates being more stable than carboxylate esters against acid hydrolysis. 35- What chemical rationale underlies the development of malathion, an insecticide that acts as an irreversible acetylcholine esterase inhibitor? Malathion's development as an irreversible acetylcholine esterase inhibitor relies on the presence of a phosphorus atom, which forms a stable phosphor ester functional group upon conjugation with the acetylcholine esterase enzyme. The strong electron-donating behavior of the phosphorus atom 10 facilitates the formation of a stable acylation step, preventing subsequent deacylation. This irreversibly inhibits the acetylcholine esterase enzyme. 36- Why does the alkene act as an electrophile in the chemical synthesis of malathion, even though it is a double bond containing π electrons and typically considered a nucleophile? Malathion The alkene in this context serves as an electrophile due to its resonance effect with the ketone functional group. The movement of the double bond to the upper or the lower side induces a positive charge at the double bond position, making it available for attack by the nucleophile (- SH). 37- In the chemical synthesis of atropine, what functional group is formed upon the acid hydrolysis (H+/H2O) of the –CN functional group? The acid hydrolysis of the –CN functional group results in the formation of a carboxylic acid (- COOH) functional group. 38- What is the primary reason behind the brief duration of action of the Succinylcholine Chloride drug (nicotinic antagonist)? The main reason for the brief duration of action of Succinylcholine Chloride is its rapid hydrolysis and subsequent inactivation by esterase enzymes, which act on both ester bonds in the molecule. 11  39- Why is compound A preferred over compound B, and compound B preferred over compound C in the following chemical synthesis? Compound 1, being an acyl chloride derivative, possesses a strong electrophilic carbonyl carbon due to the high electronegativity of both the chloride and oxygen atoms. In compound 2 (acetic anhydride), the carbonyl carbon exhibits moderate electrophilicity due to the presence of two carbonyl functional groups, while in compound 3 (acetic acid), the carbonyl carbon exhibits weak electrophilicity due to the presence of resonance effects between the two oxygen atoms. Thus, utilizing compound A would facilitate a faster reaction compared to using compound B, and compound B would be faster than compound C. Good luck 12