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 Pharmacokinetics: General Principles-Lecture III, slide 2

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  • Absorption

    • Fick's Law

  • Routes of Administration

  • First-Pass Effect

  • Pulmonary Effects

  • Pharmacokinetics

    • Volume of distribution

    • Clearance

      • Renal clearance: clearance of unchanged drug and metabolites

        • Other Factors Affecting Renal Clearance

      • Factors Affecting Hepatic Clearance

      • Capacity-Limited Elimination

      • Half-life

      • Drug Accumulation

    • Bioavailablity

      • Extent of Absorption

      • First-Pass Elimination

      • Rate of Aborption

    • Some Pharmacokinetic Equations

    • Placental Transfer

    • Redistribution

    • Drug-Plasma Protein Binding

    • Renal Clearance

  • Drug Metabolism

    • Introduction

    • Phase I and Phase II Reaction Overview:

    • Phase I characteristics

    • Phase II characteristics

    • Conjugates

    • Principal organs for biotransformation

      • Sequence I

      • Sequence II

    • Bioavailability

    • Microsomal Mixed Function Oxidase System and Phase I Reactions

      • The Reaction

      • flavoprotein--NADPH cytochrome P450 reductase

      • Cytochrome P450: -- terminal oxidase

      • P450 Enzyme Induction

      • P450 Enzyme Inhibition

      • Human Cytochrome P450

    • Phase II Reactions

      • Toxicities

  • Individual Variation in Drug Responses

  • Genetic Factors in Biotransformation

  • Effects of Age on Drug Responses

  • Drug-Drug Interactions

Pharmacokinetics and some IV Anesthetics Agents

  • Barbiturates

    • Thiopental

  • Benzodiazepines

  • Ketamine and Etomidate

  • Propofol

  • Opioids

    • Membrane Bilayer Structure

 

 

 

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

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 on 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; Abdominal pain is typically steady and poorly localized; however, cramping with ileus, abdominal distention, and reduced bowel sounds are common. These symptoms are neurologic rather than inflammatory in origin.

    • Peripheral neuropathy, which may not occur in all acute attacks, is secondary to axonal degeneration.

    • CNS symptoms are numerous and in addition to anxiety, depression, hallucinations, and disorientation seizures may occur.

      • Management of seizures represent a therapeutic difficulty since nearly all antiseizure agents worsen acute intermittent porphyria -- probably clonazepam (Klonopin) is safer than phenytoin (Dilantin) or barbiturates.

    • Paresthesias & 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 & sulfonamides which induces an early but important rate-determining enzymatic step in heme synthesis, specifically delta aminolevulinic 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.

  • Safe drugs for use in patients with acute intermittent porphyria, hereditary coproporphyria and  variegate porphyria:

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

  • 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 & 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.

Source: National Center for Biotechnology Information (http://www3,ncbi.nlm.nih.gov/Omim/) (http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?176000)

 

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

 

Influence of Age on Drug Responses

  • Variation in drug responses --usually due to:

    • diminished cardiac output

      • reduces hepatic perfusion (decreases delivery of drug to the liver for metabolism)

        • prolongs duration of action of:

          • lidocaine (Xylocaine)

          • fentanyl (Sublimaze)

    •  increased body fat

      • increases Vd (another contributing factor is decreased plasma protein binding)

      • promotes accumulation of highly lipid-soluble agents such as:

        • diazepam (Valium)

        • thiopental (Pentothal)

    •  diminished protein binding

    •  diminished renal function

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 b-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.

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

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

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

 

 
 
 
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