Basic Principles of Clinical Pharmacology

ANESTHESIOLOGY DEPT.: BASIC PRINCIPLES OF CLINICAL PHARMACOLOGY Transfer of Drugs Across Membranes:  Absorption  Distribution  Metabolism  Excretion Transport Processes:  Passive Diffusion  Active Diffusion  Facilitated Diffusion Effects of Molecular Properties:  Most drugs are macromolecule  Either weak acids/weak bases  Both ionized/non-ionized forms physiologic pH Drug Absorption:  Most drugs are macromolecule  Either weak acids/weak bases  Both ionized/non-ionized forms physiologic pH March 28, 2009 6. Inhalational  Rapid uptake from the pulmonary alveoli to the blood  Low molecular weight  High lipid solubility  Large total alveolar surface area  Alveolar blood flow = cardiac output 7. Intravenous  Eliminates the need for absorption  Therapeutic blood concentrations are rapidly attained  Rapid onset of action  Effects are immediate and potentially severe at 8. Rectal  Advantages: uncooperative patients unable to tolerate oral ingestion 1st pass effect is eliminated  Disadvantages: Erratic absorption Irritation to rectal mucosa Bioavailability:  Fraction of the total dose that reaches the systemic circulation  Reduced by: incomplete absorption from the site of injection/GI tract 1st pass effect pulmonary uptake of drugs Drug Distribution:  Highly perfused organs (brain, heart, lungs, liver, kidneys) – rapid  Less perfused organs (muscle, skin, fat) – slow  Capillary membranes are freely permeable  Drugs pass quickly into the extracellular space  CNS – blood-brain-barrier  Drugs accumulation in tissues: binding to tissue components pH gradients uptake of lipophilic drugs into fat Redistribution:  Rapid entry and equally rapid egress of lipophilic drugs from richly perfused organs.  Thiopental  Fentanyl  propofol Placental Transfer:  Simple diffusion at Route of Administration: 1. Oral  Advantages: convenience, economy, safety  Disadvantages: uncooperative px, incomplete absorption, 1st pass effect  Small intestine – most important site of absorption of all drugs  1st Pass Effect – portal circulation, liver metabolism, systemic circulation 2. Sublingual  Passes directly into the systemic circulation  1st pass effect is eliminated  Effective for non-ionized, highly lipid soluble dugs 3. Transcutaneous  Only lipid soluble drugs can penetrate intact skin sufficiently to produce systemic effects 4. Intramuscular and Subcutaneous  Relatively slow absorption permitting a sustained effect  IM > SQ  Aqueous solution > non-aqueous solution 5. Intrathecal, Epidural and Perineural  Drugs are delivered close to their sites of action  Permits the use of very low doses  Eliminates the risk of adverse systemic drug effects ANESTHESIOLOGY DEPT.: BASIC PRINCIPLES OF CLINICAL PHARMACOLOGY    Lipid soluble drugs with low molecular weight vs. highly polar water soluble compounds Factors: pH levels protein binding The concentration of free non-ionized drug is the same on both sides of the placenta once equilibrium is reached Most important form – most pharmacologic activity March 28, 2009  Drug Elimination:  Excretion of unchanged drug  Metabolism (biotransformation) and subsequent excretion of metabolites  Liver and kidneys  Liver: metabolism to less active compounds and by hepatobiliary excretion of drugs or their metabolites  Kidneys: excretion of water soluble polar compounds  Lungs: anaesthetic gases and vapors  Drug clearance/elimination clearance Hepatic Drug Clearance:  Dependent on 3 factors: 1. Hepatic blood flow 2.Intrinsic ability of the liver to irreversibly eliminate drug from the blood 3. Extent of drug binding to plasma proteins or other blood constituents  At rest, 30% of cardiac output perfuses the liver  25% - hepatic artery, 5% - portal vein  Physiologic, pathologic and pharmacologic factors that alter hepatic blood flow also affects hepatic drug clearance Hepatic Drug Clearance:  Physiologic factors: exercise/stress hypotension hypovolemia  Pathologic factors: hepatocellular dysfunction congestive heart failure cardiovascular collapse hemorrhagic shock cirrhosis viral hepatitis Pharmacologic factors: propranolol volatile anesthetics spinal anesthetics Renal Drug Clearance:  Determined by the net effects of 3 processes: 1. glomerular filtration 2. tubular secretion 3. tubular reabsorption  Adults, Renal blood flow – 1,200mL/min  Renal plasma flow – 700mL/min  1/5 of the plasma is filtered by the glomerulus – GFR – 125mL/min  RBF and GFR are autoregulated – constant  Renal pathology – alters renal drug clearance Drug Metabolism:  Drugs must cross biologic membranes to reach their site of actions  Lipophilic compounds are readily absorbed  Metabolism (biotransformation) to a more polar water soluble compounds  Facilitates ultimate excretion of metabolites in the bile and urine Biotransformation Reactions:  Phase I Reactions  alter the molecular structure of xenobiotics by:  modifying an existing functional group of the drug  adding a new functional chemical group to the compound  splitting the original molecule into 2 fragments  Results from: 1. oxidation 2. reduction 3. hydrolysis  Phase II Reactions coupling or conjugation of endogenous compounds to polar chemical groups Factors: genetics extremes of ages gender drug interactions chronic ethanol consumption smoking liver pathology renal pathology anesthetics surgery  ANESTHESIOLOGY DEPT.: BASIC PRINCIPLES OF CLINICAL PHARMACOLOGY Pharmacokinetic Principles:  Pharmakon (medicine) and kinesis (movement)  Quantitative analysis of the relationship between the dose of a drug and the ensuing changes in drug concentration in the blood and other tissues.  Physiologic and perfusion models Classifications:  Vessel-rich group – brain, heart, lungs, liver, kidneys  Lean tissue group – muscle, skin  Fat tissue group  Vessel-poor group – bone, cartilage Pharmacokinetic Concepts: 1. Rate constants 2. Two Compartment Model A. FIRST ORDER KINETICS - a constant fraction of the drug is removed during a finite period of time - the absolute amount of drug removed is proportional to the concentration of the drug B. ZERO ORDER KINETICS -a constant fraction of the drug is removed after the drug concentration exceeds biotransformation capacity -the amount of drug removed is independent from the concentration of the drug 2. Half-lives  the time required for the concentration to change by a factor of 2 o 3. Volumes of distribution  quantifies the extent of drug distribution via the overall capacity of tissues vs. the capacity of blood for the drug  the apparent volume of distribution is a numeric index of the extent of drug distribution that does not have any relationship to the actual volume of any tissue or group of tissues lipophilic drugs > hydrophilic drugs March 28, 2009 COMPARTMENTAL PHARMACOKINETIC MODELS 1. One Compartment Model  illustrates the basic relationships among clearance, volume of distribution, and the elimination half-life  the body – single homogenous compartment  Drug distribution is assumed to be instantaneous with no concentration gradients within the compartment  Concentration can decreased only by elimination of drug from the system  The greater the clearance, the shorter the elimination half-life  The larger the volume of distribution, the longer the elimination half-life  The body – made up of 2 compartments: o Central Compartment – plasma, vessel-rich group o Peripheral Compartment - lean and fat tissue group & vessel-poor group  2 discrete phases in the decline of the plasma concentration: o Distribution Phase – characterized by a very rapid decrease in concentration caused by the passage of drug from the plasma into tissues (central compartment to peripheral compartment) Elimination Phase – a slower decline in the concentration (central compartment) 3. Three Compartment Model  Drug is reversibly transferred between the central compartment and two peripheral compartments after administration before elimination  3 phases: o Rapid Distribution Phase o Slower Distribution Phase o Elimination Phase Pharmacodynamic Principles:  The quantitative analysis of the relationship between the drug concentration in the blood, or at the site of action, and the resultant effects of the drug on physiologic processes  The study of the effects of drugs on the body  Quantified by dose-response studies  4. Total drug clearance   quantifies the ability of the system as a whole to irreversibly eliminate a drug analogous to creatinine clearance ANESTHESIOLOGY DEPT.: BASIC PRINCIPLES OF CLINICAL PHARMACOLOGY DOSE-RESPONSE CURVES  Provide information on the aspects of the relationship of the dose and pharmacologic effect  Drug dose or steady-state plasma concentration plotted on the abscissa (x-axis) represented in linear or logarithmic scale  Pharmacologic effect plotted on the ordinate (y-axis) represented in terms of absolute units or as a fraction of maximal effect Potency – the dose required to produce a given effect in 50% of subjects expressed as ED50 Slope of the curve – indicates the rate of increase in effect as the dose is increased Efficacy – the maximum effect attained Drug-receptor interactions Agonists – drugs that bind to receptor molecules, to produce a structural change, to initiate changes in cellular function Partial agonists – drugs that may produce a qualitatively different change in the receptor, but are not capable of producing the maximal effect, even at very high concentrations Antagonists – drugs that bind without producing a change in the receptor that results in altered cellular function Competitive antagonists – bind reversibly to receptors overcome by high concentrations of agonists Non-competitive antagonists – bind irreversibly to receptors reversed by synthesis of new receptors March 28, 2009  Benzodiazepines  MOA:  Facilitates inhibitory actions of GABA  Mimics inhibitory actions of Glycine  Structure  Benzene ring and a seven-member diazepine ring Pharmacokinetics  A. Absorption Orally, intramuscularly and intravenously  B. Distribution  Lipid Solubility Diazepam- penetrates the blood-brain barrier Midazolam- water soluble at low pH - Imidazole ring closes at physiologic pH, causing an increase in its lipid solubility Lorazepam- moderate lipid solubility  Redistribution  All three are highly protein bound (90-98%) Comparison of Pharmacologic Variables of Benzodiazepines PREOPERATIVE MEDICATIONS   Psychological Preparation Pharmacologic Preparation Various Goals for Pre-operative Medicine 1. Relief of anxiety 2. Sedation 3. Amnesia 4. Analgesia 5. Drying of Airway Secretion 6. Prevention of Autonomic reflex response 7. Reduction of Gastric Fluid volume & increased pH 8. Anti-emetic effects 9. Reduction of Anesthetic requirements 10. Facilitation of smooth induction of anesthesia 11. Prophylaxis against allergic reactions Dose Equivalent (mg) Time to effect After oral dose (hr) Elimination half-time (hr) Clearance (mL/Kg/min) Volume of distribution (L/Kg) Diazepam 10 Lorazepam 1-2 Midazolam 3-5 1-1.5 2-4 0.5-1 20-40 0.2-0.5 0.7-1.7 10-20 0.7-1.0 0.8-1.3 1-4 6.4-11.1 1.1-1.7 SEDATIVES AND HYPNOTICS Effects on Organ Systems  Cardiovascular  Slight decline in arterial BP, cardiac output & Peripheral vascular resistance ANESTHESIOLOGY DEPT.: BASIC PRINCIPLES OF CLINICAL PHARMACOLOGY  Rise in heart rate  Respiratory  Depress the ventilatory response to CO2 Cerebral  Reduce cerebral oxygen consumption, cerebral blood flow & intracranial pressure  Anterograde amnesia  Mild muscle-relaxant March 28, 2009  Distribution Physical Characteristics of Opioids that determine distribution Agent Nonionized Protein Lipid Fraction Binding Solubility Morphine ++ ++ + Meperidine Fentanyl Sufentanyl Alfentanil Remifentanyl + + ++ ++++ +++ +++ +++ ++++ ++++ +++ ++ ++++ ++++ +++ +  OPIOIDS MOA: o Bind to specific receptors throughout the CNS & other tissues o Inhibits the presynaptic release and postsynaptic response to excitatory neurotransmitters Biotransformation o Hepatic  Morphinemorphine-3-glucuronide and morphine-6-glucuronide  Meperidine- normeperidine Uses & Doses of Common Opioids Agent Morphine Use Premedication; intraoperative anesthesia; postop analgesia Premedication; intraoperative anesthesia; postop analgesia intraoperative anesthesia; postop analgesia Route IM; IV Dose 0.05-0.2 mg/kg Meperidine IM; IV 0.5-1mg/kg Fentanyl IM; IV 2-150 ug/kg  Structure  Pharmacokinetics  Absorption  Intramuscular injection- morphine & meperidine  Oral- fentanyl  Transdermal- fentanyl Effects on Organ Systems  Cardiovascular  Decrease BP  Respiratory  Depress ventilation  Cerebral  Reduce cerebral oxygen consumption, cerebral blood flow & intracranial pressure  Gastrointestinal  Slow gastric emptying  Endocrine ANESTHESIOLOGY DEPT.: BASIC PRINCIPLES OF CLINICAL PHARMACOLOGY  Blocks the release of hormones as stress response to surgical stimulation Drug Interactions  Meperidine + MAO inhibitors- respiratory arrest, hypertension or hypotension, coma & hyperpyrexia  Barbiturates, benzodiazepines, & other CNS depressants Other Sedative Drugs  Hydroxyzine  Norphenothiazine tranquilizer  Sedative & anxiolytic  Antihistamine & antiemetic  Additive effect to opioids  Diphenhydramine  Histamine receptor antagonist  Sedative & anticholinergic effect  Antiemetic  Combines with cimetidine, steroids & other drugs for prophylaxis with chronic atopy, before chemonucleolysis & dye studies Phenothiazines  Promethazine,Promazine & Perphanazine  Sedative, anticholinergic, antiemetic 0,no March 28, 2009 effect;+,small effect;++, moderate;+++, large Side effects:  Central Anticholinergic syndrome  Relax the lower esophageal sphincter  Mydriasis & cycloplegia  Block vagal activity, relaxation of bronchial smooth muscle and increase in respiratory dead space  Increases body temperature HISTAMINE RECEPTOR ANTAGONIST  Block the ability of histamine to induce secretion of gastric fluid w/ a high hydrogen ion concentration a. Cimetidine  150-300 mg, orally or parenterally  Duration: 3-4 hours  Inhibits the mixed-function oxidase enzyme system  Cardiac arrythmias, hypotension, cardiac arrest & CNS depression b. Ranitidine  50-200 mg  Duration: 1 hour c. Famotidine  40 mg, orally d. Nizatidine  150-300 mg orally ANTACIDS  Neutralize the acid in gastric contents  A single dose of antacid given 15-30 minutes before induction of anesthesia is almost 100% effective in increasing gastric fluid pH above 2.5  0.3 M Sodium Citrate  Colloid antacid solution a. Omeprazole  Suppresses gastric acid secretion by binding to the proton pump of the parietal cell  Gastric Fluid and Volume  Aspiration pneumonitis  Obese, diabetic, pregnant, hiatal hernia, GERD Summary of fasting recommendations to reduce pulmonary aspiration Ingested material Clear liquids Breast milk Infant formula Nonhuman milk Light meal (toast & clear liquids) Minimum Fasting Period ( Apply to all ages) 2 hours 4 hours 6 hours 6 hours 6 hours ANTICHOLINERGICS  Increase gastric fluid pH or reduce volume  Atropine  glycopyrrolate ANESTHESIOLOGY DEPT.: BASIC PRINCIPLES OF CLINICAL PHARMACOLOGY IV: 40 mg Oral: 40-80mg  GASTROKINETIC AGENTS  Reduce gastric fluid volume  Metoclopramide  Dopamine antagonist that stimulates upper gastrointestinal motility, increases gastroesophageal sphincter tone and relaxes the pylorus & duodenum  Anti-emetic  Effect may be offset by concomitant atropine administration or prior injection of opioids ANTIEMETICS  4 risk factors for predicting postoperative nausea & vomiting after inhalational anesthesia:  Female gender  Prior history of motion sickness or postoperative nausea  Nonsmoking  Use of postoperative opioids ADRENERGIC AGONISTS  Alpha-2 Adrenergic Agonists  Clonidine  2.5-5 ug/kg  Produce sedation, reduce maximum allowable concentration, prevent hypertension and tachycardia  Dexmedomidine OTHER DRUGS WITH PREOPERATIVE MEDICATIONS  BETA-BLOCKERS  Known or suspected CAD  Metoprolol or Atenolol  Contraindications:  Allergy to beta-blockers nd rd  2 or 3 degree heart block  Congestive heart failure  Acute bronchospasm  bradycardia  ANTIBIOTICS  Before the operation for contaminated, potentially, or dirty surgical wounds  Prophylactic  Clean surgical procedure  Immunosuppressed patients  Elderly  Steroid medication March 28, 2009  Prevention of endocarditis STEROIDS  Indication  For patients treated with hypoadrenocorticism or with suppression of the pituitary –adrenal axis  Patients who has received corticosteroid therapy for at least 1 month in the past 612 months INSULIN  Perioperative stress may increase serum glucose concentration  ¼-1/2 of usual daily dose of intermediate acting insulin in the morning of surgery & begin infusion of glucose containing fluid  No insulin or no glucose preoperatively & to measure serum glucose levels frequently during anesthesia; regular insulin or glucose is then administered intraop & postop  Begin an infusion of insulin & glucose immediately preoperatively & to check serum glucose levels frequently  Differences in Preoperative Medication between Pediatric and Adult patients  Psychological  Age 0-6 months: stress on family 8m-4yr: separation anxiety 4-6 yr: misconception on surgical mutilation 6-13 yr: fear of not waking up >13yr: fear of loss of control, body image issues  Pharmacologic  Sedative-hypnotics Midazolam Ketamine methohexital  Anticholinergics Atropine, Glycopyrrolate, Scopolamine Down syndrome Opioids Methadone Morphine Fentanyl 