Drug Receptors & Drug Safety

Question 1

Describe the drug-receptor concept and its consequences for pharmacotherapy.

Answer 1

A receptor is defined as the component of the biologic system to which a drug binds to bring about change in the function of the system. The specificity of fit of drug to receptor (recognition) induces conformational change in receptor protein.Consequences: Allows the determination of a quantitative relation between dose or concentration of drug and its pharmacologic effects via use of dose-response curves.Receptors are responsible for selectivity of drug action (increase in benefit:risk ratio).Receptors mediate the actions of pharmacologic agonists and antagonists.

Question 2

Explain the theoretical aspects and therapeutic consequences of the hyperbolic shape of the dose-response curve.

Answer 2

Drug receptor theory assumes that the interaction follows simple mass action relationships, binding is reversible, and response is proportional to receptors [R] occupied by drug [D] as follows: R+D ↔ RD → RD is proportional to RESPONSEConsequences: This means that at low doses of drug (below the EC50, which generally constitutes the therapeutic range of doses) the response usually increases in direct proportion to the dose. This is consistent with receptor theory that states that the greater the number of receptors occupied by drug the greater the response produced.The curve levels off at high drug doses. Thus, there is a limit to the increase in response that can be achieved by increasing the drug dose [limit in # of receptors].

Question 3

Describe the advantages of the log dose-response curve versus the dose-response curve.

Answer 3

Allows a wide range of doses to be plotted allowing easy comparison of different drugs (potency and efficacy).The dose-response relationship is nearly a straight line over a large range of doses which generally corresponds to the the therapeutic range.

Question 4

What does potency mean?

Answer 4

Potency: refers to the concentration (EC50) or dose (ED50) required to produce 50% of that drugs individual maximal effect (not the 100% value of that system). Potency depends partly on the affinity (Kd) of receptors for binding the drug and on the the efficiency of this drug receptor complex to generate a response.

Question 5

What is efficacy?

Answer 5

Efficacy [Emax]: reflects the limit of the dose-response relationship on the response axis (y-axis). It indicates the relationship between binding to the receptor and the ability to initiate a response at the molecular, cellular, tissue or system level.

Question 6

What is an agonist?

Answer 6

Agonist: Full agonists are drugs that occupy receptors and bring about a full/maximal response. Maximal response is defined as that produced by the most powerful agonists on that tissue.

Question 7

What is a partial agonist?

Answer 7

Partial Agonist: are drugs that occupy the same receptor as the full agonist but bring about less than the maximum response.

Question 8

What is an antagonist?

Answer 8

Antagonist: a drug that inhibits the action of an agonist but has no effect in the absence of an agonist.

Question 9

Explain the use of log dose-response curves to compare potency and efficacy of different drugs.

Answer 9

Drugs A,B are more potent that drugs C,D by virtue of their position along the x-axis. The potency of drug A < B, a partial agonist b/c its EC50 is greater than that of drug B. Despite the greater potency of B, drugs A,C,D have greater efficacy (the extent a given clinical effect can be achieved)

Question 10

What is a competitive reversible antagonist?

Answer 10

Competitive reversible: binds reversibly (B) to the active site of a receptor but does not stabilize the conformation change required for receptor activation. The agonist (A) can, however, outcompete the antagonist for the receptor, thus its efficacy remains unchanged. Ex. Metoprolol is a competitive reversible antagonist of norepinephrine at ß1 receptor in the heart that lowers heart rate.

Question 11

What is a noncompetitive irreversible antagonist?

Answer 11

Noncompetitive irrerversible: binds irreversibly/covalently to the active site of the receptor. B/c it is irreversibly bound it cannot be outcompeted thus it does lower the maximal efficacty of the agonist. Ex. Low dose aspirin covalently acetylates the active site of the enzyme cycloxygenase in platelets resulting in an irriversible inhibition.

Question 12

What is a physiological antagonist?

Answer 12

Physiological: Most commonly activates or blocks a receptor that mediates a physiologic response that is opposite to that of the original receptor for the agonist. Ex. Histamine causes bronchoconstriction via histamine receptors but epinephrine via adrenergic receptors produce bronchodilation.

Question 13

What is a chemical antagonist?

Answer 13

Chemical: Does not involve receptor binding. The antagonism occurs via inactivation of the agonist by modifying it or sequestering it so it is no longer capable of binding to and and activating the receptor: Ex. EDTA (a chelating agent combined with lead ions).

Question 14

Compare and contrast graded dose-response curves and population dose-response curves and explain the use of population dose-response curves to evaluate drug safety (Therapeutic Index and Standard Safety Margin)

Answer 14

Therapeutic Index (TI) = LD50 / ED50: Factor by which the dose that is therapeutically effective in 50% of the population (ED50) must be increased to cause death (or more commonly a selected side effect) in 50% (LD50 or TD50) of the population. The higher the Therapeutic Index, the safer the drug. Most drugs in clinical use have therapeutic indices greater than 10-20.Standard Safety Margin (SSM) = [(LD1 / ED99) - 1] X 100. Percent by which the dose effective in 99% of the population (ED99) must be increased to cause death (or a selected side effect) in 1% of the population (LD1 or TD1) [see figure B above]. This is a more conservative measure than the therapeutic index. It is more reliable if the patient response to the therapeutic and / or toxic effects of a specific drug varies widely, in that it takes into account the extremes of a population, rather than the midrange.

Question 15

Describe the general FDA categories for drug use in pregnancy and the implications for drug prescribing.

Answer 15

Drugs are categorized A, B, C, D, X, from best to worst for the fetus. Not on the test this time around.

Question 16

How can pharmacokinetic drug interactions change plasma concentration?

Answer 16

Pharmacokinetic drug interactions can result in elevated drug concentrations (via reduced elimination rates or protein-bound drug displacement) leading to toxicity OR they may cause decreases in plasma concentrations (via more rapid drug elimination or decreased drug absorption) leading to levels below therapeutic effectiveness.

Question 17

How can absorption drug interactions change drug concentrations?

Answer 17

a. Effects on gastric motility and rate of absorption: Decreases in motility slow the passage of the drug to the larger absorptive area of small intestine and the decreased absorption rate may result in lower peak plasma drug levels (no change in extent of absorption [bioavailability]). Increases in rate of absorption less important clinically.b. Physiochemical inactivation via changes in pH or formation of insoluble complexes does reduce bioavailability.

Question 18

How can distribution drug interactions change drug concentrations?

Answer 18

a. Protein binding / displacement interactions: Competitive binding may increase amount of free drug; complex interaction, significance probably overstated.b. Cellular distribution interactions.

Question 19

How do metabolism drug interactions change drug concentrations?

Answer 19

a. Metabolic rate may be increased (inducers) resulting in reduced and possibly subtherapeutic levels or decreased (inhibitors) resulting in increased and possibly toxic levels.b. Most interactions occur via effects on cytochrome P-450 system (CYP).

Question 20

How can excretion drug interactions change drug concentration?

Answer 20

a. Most excretion interactions occur in the kidneys.b. Mechanism includes change in glomerular filtration rate (GFR) (e.g., aminoglycosides), tubular secretion (e.g., penicillins), or urine pH (e.g., amphetamine, aspirin).

Question 21

What are the pharmacodynamic drug interactions that can change plasma concentration?

Answer 21

1. Antagonistic Effects: Occur when 2 drugs with opposite pharmacologic effects given together.2. Synergistic or Additive Therapeutic Effects: Occurs when drugs with similar therapeutic effects given together.3. Synergistic or Additive Side Effects: Similar to above, but involves side effects of drugs.4. Indirect Pharmacodynamic Effect: Pharmacologic effect of one drug indirectly affects another drug’s action.

Question 22

What are the four types of poison control that decrease absorption?

Answer 22

Emesis, gastric lavage, chemical adsorbtion, and osmotic cathartics.

Question 23

Please tell me about emesis: what is it and when is it contraindicated?

Answer 23

Emesis: Empties stomach contents rapidly.Contraindications to use of emetic agent: a. Patient comatose / stuporous (lack of gag reflex ␣ risk of aspiration).b. Ingestion of corrosive poisons (i.e., strong acids or alkalis).c. Ingestion of CNS stimulant such as strychnine (risk of seizures).d. Ingestion of petroleum distillate (risk of pneumonitis).e. Pregnancy Category C: (weigh benefit vs risk, unknown if drug can cause harm).

Question 24

Please tell me about gastric lavage.

Answer 24

Most rapid and complete method of emptying stomach, but lavage plus emesis removes only about 30% of most oral poisons1. Washing of stomach contents with saline and removal via nasogastric tube.2. Best within 60 minutes of poison ingestion, but may be indicated even late because of possibility of delayed absorption.

Question 25

Please tell me about chemical adsorption.

Answer 25

Activated Charcoal (more effective than MgO / tannic acid [Res-Q␣]).1. Binds drug in gut to limit absorption (remember: also binds ipecac).2. Effective without prior gastric emptying and can even reduce elimination half-lives of drugs that have been given IV (back-diffusion of drug from blood with ion-trapping in stomach).3. Generally underutilized or used in insufficient doses, best to give in 10:1 ratio to toxin; serial administration may be helpful (every 4 hrs).4. Difficult to administer and poorly accepted in children, thus home treatment with charcoal is not currently recommended by AAP

Question 26

Please tell me about osmotic cathartics.

Answer 26

Decrease time of toxin in GI tract (via osmotic laxative effect). Indicated if toxin ingestion > 60 min, if toxin is in enteric coated tablets, or if toxin is hydrocarbon.1. Sorbitol 70%: Recommended, given with charcoal to prevent “briquet” formation.2. Magnesium citrate or sulfate: Avoid in renal disease or poisonings with nephrotoxic agents.3. Sodium sulfate: Avoid use of sodium-containing cathartics in congestive heart failure or hypertension (systemic absorption ␣ fluid overload).4. Polyethylene glycol (Golytely␣): Whole bowel irrigation that promotes elimination of entire contents of intestines. For poisoning with sustained-released drugs, metal ions, drug packets.

Question 27

Please tell me about hemodialysis.

Answer 27

Blood pumped through filter.a. Important to know Vd of drug; most effective for toxins with small Vd (if large Vd, poorly removed by this method as most of drug is outside plasma).b. Toxin should have low protein binding capacity (if bound to protein won’t cross dialysis membrane). [methanol and ethylene glycol, salicylates, theophylline, lithium, ethanol]c. Also assists in correction of fluid and electrolyte imbalance.

Question 28

Please tell me about hemoperfusion.

Answer 28

Hemoperfusion: Blood pumped through column of adsorbent material.a. Useful for high molecular weight toxins with poor water solubility.b. Potential risks include bleeding (removal of platelets) and electrolyte disturbances.

Question 29

Compare and contrast the concepts of toxicokinetics (seen with toxic amounts of drugs) to “normal” pharmacokinetics (seen with therapeutic doses and therapeutic plasma levels).

Answer 29

Toxicokinetics. The study of the absorption, distribution, and elimination of toxic parent compounds and metabolic products that aids in prediction of amount of toxin that reaches site of injury and the resulting damage. NOTE: A toxic dose of a drug may result in alterations of “normal” pharmacokinetics.1. ABSORPTION (bioavailability [F]): Large amount of ingested drug may slow tablet dissolution, alter GI emptying, or injure GI tract, altered absorption, delayed peak effect.2. VOLUME OF DISTRIBUTION [Vd]: Useful in predicting which drugs will be removed by dialysis / exchange transfusion (best if Vd < 1 L/kg, i.e., low values so most of drug is in plasma).3. CLEARANCE (Metabolism / Excretion): Important to know contribution of each organ (kidney / liver) to elimination of the toxin or drug in planning treatment strategy.4. HALF-LIFE (t1/2): Published values are for therapeutic doses, may be prolonged in toxic overdoses due to saturation of the elimination mechanisms.

Question 30

Describe the mechanism of acetaminophen overdose toxicity and its treatment (role of hepatic bioactivation to toxic metabolite and depleted hepatic glutathione in hepatocellular injury).

Answer 30

ACETAMINOPHEN [120,000 cases of acetaminophen toxicity reported in 2002].1. Therapeutic doses of acetaminophen (< 4 g/day) are primarily eliminated by phase II conjugation reactions with glucuronic acid or sulfate. A small fraction is metabolized by phase I (CYP2E1) enzymes to a hepatotoxic metabolite that is then detoxified by phase II conjugation with glutathione.2. Toxic doses of acetaminophen (single dose > 10-20 g) will BOTH saturate the phase II metabolic pathways leading to increased formation of the phase I hepatotoxic metabolite AND deplete glutathione stores available for detoxication, resulting in increased likelihood of hepatocellular injury.3. Treatment includes gastric lavage, supportive therapy, and administration of N-acetylcysteine [Mucomyst® oral, Acetadote® IV], which acts as a precursor for glutathione synthesis AND as a nucleophile to capture the electrophilic hepatotoxic metabolite.

Question 31

Describe the basic pharmacodynamic parameters of methanol and ethylene glycol that underlie their toxicities (rapid oral absorption, metabolism by common hepatic enzyme systems, these metabolic products selectively damage different tissues or organs, and toxicities of both can be treated through similar interventions).

Answer 31

Methanol and ethylene glycol have minimal toxicity until they undergo metabolism to formic acid and oxalic acid, respectively. Formic acid results in retinal damage and blindness while oxalic acid forms insoluble crystals in the kidney resulting in acute renal failure. Treatment includes correction of metabolic acidosis with NaHCO3, removal of parent compounds and metabolites with hemodialysis, and suppression of production of toxic metabolites by inhibiting the rate-limiting enzyme, alcohol dehydrogenase, with ethanol (a substrate and competitive inhibitor) or fomepizole [Antizol®] (a specific inhibitor of alcohol dehydrogenase).

Question 32

What does syrup of ipecac do?

Answer 32

Syrup of ipecac: Emesis agent.a. Produces emesis after 15-30 minute lag, may repeat once in 20 minutes.b. Mechanism: local irritation and CNS stimulation of chemoreceptor zone (CTZ).c. Effective orally, must be given before charcoal.

Question 33

What does activated charcoal do?

Answer 33

Chemical adsorbtion1. Binds drug in gut to limit absorption (remember: also binds ipecac).2. Effective without prior gastric emptying and can even reduce elimination half-lives of drugs that have been given IV (back-diffusion of drug from blood with ion-trapping in stomach).3. Generally underutilized or used in insufficient doses, best to give in 10:1 ratio to toxin; serial administration may be helpful (every 4 hrs).

Question 34

What does sorbitol do?

Answer 34

An osmotic cathartic.Sorbitol 70%: Recommended, given with charcoal to prevent “briquet” formation.

Question 35

What 2 chemicals prevent passive reabsorption via alteration of urinary pH and ion trapping?

Answer 35

NaHCO3: Alkalinize urine with NaHCO3, trap weak acids [pKa 3.0-7.5] like aspirin or barbiturates.NH4Cl: Acidify urine with NH4Cl or ascorbic acid, trap weak bases [pKa 7.5-10.5] like phencyclidine or amphetamine.

Question 36

What are these drugs used for? Dimercaprol, Penicillamine, Succimer, Hydroxocobalamin, CaNa2EDTA, Deferoxamine

Answer 36

Chelation therapy

Question 37

What are fomepizole used for?

Answer 37

Ethylene glycol poisining. Administration of fomepizole (4-methylpyrazole, Antizol␣), a specific inhibitor of alcohol dehydrogenase that does not produce CNS depression. Recently approved, probably more effective than ethanol, but much more expensive.

Question 38

What is n-acetyl cysteine used for?

Answer 38

Acetominaphen overdose: is recommended within 12-36 hours of ingestion (most effective given within 10 hours). This drug is thought to serve as a precursor for glutathione synthesis, providing a source of cysteine (the limiting amino acid precursor). N- acetylcysteine also functions as a nucleophile to capture NAPQI produced from residual acetaminophen. Administered orally, as a loading dose (140 mg/kg), followed by 70 mg/kg every 4 hours for 17 doses. Intravenous formulation available (Acetadote␣) with 20 or 48 hour administration protocol. Advantages of IV administration include: no nausea and vomiting and no interference with action if emetic agent or charcoal used.