أسئلة الثالثة فارما PPPM (قبل التعديل)
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Questions and Answers

Why is stereoisomerism important in pharmacology?

  • Stereoisomers always have equal potency and effects.
  • One stereoisomer can be beneficial while another is toxic or has vastly different potency. (correct)
  • Receptor sites are universally sensitive to all stereoisomers of a drug.
  • Drugs are always administered as pure isomers to avoid complications.

A drug with a molecular weight of 1500 Da is developed. Which of the following is most likely?

  • It can easily cross the placental barrier.
  • It must be administered parenterally. (correct)
  • It can be effectively absorbed orally.
  • It will be rapidly distributed throughout the body.

What is the primary focus of chronopharmacology?

  • Studying the effects of drugs on sleep patterns.
  • Administering drugs based on the body's natural circadian rhythms. (correct)
  • Creating drugs that are effective regardless of the time of day.
  • Developing drugs with extremely long half-lives.

A researcher discovers that a particular enzyme responsible for metabolizing a drug is most active in the evening. According to chronopharmacological principles, when should this drug ideally be administered for maximum effectiveness?

<p>Late evening (C)</p> Signup and view all the answers

A drug is known to be present in a 'racemic mixture.' What does this imply about its isomeric composition?

<p>It is a mixture of two or more stereoisomers. (B)</p> Signup and view all the answers

Why might a single drug act as both an agonist and an antagonist at the same receptor?

<p>The drug is present as a racemic mixture of stereoisomers with opposing effects. (B)</p> Signup and view all the answers

Which characteristic of a drug primarily determines whether it can cross the placental barrier?

<p>The drug's molecular weight (D)</p> Signup and view all the answers

Which of the following physiological functions is LEAST likely to be influenced by circadian rhythms, impacting drug response?

<p>Hair Follicle Density (B)</p> Signup and view all the answers

Why are acute bronchial asthma episodes more common at night?

<p>Circadian variation of cortisol and other inflammatory mediators. (A)</p> Signup and view all the answers

Why might antihypertensive medications be more effective when administered in the morning?

<p>Blood pressure tends to peak during the afternoon. (C)</p> Signup and view all the answers

In which situation is drug accumulation most likely to occur?

<p>When the rate of drug administration exceeds the rate of its elimination. (C)</p> Signup and view all the answers

Why might a patient with liver or renal disease be at higher risk of drug accumulation?

<p>Reduced ability to eliminate drugs, leading to accumulation. (B)</p> Signup and view all the answers

What is the primary characteristic of 'summation' in drug combinations?

<p>The combined effect is equal to the sum of their individual effects (1+1=2). (B)</p> Signup and view all the answers

Penicillin and aminoglycosides are sometimes used in combination to treat bacterial infections. What type of drug interaction does this represent?

<p>Synergism (B)</p> Signup and view all the answers

How does 'potentiation' differ from 'synergism' in drug combinations?

<p>In potentiation, one drug increases the effect of another drug that has no notable effect on its own, while synergism requires both drugs to have an effect. (D)</p> Signup and view all the answers

Failing hearts can be more sensitive to digitalis than normal hearts. Which of the following best describes why?

<p>Pathological Status (B)</p> Signup and view all the answers

Which mechanism primarily explains receptor desensitization in pharmacodynamic tolerance?

<p>Slow conformational changes in the receptors. (B)</p> Signup and view all the answers

Why is pyridoxine (vitamin B6) often administered alongside isoniazid?

<p>To counteract the peripheral neuropathy caused by isoniazid. (D)</p> Signup and view all the answers

What is the primary cause of pharmacokinetic tolerance?

<p>Increased metabolic degradation of a drug. (A)</p> Signup and view all the answers

Which of the following drugs is most likely to induce a systemic lupus erythematosus (SLE)-like syndrome in slow acetylators?

<p>Hydralazine (D)</p> Signup and view all the answers

Behavioral tolerance involves which of the following adaptations?

<p>The brain learning to actively overcome drug-induced effects. (C)</p> Signup and view all the answers

What physiological change underlies the rebound effect observed after stopping an antagonist drug?

<p>Up-regulation of receptors. (A)</p> Signup and view all the answers

A patient requires a significantly higher dose of warfarin than normal to achieve the desired anticoagulant effect. Which of the following is the most likely explanation for this?

<p>A genetic variant of vitamin K epoxide reductase with reduced sensitivity to warfarin. (B)</p> Signup and view all the answers

Which of the following best describes the withdrawal effect?

<p>Exaggerated recurrence of original symptoms plus new symptoms. (D)</p> Signup and view all the answers

A child with vitamin D-resistant rickets requires very high doses of vitamin D for treatment. What pharmacological principle does this scenario illustrate?

<p>Resistance (A)</p> Signup and view all the answers

Why is it dangerous to abruptly discontinue beta-blockers?

<p>It may result in severe tachycardia, arrhythmia, or myocardial infarction. (A)</p> Signup and view all the answers

Why do individuals with dark eyes often exhibit a reduced response to mydriatic drugs?

<p>Genetic factors influencing receptor sensitivity (C)</p> Signup and view all the answers

What is the key difference between tolerance and tachyphylaxis in the context of drug response?

<p>Tolerance develops over a longer time period, while tachyphylaxis occurs rapidly. (D)</p> Signup and view all the answers

What condition can arise from the sudden withdrawal of corticosteroids after long-term use?

<p>Acute Addisonian crisis (B)</p> Signup and view all the answers

Abrupt withdrawal of Warfarin can lead to which of the following conditions?

<p>Thrombotic catastrophes (A)</p> Signup and view all the answers

A patient initially responds well to a certain dose of a drug, but over several weeks, the same dose elicits a weaker response. Which of the following pharmacological phenomena is most likely occurring?

<p>Tolerance (D)</p> Signup and view all the answers

A patient receives multiple doses of a drug within a short period. The effectiveness of the drug diminishes rapidly with each subsequent dose. This phenomenon is best described as:

<p>Tachyphylaxis. (A)</p> Signup and view all the answers

Succinylcholine apnea, a severe muscle paralysis, can occur in individuals with deficient pseudocholinesterase (PsChE) due to what mechanism?

<p>Decreased metabolism of succinylcholine, prolonging its neuromuscular blocking effect. (D)</p> Signup and view all the answers

Why are individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency at risk of acute hemolysis when exposed to certain drugs?

<p>G6PD deficiency impairs the production of reduced glutathione, which protects red blood cells from oxidative damage. (C)</p> Signup and view all the answers

Thiopurine methyltransferase (TPMT) deficiency can result in severe myelotoxicity and bone marrow suppression in patients treated with thiopurine drugs because:

<p>TPMT deficiency promotes the conversion of thiopurine drugs into more toxic compounds. (B)</p> Signup and view all the answers

Why is screening for thiopurine methyltransferase (TPMT) deficiency recommended before initiating treatment with thiopurine anticancer drugs?

<p>To identify patients who are at increased risk of developing severe toxicity due to decreased drug metabolism. (B)</p> Signup and view all the answers

Isoniazid is metabolized in the liver via acetylation. What is the consequence of being a 'rapid acetylator' when taking isoniazid?

<p>Increased risk of hepatocellular necrosis due to accumulation of toxic metabolites. (C)</p> Signup and view all the answers

A patient with a known pseudocholinesterase deficiency requires anesthesia for an emergency surgery. Which neuromuscular blocking agent should be avoided, and why?

<p>Succinylcholine, because its metabolism is significantly reduced, leading to prolonged paralysis. (A)</p> Signup and view all the answers

An individual with G6PD deficiency is prescribed an antimalarial drug. What is the most critical adverse effect they should be monitored for?

<p>Acute Hemolytic Anemia (B)</p> Signup and view all the answers

A patient is started on 6-mercaptopurine for leukemia. Genetic testing reveals they are TPMT deficient. What is the most likely dose adjustment required and why?

<p>Decrease the dose significantly due to increased risk of myelosuppression. (B)</p> Signup and view all the answers

Which of the following best explains why administering anti-asthmatic medications in the evening is often more effective?

<p>To counteract the circadian rhythm-related increase in inflammatory mediators that occurs during the night. (A)</p> Signup and view all the answers

Why does the rate of drug administration exceeding the rate of elimination lead to drug accumulation?

<p>Reduced hepatic and renal clearance impairs the body's ability to remove the drug. (D)</p> Signup and view all the answers

A patient with compromised liver function is prescribed a medication. Which of the following aspects of drug disposition is MOST likely to be affected?

<p>Metabolism, due to impaired hepatic enzyme activity. (B)</p> Signup and view all the answers

In a drug combination exhibiting 'summation', what is the expected combined effect in relation to the individual effects of each drug?

<p>The combined effect is equal to the sum of the individual effects of each drug. (B)</p> Signup and view all the answers

Why is the combination of penicillin and aminoglycosides considered an example of synergism?

<p>Penicillin and aminoglycosides have different mechanisms of action, leading to a combined bactericidal effect greater than the sum of their individual effects. (B)</p> Signup and view all the answers

In potentiation, how does one drug enhance the effect of another when it has no notable effect of its own?

<p>By inhibiting the breakdown of the other drug, leading to higher circulating levels. (B)</p> Signup and view all the answers

How might altered drug metabolism in patients with liver disease lead to an exaggerated response to a standard drug dose?

<p>Impaired hepatic enzyme activity can decrease drug clearance, increasing systemic exposure. (A)</p> Signup and view all the answers

Why might a patient with a failing heart exhibit increased sensitivity to digitalis compared to a patient with a healthy heart?

<p>Altered electrolyte balance and increased sympathetic tone in the failing heart enhance digitalis's effects. (B)</p> Signup and view all the answers

Why does isoniazid accumulation in slow acetylators lead to peripheral neuropathy?

<p>Isoniazid interferes with pyridoxine metabolism, leading to neuronal dysfunction. (C)</p> Signup and view all the answers

Which drug, when administered to a slow acetylator, carries the highest risk (+++) of inducing a systemic lupus erythematosus (SLE)-like syndrome?

<p>Hydralazine (B)</p> Signup and view all the answers

Why do some individuals with a variant of vitamin K epoxide reductase require significantly higher doses of warfarin?

<p>The variant enzyme has reduced affinity for warfarin, decreasing its inhibitory effect. (C)</p> Signup and view all the answers

What is the most likely mechanism behind the reduced responsiveness to mydriatic drugs observed in individuals with dark eyes?

<p>Genetic variations in receptor subtypes affecting drug binding affinity. (C)</p> Signup and view all the answers

How does tachyphylaxis differ mechanistically from tolerance?

<p>Tachyphylaxis develops rapidly with repeated dosing, while tolerance develops gradually over time. (B)</p> Signup and view all the answers

How does the development of tolerance affect the dose-response curve of a drug?

<p>The dose-response curve shifts to the right, indicating decreased sensitivity. (D)</p> Signup and view all the answers

In the context of heritable conditions that lead to decreased drug response, what is the underlying cause for patients with vitamin D-resistant rickets needing high doses of vitamin D?

<p>Defective vitamin D receptors with reduced affinity to vitamin D. (C)</p> Signup and view all the answers

A patient develops tolerance to a drug over several weeks. Which compensatory mechanism is least likely contributing to this phenomenon?

<p>Increased drug absorption from the administration site (B)</p> Signup and view all the answers

A novel drug exhibits stereoisomerism, with one enantiomer demonstrating significantly higher receptor affinity and efficacy. Which factor most likely explains the difference in pharmacological activity between the enantiomers?

<p>The receptor binding site exhibits stereospecificity, favoring the spatial arrangement of one enantiomer over the other. (A)</p> Signup and view all the answers

A drug with a molecular weight of 1200 Da is being developed for oral administration. What is the most likely limitation this drug will face?

<p>The drug's absorption and distribution may be limited, possibly requiring parenteral administration. (D)</p> Signup and view all the answers

A new drug is most effective when administered in the late afternoon due to circadian variations in target enzyme expression. Which strategy best aligns with chronopharmacological principles to optimize the drug's efficacy?

<p>Utilizing a drug delivery system that releases the drug at a controlled rate, timed to coincide with peak enzyme activity. (C)</p> Signup and view all the answers

A drug exists as a racemic mixture, and one enantiomer is significantly more potent at the target receptor. If the drug is administered at a dose typically used for the pure, more active enantiomer, what is the most likely consequence?

<p>The drug's overall efficacy will be lower compared to the pure enantiomer, and the patient may experience diminished therapeutic benefit. (A)</p> Signup and view all the answers

A drug demonstrates properties of both an agonist and an antagonist at the same receptor. Which of the following scenarios best explains this?

<p>The drug acts as a partial agonist, producing a submaximal response and competitively inhibiting the binding of full agonists. (C)</p> Signup and view all the answers

A pregnant woman is prescribed a medication. What is the most critical physicochemical property of a drug that determines its ability to cross the placental barrier and potentially affect the fetus?

<p>The drug's molecular weight and lipophilicity. (D)</p> Signup and view all the answers

In the context of chronopharmacology, which physiological process, known to exhibit significant circadian variation, would most impact the dosing regimen of certain cardiovascular medications?

<p>Blood pressure and heart rate (A)</p> Signup and view all the answers

Considering that many physiological functions demonstrate circadian rhythms, what is the most crucial implication for drug administration timing to maximize therapeutic effects?

<p>Tailoring drug administration to align with the circadian rhythm of the targeted disease or physiological process. (D)</p> Signup and view all the answers

Succinylcholine apnea, a prolonged paralysis following succinylcholine administration, primarily results from which of the following mechanisms in individuals with pseudocholinesterase (PsChE) deficiency?

<p>Impaired metabolism of succinylcholine, resulting in prolonged presence at the neuromuscular junction. (B)</p> Signup and view all the answers

Why are individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency at heightened risk of acute hemolysis when exposed to certain drugs like antimalarials?

<p>G6PD deficiency compromises the NADPH-dependent reduction of glutathione, increasing oxidative stress and red blood cell damage. (B)</p> Signup and view all the answers

Thiopurine methyltransferase (TPMT) deficiency increases the risk of myelosuppression and bone marrow suppression in patients treated with thiopurine drugs like 6-mercaptopurine because:

<p>TPMT deficiency blocks the metabolism of thiopurine drugs, leading to accumulation of highly toxic compounds that damage bone marrow. (B)</p> Signup and view all the answers

Why is screening for thiopurine methyltransferase (TPMT) deficiency recommended before initiating treatment with thiopurine anticancer drugs, such as 6-mercaptopurine?

<p>To minimize the risk of severe myelosuppression and bone marrow suppression due to increased levels of active drug. (C)</p> Signup and view all the answers

Pharmacokinetic tolerance to a drug like ethanol primarily results from which of the following mechanisms?

<p>Induction of hepatic enzymes, leading to increased drug metabolism. (D)</p> Signup and view all the answers

Behavioral tolerance to psychoactive drugs is best described as:

<p>A drug-independent learning process that allows the brain to overcome drug effects through practice. (A)</p> Signup and view all the answers

What is the underlying mechanism for the 'rebound effect' observed after the abrupt cessation of an antagonist drug?

<p>An adaptive increase (up-regulation) in the number of receptors, leading to an exaggerated response when the antagonist is removed. (B)</p> Signup and view all the answers

Why does sudden withdrawal from beta-blockers pose a risk of severe tachycardia or arrhythmia?

<p>Prolonged beta-blockade leads to an up-regulation of beta-receptors, resulting in an exaggerated response to catecholamines upon withdrawal. (D)</p> Signup and view all the answers

Why does abrupt withdrawal of corticosteroids after long-term use lead to an acute Addisonian crisis?

<p>Long-term corticosteroid use suppresses the hypothalamic-pituitary-adrenal (HPA) axis, impairing the body's ability to produce endogenous corticosteroids. (D)</p> Signup and view all the answers

A patient has been taking a drug that acts as an antagonist at a specific receptor for an extended period. If the medication is suddenly discontinued, which of the following is LEAST likely to occur?

<p>A decrease in the number of receptors on the cell surface. (B)</p> Signup and view all the answers

After prolonged exposure to a drug, a patient develops tolerance. Which scenario best describes how receptor down-regulation contributes to this tolerance?

<p>The number of functional receptors decreases, requiring a higher dose of the drug to achieve the original effect. (C)</p> Signup and view all the answers

Flashcards

Drug Cumulation

Occurs when drug administration rate exceeds elimination rate, especially with liver or kidney disease.

Summation (Drug Combination)

Combined drug effect equals the sum of individual effects (1+1=2).

Synergism (Drug Combination)

Combined drug effect is greater than the sum of individual effects (1+1=3).

Potentiation (Drug Combination)

One drug greatly increases the effect of another, which has little effect alone (1+0=2).

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Antagonism (Drug Combination)

One drug abolishes the effect of another (1 + 1 = 0).

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Pharmacogenetic Factors (Idiosyncrasy)

Altered drug response due to genetic abnormality in drug metabolism.

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Pathological Status Impact

Liver or kidney diseases significantly alter drug response due to altered metabolism.

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Nocturnal Asthma Episodes

Occurs due to circadian variation of cortisol and other inflammatory mediators.

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Stereoisomerism in Drugs

Drugs often have multiple stereoisomers (enantiomers), like L-thyroxin & D-thyroxin.

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Receptor Sensitivity

Receptor sites are sensitive to one stereoisomer but not others.

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Isomer Potency/Toxicity

One stereoisomer is more potent than the other, or one may be beneficial while the other is toxic.

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High Molecular Weight Drugs (>1000 Da)

Drugs with a MW over 1000 Da are not easily absorbed or distributed.

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Placental Barrier & Large Drugs

Large drug particles cannot cross the placental barrier, so should be given parenterally.

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Chronopharmacology

The science of tailoring medication based on the body's circadian rhythm.

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Circadian Rhythm in Body Functions

Many body functions, such as liver metabolism and blood pressure, follow a daily circadian rhythm.

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Time-Dependent Enzyme Activity

Enzymes responsible for drug metabolism are active at different times of the day.

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Pseudocholinesterase (PsChE)

Enzyme that metabolizes succinylcholine.

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PsChE Deficiency & Succinylcholine

Genetic condition where succinylcholine metabolism is impaired, leading to prolonged muscle paralysis.

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Glucose-6-Phosphate Dehydrogenase (G6PD)

Most common human enzyme defect; Catalyzes NADPH production.

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G6PD Deficiency & Drug Exposure

Individuals with this deficiency may suffer acute hemolysis when exposed to oxidizing drugs.

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Thiopurine Methyltransferase (TPMT)

Enzyme that methylates thiopurine drugs, reducing their toxicity.

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TPMT Deficiency & Thiopurines

Genetic deficiency leading to increased toxicity of thiopurine drugs and bone marrow suppression.

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Acetylation

Process by which drugs like isoniazid are metabolized in the liver.

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Acetylation Rate (Genetics)

Genetic variations influence the rate at which individuals acetylate drugs.

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Slow Acetylators

Individuals who metabolize certain drugs more slowly due to genetic variations in N-acetyltransferases.

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Isoniazid-induced Peripheral Neuropathy

A common side effect in slow acetylators due to isoniazid accumulation, treatable with pyridoxine (vitamin B6).

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Drugs Causing SLE-like Syndrome in Slow Acetylators

Hydralazine, Procainamide, Isoniazid, Quinidine, and Phenytoin

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Resistance to Coumarin Anticoagulants

A heritable condition where individuals require significantly higher doses of coumarin anticoagulants due to a variant of the enzyme Vitamin K epoxide reductase.

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Resistance to Vitamin D (Vitamin D-Resistant Rickets)

Individuals with this condition require very large doses of Vitamin D to achieve therapeutic effects.

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Resistance to Mydriatics and Eye Color

Individuals with darker eyes are genetically less responsive to mydriatic drugs.

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Tolerance

Progressive decrease in drug response over a long period, requiring higher doses to achieve the same effect.

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Tachyphylaxis

Rapidly developing tolerance where the drug response decreases quickly with successive administrations.

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Pharmacodynamic Tolerance

Reduced responsiveness to a drug after prolonged exposure, requiring higher doses to achieve the same effect.

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Receptor Desensitization

Decreased receptor sensitivity due to prolonged drug exposure, altering receptor shape.

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Receptor Down-regulation

Reduced receptor numbers due to prolonged drug exposure.

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Exhaustion of Mediators

Reduced drug effectiveness due to depletion of neurotransmitters or mediators.

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Pharmacokinetic Tolerance

Tolerance resulting from increased metabolic breakdown of the drug.

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Behavioral Tolerance

Tolerance developed through learned adaptation to drug effects.

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Rebound Effect

Symptoms returning in an exaggerated form when a drug is stopped.

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Withdrawal Effect (Syndrome)

Adverse symptoms occurring upon drug cessation, beyond the original symptoms.

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Drug Stereoisomers

Drugs commonly have multiple forms that are mirror images of each other.

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Stereoisomer Receptor Fit

Receptors typically bind to one stereoisomer much better than another.

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Stereoisomer Effects

One stereoisomer of a drug can be much more potent or even toxic compared to another.

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Racemic Mixtures

Many drugs are mixtures of different stereoisomers.

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Drug Molecular Weight Range

Most drugs have a molecular weight between 100 and 1000 Daltons.

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Drugs > 1000 Da

These drugs are poorly absorbed and distributed; often given via injection.

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Placental Barrier & Drug Size

Drugs that are larger cannot cross the placental barrier.

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Asthma Med Timing

Administering anti-asthmatic meds in the evening exploits the circadian rhythm.

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Hypertension Med Timing

Administering antihypertensive meds in the morning exploits the circadian rhythm.

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Organ Dysfunction Impact

Response to a drug is altered due to changes in drug metabolism from liver and kidney diseases.

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Failing Heart & Digitalis

Heart failure increases sensitivity to digitalis compared to a normal heart.

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Idiosyncrasy Definition

Abnormal drug response due to genetic abnormality in drug metabolism.

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Demographic Factors Impact

Factors like age, sex and weight can affect the response to drugs

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Pseudocholinesterase deficiency

Genetic deficiency in pseudocholinesterase, leading to prolonged paralysis after succinylcholine administration due to impaired metabolism.

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G6PD Function and Deficiency

Catalyzes NADPH production; deficiency can cause acute hemolysis when exposed to oxidizing drugs.

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TPMT Deficiency Effects

Leads to increased conversion of thiopurine drugs into toxic compounds causing myelotoxicity and bone marrow suppression.

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Rapid acetylators

Excessive isoniazid toxic metabolites accumulate in the liver causing hepatocellular necrosis.

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Acetylation Classifications

People can either be classified as rapid acetylators or slow acetylators.

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Isoniazid & Peripheral Neuropathy

Isoniazid accumulates, interfering with pyridoxine (vitamin B6) metabolism, causing nerve damage.

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SLE-Causing Drugs (Slow Acetylators)

Hydralazine, Procainamide, Isoniazid, Quinidine, Phenytoin can cause SLE-like syndrome, especially in slow acetylators

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Coumarin Resistance

Some individuals need much higher doses of coumarin anticoagulants (like warfarin) due to genetic variation in Vitamin K epoxide reductase.

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Vitamin D-Resistant Rickets

Individuals need very high doses of vitamin D because they do not respond to normal doses.

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Mydriatic Resistance & Eye Color

Individuals with dark eyes need more drops of mydriatics.

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Tolerance (Drug Response)

Progressive decrease in drug response with repeated administration, requiring increased doses to achieve the original effect.

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Higher Doses Needed

The same response could be obtained by higher doses.

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Withdrawal Effect

Adverse symptoms upon drug cessation, including novel symptoms beyond the original condition.

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Study Notes

Factors Affecting Dose-Response Relationship

  • Factors related to the drug and the patient affect the dose-response relationship.

Drug Shape (Stereoisomerism)

  • Most drugs have multiple stereoisomers (enantiomers) like L-thyroxin and D-thyroxin.
  • Receptor sites are usually sensitive to one stereoisomer, not another.
  • One isomer can be hundreds of times more potent than another.
  • One isomer can be beneficial while the other is toxic.
  • Racemic mixtures in drugs may explain agonist/antagonist activity.

Molecular Weight (MW)

  • Most drugs' molecular weight is between 100-1000 Da.
  • Drug particles larger than 1000 Da cannot be absorbed or distributed, so they must be given parenterally, and cannot cross the placental barrier.

Time of Drug Administration (Chronopharmacology)

  • Tailoring drug medication to the body's circadian rhythm can improve response or reduce side effects.
  • Many body functions like liver metabolism, RBF, blood pressure, and heart rate have daily circadian rhythms.
  • Some drug-metabolizing enzymes are more active at certain times of day.
  • Diseases like asthma attacks and myocardial infarction show circadian phase dependence.
  • Acute bronchial asthma is common at night due to cortisol variation, making evening anti-asthmatic medication better.
  • Blood pressure peaks in the afternoon, suggesting morning antihypertensive medication is better.

Drug Cumulation

  • Cumulation occurs when the drug administration rate exceeds its elimination rate.
  • Especially seen in patients with liver or renal disease.
  • Digoxin is an example of a cumulative drug due to its slow elimination rate.

Drug Combination

  • Drug combination is common in clinical practice.
Summation or Addition
  • The combined effect of two drugs equals the sum of their individual effects (1+1=2).
  • Occurs between drugs having the same mechanism.
  • Example: using two simple analgesics together.
Synergism
  • The combined effect of two drugs is greater than the sum of their individual effects (1+1=3)
  • Drugs typically have different mechanisms of action.
  • Example: Penicillin + aminoglycosides exert bactericidal effect
Potentiation
  • Similar to synergism but, one drug's effect greatly increases when taken with another drug that has no notable effect alone (1+0=2).
  • Example: Phenobarbitone can potentiate aspirin's analgesic action, even without analgesic action alone
Antagonism
  • One drug abolishes another drug's effect (1+1=0).

Age, Sex & Weight

  • Patient characteristics influence drug response.

Pathological Status

  • Liver or kidney diseases significantly alter drug response due to changed metabolism.
  • A failing heart is more sensitive to digitalis than a normal heart.

Pharmacogenetic Factors (Idiosyncrasy)

  • Abnormal drug response from genetic abnormality in drug metabolism.
Pseudo-cholinesterase Deficiency
  • Succinylcholine is a neuromuscular blocker metabolized by pseudo-cholinesterase enzyme.
  • Individuals with deficient PsChE taking succinylcholine may experience severe paralysis and death from respiratory paralysis (succinylcholine apnea)
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
  • G6PD is the most common human enzyme defect.
  • It catalyzes NADP+ into NADPH, maintaining glutathione in RBCs in its reduced form.
  • Reduced glutathione keeps Hb in the reduced (ferrous) form, preventing methemoglobin formation and cell membrane injury by oxidizing drugs.
  • Individuals with G6PD deficiency face may suffer acute hemolysis if they are exposed to oxidizing drugs.
Thiopurine Methyl-Transferase (TPMT) Deficiency
  • TPMT methylates thiopurine anticancer drugs (e.g. 6-mercaptopurine and 6-thioguanine) into less toxic compounds.
  • Genetic TPMT deficiency increases conversion of parent thiopurine drugs into more toxic compounds leading to severe myelotoxicity and bone marrow suppression, which can be fatal.
  • TPMT deficiency prevalence is 1:300.
  • Screening for TPMT deficiency is necessary for patients treated by thiopurine anticancer drugs.
Acetylator Phenotypes
  • Many drugs, like isoniazid, are metabolized in the liver by acetylation.
  • The acetylation reaction is under genetic control, classifying people as rapid or slow acetylators.
    • Rapid acetylators: Excess isoniazid toxic metabolites accumulate in the liver causing hepatocellular necrosis
    • Slow acetylators: Isoniazid accumulates in peripheral tissues causing peripheral neuropathy by interference with pyridoxine metabolism, so pyridoxine "vit B6" is added to isoniazid therapy to prevent neurotoxicity.
  • Some drugs metabolized by acetylation can cause systemic lupus erythematosus-like syndrome (SLE) in slow acetylators.
Examples Of Heritable Conditions Causing Decreased Drug Response
  • In normal individuals, warfarin anticoagulant acts by inhibiting the enzyme vit K epoxide reductase responsible for reduction of the oxidized vit K to its reduced form.
  • Some individuals need 20x the usual dose of coumarin to get the response
  • Children with vit D-resistant rickets need huge doses of vit D to be treated.
  • Dark eyes are genetically less responsive to the effect of mydriatics

Hyporeactivity to Drugs

  • Tolerance and tachyphylaxis: decreased drug response.
    • Tolerance: Progressive decrease in drug response; occurs over long periods, and the same response is obtained by higher doses.
    • Tachyphylaxis: Acute tolerance, occurs very rapidly.

Mechanisms of Hyporeactivity

Pharmacodynamic Tolerance
- **Receptor Desensitization**: Prolonged exposure to the drug causes slow conformational changes in the receptors, so the receptor shape becomes less well fitted with the drug.
- **Receptor Down-Regulation**: Prolonged exposure to drug decreases the number of functional receptors.
Pharmacokinetic Tolerance
- **Exhaustion of mediators**: Depletion of catecholamines by amphetamine.
- Due to increased metabolic degradation of a drug by induction of hepatic enzymes. Chronic administration of ethanol.
Behavioral Tolerance
  • Learning to overcome drug-induced effects through practice.
  • Seen with psychoactive drugs.

Hyperreactivity to Drugs

Rebound Effect

  • Recurring of symptoms in exaggerated form when a drug is suddenly stopped after long administration period.
  • Prolonged administration of an antagonist causes an increase in receptors --> severe reaction occurs.
  • e.g. severe tachycardia and arrhythmia after sudden stopping of beta-blockers.

Withdrawal Effect (Syndrome)

  • Addition of new symptoms when a drug is suddenly stopped.
  • Withdrawal effects occur after suddenly stopping opioids in opioid addicts.

Drugs That Should Not Be Stopped Suddenly

  • Beta-blockers: severe tachycardia, arrhythmia, and even myocardial infarction.
  • Clonidine: severe hypertension (hypertensive crisis).
  • Cimetidine: severe hyperacidity and even peptic ulceration.
  • Corticosteroids: acute Addisonian crisis.
  • Morphine: withdrawal symptoms.
  • Warfarin: thrombotic catastrophes.

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