Medical Pharmacology Chapter 2: General Principles: Pharmacokinetics

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  • "P450 Enzyme System (Inducers, Inhibitors & Subtypes")

  • Cytochrome P450 Enzyme Induction:

    • Following repeated administration, some drugs increase the amount of P450 enzyme usually by:

      • Increase enzyme synthesis rate (induction)

      • Reduced enzyme degradation rate

  • Cytochrome P450 enzyme inhibition:

    • Certain drugs, by binding to the cytochrome component, act to competitively inhibit metabolism. Examples:

      •  Cimetidine (Tagamet) (anti-ulcer --H2 receptor blocker) and Ketoconazole (Nizoral) (antifungal) bind to the heme iron a cytochrome P450, reducing the metabolism of:

        • Testosterone

        • Other coadministered drugs

        • Mechanism of Action: competitive inhibition

    •  Catalytic inactivation of cytochrome P450.

      •  Macrolide antibiotics (troleandomycin, erythromycin estolate (Ilosone)), metabolized by a cytochrome P450:

        • Metabolites complex with cytochrome heme-iron: producing a complex that is catalytically inactive.

      •  Chloramphenicol (Chloromycetin): metabolized by cytochrome P450 to an alkylating metabolite that inactivates cytochrome P450

      •  Other inactivators: Mechanism of Action: -- targeting the heme moiety:

        • Steroids:

          • Ethinyl estradiol (Estinyl)

          • Norethindrone (Aygestin)

          • Spironolactone (Aldactone)

        • Others:

          • Propylthiouracil

          • Ethchlorvynol (Placidyl)

  • Phase II Metabolism

    • Some Phase II Reactions

      Type of Conjugation

      Endogenous Reactant

      Transferase (Location)

      Types of Substrates

      Examples

      Glucuronidation

      UDP glucuronic acid

      UDP glucuronosyl transferase (microsomal)

      phenols, alcohols, carboxylic acids, hydroxylamines, sulfonamides

      morphine, acetaminophen, diazepam, digitoxin, digoxin, meprobamate

      Acetylation

      Acetyl-CoA

      N-Acetyl transferase (cytosol)

      Amines

      Sulfonamides, isoniazid, clonazepam, dapsone, mescaline

      Glutathione conjugation

      Glutathione

      GSH-S-transferase (cytosolic, microsomes)

      Epoxides, nitro groups, hydroxylamines

      Ethycrinic acid, bromobenzene

      Sulfate conjugation

      Phosphoadenosyl phosphosulfate

      Sulfotransferase (cytosol)

      Phenols, alcohols, aromatic amines

      Estrone, 3-hydroxy coumarin, acetaminophen, methyldopa

      Methylation

      S-Adenosyl-methionine

      Transmethylases (cytosol)

      Catecholamines, phenols, amines, histamine

      Dopamine, epinephrine, histamine, thiouracil, pyridine

      • Adapted from Table 4-3, Correia, M.A., Drug Biotransformation. in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 57.

  • Overview: Phase II reactions involve non-microsomal enzymes

    • Reaction types:

      1. Conjugation

      2. Hydrolysis

      3. Oxidation

      4. Reduction

        1. Location (non-microsomal enzymes): primarily hepatic (liver); also plasma and gastrointestinal tract

        2. Non-microsomal enzymes catalyze all conjugation reactions except glucuronidation

    • Nonspecific esterases in liver, plasma, gastrointestinal tract hydrolyzed drugs containing ester linkages, including

      • Succinylcholine (Anectine),

      • Atricurium (Tracrium),

      • Mivacurium (Mivacron),

      • Esmolol (Brevibloc) as well as ester-type local anesthetics.

    • Conjugation reactions are usually "detoxification reaction". 

      • Conjugates tend to be more polar compared to the parent compound, more easily excreted, and usually pharmacologically inactive.

    • Conjugation reactions require "high-energy" intermediates in specific transfer enzymes which include both microsomal and cytosolic transferases.

      • Conjugation with glucuronic acid: 

        • Glucuronic acid is available from glucose and its conjugation with lipid-soluble drugs results in a lipophilic glucuronic acid derivative which is typically pharmacologically inactive and more water-soluble compared to the parent compound. 

          • Therefore, the glucuronic acid derivative molecule is more readily excreted in both urine or bile.

      • Transferases are enzymes which catalyzes the coupling of an endogenous substance with the drug.

        • For example, transferase which catalyzes the "transfer" of uridine-5'-diphosphate (UDP) derivative of glucuronic acid and a drug.

          • A transferase may catalyze an inactivated drug with an endogenous substrate. For example a S-CoA derivative of benzoic acid with an endogenous substrate.

  •  Toxicity:

    • Certain conjugation reactions form toxic reactive species (hepatotoxicity).  For example, acyl glucuronidation of nonsteroidal anti-inflammatory drugs may result in toxicity.  Another example would be N-acetylation of isoniazid.

    •  Drugs metabolized to toxic products:

      • Acetaminophen hepatotoxicity  (normally safe in therapeutic doses)

      • Therapeutic doses:

        • Glucuronidation + sulfation to conjugates (95% of excreted metabolites); 5% due to alternative cytochrome P450 depending glutathione (GSH) conjugation pathway

      •  At high doses:

        • Glucuronidation and sulfation pathways become saturated

        • Cytochrome P450 dependent pathway becomes now more important.With depletion of hepatic glutathione, hepatotoxic, reactive, electrophilic metabolites are formed.

          • In this circumstance antidotes would include N-acetylcysteine and cysteamine. N-acetylcysteine protects patients from fulminant hepatotoxicity and death following acetaminophen overdose.

  1. Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.

  2. Benet, Leslie Z, Kroetz, Deanna L. and Sheiner, Lewis B The Dynamics of Drug Absorption, Distribution and Elimination. In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 3-27

  3. Correia, M.A., Drug Biotransformation. in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 50-61

  • Basis for individual to individual variation in drug responses

    • Response Variation Secondary to Pharmacokinetic Differences

      • Bioavailability

      • Renal function

      • Liver function

      • Cardiac function

      • Patient Age

    • Response Variation Secondary to Pharmacodynamic Differences

      • Enzyme activity

      • Genetic differences

    • Response Variation Secondary to Drug Interactions

Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.

  • Genetic Factors: in Biotransformation of Drugs

    • Genetic influences: Variation in drug metabolism rates or in receptor sensitivity:

    • Metabolism:

      • Patients can be categorized as either rapid or slow acetylators; a classification which refers to the patients ability to relatively rapidly or slowly catalyze acetylation reactions. 

        • Biotransformation of some drugs are affected by acetylation rates, examples include hydralazine (Apresoline) and isoniazid (INH).:

    • Pharmacogenetics: One major concern is that on underlying disease state may not be appreciated until an unexpected reaction to an anesthetic agent in fact occurs.  The anesthetic agent essentially exposes on underlying disease state and then appropriate inner operative responses required. 

      • Examples:

        • Atypical cholinesterase enzyme suggested by prolonged succinylcholine (Anectine) or mivacurium (Mivacron)-induced neuromuscular blockade

        • Succinylcholine (Anectine) or volatile anesthetic induced malignant hyperthermia:

          • Malignant hyperthermia is a very serious reaction requiring a definitive treatment approach including dantrolene (Dantrium).

        • If the patient exhibits glucose-6-phosphate dehydrogenase deficiency certain drugs may induce hemolysis

        • Barbiturates may induce intermittent porphyria attacks.  It is extremely important to determine therefore preoperatively if the patient has history of intermittent porphyria.

Acute intermittent porphyria

  • Background: 

    • Porphyria is an inherited condition in which too much of the chemical porphyrin is synthesized.

      • Porphyrin is used to make heme, the oxygen-carrying component of blood.

      • Specifically, acute intermittent porphyria is inherited as an autosomal dominant disorder which causes unphysiologic, excessive amounts of urinary aminolevulinic acid and prophobilinogen.

    • Porphyrias are associated with overproduction of  porphyrins and for acute intermittent porphyria the exacerbation is induced by barbiturates, sulfonamides, and the antifungal drug griseofulvin.

    • These drugs induce enzymes (increase the amount of enzymes) that cause increased porphyrins synthesis.

      • Porphyrin

       

  • The specific defect that leads to acute intermittent porphyria is due to a defect in the specific enzyme called porphobilogen deaminase (PBG deaminase) also called uroporphyrinogen synthesis, or HMB synthase, a heme-synthesizing enzyme

    • HMB synthase catalyzes the conversion of porphobilinogen to hydroxymethylbilane which is the immediate precursor of uroporphyrinogen III.

    • In this autosomal dominant condition (acute intermittant porphyria, there is only 50% normal HMB (hydroxymethylbilane) synthase activity which results in porphobilinogen buildup.

      		•

        Desnick, Robert J., The Porphyrias in Harrison's Priniciples of Internal Medicine, (Braunwald, E., Fauci, A.S. Kasper, D.L., Hauser, S.L., Longo, D.L. and Jameson, J.L.,eds)  15th Edition, ch. 346, pp 2261-2263.McGraw-Hill, New York, 2001

  • Pathology: : biosynthetic byproducts may turn the urine red and even can cause, following deposition, reddish brown teeth.

  • Acute episodes of neuropathic syndromes involving abdominal pain is the most common symptom; paresthesias and paralysis may occur with even death resulting from respiratory paralysis. 

    • Acute attacks can involve psychotic episodes and hypertension, and although these attacks usually do not occur before puberty, they can be precipitated by barbiturates and sulfonamides which induces an early but important rate-determining enzymatic step in heme synthesis, specifically δ-minolevulinic acid synthesis 

  • Other factors known to precipitate acute intermittent porphyria include alcohol, starvation, infection, and hormonal changes; acute intermittent porphyria exacerbations are more common in females.

  • Clinical management: 

    1. Supportive treatment

    2. Dextrose infusion

    3. High carbohydrate intake

    4. Hematin infusion (heme), a feedback inhibitor of heme  synthesis (drug may cause renal damage)

      • For management of abdominal pain associate with acute attacks, narcotic analgesics may be used and relief from nausea, vomiting, anxiety and restlessness may be provided by phenothiazine administration.

  • Examples of likely safe drugs for use in patients with acute intermittent porphyria, hereditary coproporphyria and  variegate porphyria:

    • Narcotic analgesics, aspirin, acetaminophen (Tylenol, Panadol), phenothiazines, penicillin and derivatives, streptomycin, glucocorticoids, bromides, insulin, atropine.

  • Examples of likely unsafe drugs for use in patients with acute intermittent porphyria, hereditary coproporphyria and  variegate porphyria:

    • Barbiturate, sulfonamide antibiotics, meprobamate (Miltown), glutethimide (Doriden), methyprylon (Noludar), ethchlorvynol (Placidyl),carbamazepine (Tegretol), succinamides,carbamazepine (Tegretol), valproic acid (Depakene, Depakote), griseofulvin, ergot alkaloids, synthetic estrogens and progestogens, danazol (Donocrine), alcohol.

  • Prevalence: highest in Sweden, frequency is 1 in 1000

  • Prevalence based on previous manifestation of acute intermittent porphyria (AIP), about 1 in 50,000; however, this number probably underestimate the number of individuals with latent AIP.

  1. Source: National Center for Biotechnology Information (http://www3,ncbi.nlm.nih.gov/Omim/) (http://www3.ncbi.nlm.nih.gov/htbin-post/0mim/dispmim?186000#DIAGNOSIS)

  2. Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.

  3. Desnick, Robert J., The Porphyrias in Harrison's Priniciples of Internal Medicine, (Braunwald, E., Fauci, A.S. Kasper, D.L., Hauser, S.L., Longo, D.L. and Jameson, J.L.,eds)  15th Edition, ch. 346, pp 2261-2263.McGraw-Hill, New York, 2001

  • Influence of Age on Drug Responses

    • Variation in drug responses may be due to several factors such as:

      • Diminished cardiac output:

        • A reduction in cardiac output reduces hepatic perfusion which may decrease delivery of drug to the liver for metabolism.  This type of an effect would prolonged duration of action of, for example, lidocaine (Xylocaine) or fentanyl (Sublimaze).

      •  Increased body fat:

        • An increase in body fat tends to increase Vd . 

          • An increased Vd would tend to prolong clearance time.

        • Increased body fat also promotes accumulation of highly lipid-soluble agents such as diazepam (Valium) and thiopental (Pentothal).

      • Altered protein binding can affect drug responses because only the "free", unbound drug is active and for a highly protein-bound drug small changes in the extent of protein binding can substantially influence the free drug concentration [free drug].

      • Decreased or compromised renal function can prolong drug action  if renal excretion is the primary mechanism for clearance.

Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.

  • Drug-Drug Interactions

    • Definition: Drug interaction -- when one drug affects the pharmacological response of a second drug given at the same time.

    • Drug interactions may be due to:

      •  Pharmacodynamic effects

      •  Pharmacokinetic effects

    • Consequences of drug interactions:

      • Increased drug effects; decreased drug effects

      • Desired consequences; adverse or undesired effects

    • Examples -- positive, beneficial drug interaction effects:

      • Propranolol + hydralazine (reflex tachycardia (undesirable) caused by hypotensive hydralazine-mediated response is prevented by propranolol-mediated β-adrenergic receptor blockade

      • Opioid-induced respiratory depression may be counteracted by administration of the opioid receptor antagonist naloxone

    •  Adverse effects -- toxic reactions

      •  One drug may interact with another to impede absorption

      •  One drug may compete with another for the same plasma protein-binding sites

      •  One drug may affect metabolism of another by either enzyme induction or enzyme inhibition

      •  One drug may change the renal excretion rate of the other.

  1. Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.

  2. Dolin, S. J. "Drugs and pharmacology" in Total Intravenous Anesthesia, pp. 13-35 (Nicholas L. Padfield, ed), Butterworth Heinemann, Oxford, 2000