Worksheet 3

Gastrointestinal Pharmacology

• The largest internal organ is the liver.
• Hepatocytes main functions include absorbing nutrients from the portal vein, storing and releasing carbs, proteins, and lipids; synthesizing cholesterol, glucose, coagulation factors, and bile salts; detoxifying, modifying, and excreting drugs, as well as bilirubin uptake, conjugation, and secretion
• Kupffer cells act as macrophages to maintain hepatic homeostasis.
• The hepatic artery supplies about 20% of hepatic blood flow, while the portal vein supplies about 80%; the liver receives approximately 30-40% of the cardiac output each minute
• Inhalational anesthetics decrease hepatic blood flow.
• Parasympathetic autonomic nervous system enhances mechanical activity of the gastrointestinal (GI) tract, whereas the sympathetic autonomic nervous system inhibits the mechanical activity
• The lower esophageal sphincter (LES) prevents gastric contents from entering the esophagus
• Gastric mucosa (stomach) stores, processes food for digestion and secretes H+.
• Three mechanisms that cause delayed gastric emptying are diabetic Gastroparesis with increased blood sugar, impaired neural control, and inflammation; GERD and acute viral gastroenteritis; medications such as GLP-1, Beta agonists, Tricyclic AntiDs, and ↑ETOH
• The 2 main therapeutic goals of antacids and GI motility drugs are to reduce gastric volume and increase gastric fluid pH.
• Oral antacids remove H+ ions, ↓ H secretion,  LES, and motility to change gastric fluid pH, this can cause metabolic alkalosis

Antiemetics

• H1 and H2 histamine receptors are typical targets for drugs given in anesthesia
• Diphenhydramine and promethazine target Histamine 1 receptors in anesthesia.
• Diphenhydramine and promethazine antagonize muscarinic, cholinergic, serotonin, & alpha-adrenergic receptors.
• Sedation and antiemetic actions are perioperative uses for this drug class

H2 Receptor Antagonists

• Histamine 2 receptors are involved in gastric acid secretion and immune cell differentiation
• Famotidine is given in anesthesia and targets the above receptors
• Famotidine blocks cAMP and the activation of H+/K+ ATPase.
• Famotidine IV dose is 20 mg.

Proton Pump Inhibitors

• These drugs directly inhibit the H+/K+/ATPase (proton) pump
• Omeprazole and pantoprazole are common proton pump inhibitors.
• Headaches, agitation, confusion, abdominal pain, N/V, and or GI tract bacterial overgrowth are some side effects of the above
• Metoclopramide increases LES tone and peristaltic contractions.
• Dystonia, restlessness, sedation, and dysphoria are reactions that can occur with dopamine inhibition in the central nervous system.
• The vestibular apparatus and nucleus tractus solitarius are structures within the central nervous system that are involved in the pathophysiology of nausea.
• Neurotransmitters and their receptors that are mostly involved in the pathogenesis of nausea and vomiting, and include Dopamine (D2), Acetylcholine (M), Serotonin (5HT3), Histamine (H1), and Substance P (NK1).
• PONV risk factors associated with the patient include age, gender, smoking status, history of motion sickness, and PONV,.
• PONV risk factors associated with anesthesia include volatile anesthetics, NO, Opioids, and Neostigmine
• PONV risk factors associated with the surgery include duration, laparoscopic technique, Gynecologic, ENT, Breast & Plastic Sx, Orthopedics, and Ophthalmic
• Granisetron is a 5 HT3 Receptor Antagonist
• Headache and diarrhea are side effects associated with ondansetron
• Dry mouth, blurred vision, rash, hyperthermia, tachycardia, restlessness, hallucinations, seizures, coma, and respiratory failure are some side effects associated with transdermal scopolamine.
• Dexamethasone is a corticosteroid highly effective and mostly used as an antiemetic
• Droperidol may cause QT prolongation in high doses
• Aprepitant is a Neurokinin-1 Receptor Antagonist
• Propofol and Midazolam are two anesthetics which are effective antiemetics.

Dietary Supplements

• Major surgery, trauma, burns, malnourished patients, those undergoing chemotherapy, and hepatic/renal dysfunction are indicators for nutritional support
• Inability to take or absorb PO nutrition as well as length of requirement are indications for surgical placement of a feeding tube versus a nasoenteric tube
• Dumping Syndrome can occur with rapid introduction of hyperosmolar tube feeds into the gut.
• Enteral nutrition anesthetic considerations include risk of aspiration from positioning during surgery, location of surgery, location of feeding tube such as NG, OG, Post-pyloric, and PEG as well as cuffed ETT or Tracheostomy
• Side effects of parenteral nutrition to assess for include hypervolemia, hypercarbia from increased CO2 due to excess carbohydrates, alterations in blood sugar, especially if stopped abruptly, and sepsis and infection risks from access
• Fat-soluble vitamins include A, D, E, and K
• Echinacea may cause immune suppression, hepatitis, and allergic reaction/anaphylaxis
• Ephedra may cause HTN, and vasoconstriction, arrhythmias, catecholamine depletion, or sensitized myocardium
• Garlic should be held for 1-2 weeks before a regional anesthetic
• Ginger interacts with Anticoagulants (5HT-3 antagonists), NSAIDs
• Ginkgo inhibits Platelet Activating Factor
• Ginseng may cause decreased BS and agitation
• Cardiac-related side effects that occur with ginseng are increased bleeding, increased blood pressure, and increased heart rate
• Kava potentiates GABA-mediated effects, it does not bind to GABA, therefore, the dosage range for propofol should not be affected
• St. John’s Wort is commonly used for depression, psych disorders, and neuropathy
• Abrupt discontinuation of Valerian may cause excitability, cardiac and hepatotoxicity, which are similar to Benzodiazepine withdrawal

Pharmacodynamics and Populations

• The effects of a drug on the body is pharmacodynamics, this relationship is between the effect site concentration and clinical effects
• The effect site, where the drug has its clinical effect, is known as PharmacoBIOPHASICS
• Depolarization, repolarization, hyperpolarization are three phases of the neuronal action potential after a stimulus.
• The neuronal synapse releases neurotransmitters through voltage-gated calcium channels
• The sodium-Potassium Pump helps restore resting membrane potential
• Chirality is molecules with 3-D asymmetry, producing mirror images that cannot be superimposed, resulting in a racemic mixture with two enantiomers in equal proportions

Ligand-Gated Ion Channels

• The glycine receptor is an inhibitory ligand-gated ion channel
• Efficacy is the degree at which the ligand can effect a response when bound to a receptor, or the ability to maximum response or clinical effect.
• Potency refers to the amount of drug to cause a specific clinical response at a certain concentration
• The ED50 is a measurement of potency that produces a effective response in 50% of the population
• The therapeutic index is a ratio comparing a drug's concentration causing therapeutic effects to levels causing death in animals or toxicity in humans
• Competitive antagonists block agonists from binding to a receptor, therefore increases to the agonist can reverse the antagonism, while non-competitive antagonists cannot be reversed when more agonist is added
• An additive drug interaction is when the effect of two drugs equals the mathematical summation of their effects when given alone
• Older adult patients are not at higher risk of postoperative nausea and vomiting with anesthesia than younger patients.
• Two neurophysiologic changes in the older adult affecting pharmacology; decreased albumin levels, and toxicity risks due to decreased kidney/liver function or polypharmacy
• Older patients have increased GFR and liver blood, leading to increased hepatic drug clearance and metabolite production
• Neonates have immature kidney function that reduce urine pH which reduces renal excretion
• Cardiac output increases an average of 35-50% in obstetric patients depending on trimester, this can be up to 300% directly after post-delivery
• Increased circulating progesterone decreases requirements, SVR and CSF effects distribution. Increased adipose tissue. Blood and total body water volume, which causes increase in sensitivity to vasoactive drugs
• Increases in renal blood flow, GFR, 2D6 & 3A4 enzymes with decreases in cholinesterase are common responses to changes in liver activity
• Dose adjustments are made for renal elimination with faster induction and emergence.
• Delayed gastric emptying increases risks for: PONV & Pulmonary Aspiration

Pharmacokinetics and Medication Safety

• Pharmacokinetics refers to drug effects, and plasma concentration, within the body
• Absorption, distribution, metabolism, elimination are the four components of pharmacokinetics.
• Acids donate protons, and bases accept them
• Pka measures pH with half the acid molecules likely to be deprotonated, and weaker acids have higher pka
• The nonionized form is typically the active formation to be absorbed

Bioavailability

• Bioavailability refers to a chemically unchanged drug fraction that enters systemic circulation
• 100% of a IV drug is bioavailable
• Factors influencing drug distribution include route of administration, first-pass hepatic metabolism, drug solubility, and chemical stability
• Most drugs bind to albumin
• The centra compartment includes the heart, lungs, liver, kidneys, and blood, while peripheral compartments include the brain, skin, muscle, and fat, with the distribution based on speed
• Enzyme induction uses INCREASES clearance to decreased plasma levels, whereas enzyme inhibition DECREASES clearance to INCREASE plasma levels
• Renal insufficiency reduces elimination and increases toxicity
• A drug's half-life is related indirectly to kidney and liver extraction
• Two conditions that increase a drug's half-life: Decreased renal blood flow and displacement of drug from albumin
• Steady state is when the drug entering equals the drug exiting the body.

Governmental Regulation of Medications

• The 1938 Food, Drug, and Cosmetic Act (FDCA) defines a drug as any article affecting the human body's function or structure, classified by intended dose and ingredients
• Types of medication errors include administration-dilution, substitution, and incorrect or inaccurate labeling
• Medication error prevention includes: barcode scanning, standardization, smart pumps, prefilled syringes

Renal Physiology and Diuretics

• Hormones Produced by the Kidneys are Renin & Erythropoietin
• 20%-25% of the cardiac output is received by the kidneys
• Aldosterone causes distal reabsorption of Na+ and water whereas excretion of K+
• Hypotension and hypovolemia activates Renin Release
• Renin Release is done by Juxtaglomerular cells in the Macula Densa
• Angiotensin II leads to Vasoconstriction in Blood Vessels
• What two substances are reabsorbed by the kidneys; Salt and Water
• Vasopressin and Aldosterone causes Blood volume Increase from Water Reabsorption
• Atrial natriuretic Peptide (Factor) causes Increase in Excretion of Salt and Water
• Role of Kidneys in Acid-Base Balance, Peritubular Capillaries reabsorbing Bicarbonate Ions while secreting hydrogen Ions
• Passive Movement in kidney creates Urine during FILTRATION
• Decreased Afferent Arteriole Tone causes an Increase in GFR because the efferent arteriole is constricted
• Water is reabsorbed with Sodium
• Osmosis = passive mechanism of reabsorption
• Hypertension and Congestive Heart Failure (CHF) are problems Diuretics Treat

Diuretics

• Carbonic Anhydrase Inhibitors (Acetazolamide) decrease the Reabsorption of sodium, bicarbonate, and water
• Osmotic Diuretics are Unmetabolized, Freely Filtered in Glomeruli
• Mannitol increases osmolarity of blood and renal tubule fluid.
• .25-1 g/kg dose of Mannitol
• Loop Diuretics block the sodium-potassium-2 chloride co-transporter
• Prostaglandins are produced more by Loop diuretics
• Loop Diuretics leads to Hypokalemia, leading to risk of metabolic alkalosis, and potentiation of non relaxing neuromuscular Blocking
• Ototoxicity associated with Loop Diuretics
• Thiazide block the sodium-chloride co-transporter
• Thiazides Increases blood glucose
• Spironolactone block Aldosterone.
• Triamterene Prevents Sodium Reabsorption
• Distal Convoluted Tubule is the site for Potassium Sparing action
• Cyclic AMP created secondary as a Dopamine (D1 receptor) message
• Higher doses of Dopamine cause beta receptor activation, increasing cardiac output, and leads to alpha receptor activation causing Vasoconstriction
• Increased risk of kidney injury for perioperative patients include Hypovolemia, Decreased Cardiac Output; Increased SNS Stimulation; Aminoglycosides

Fluids, Electrolytes, and Blood

• Potassium is the main cation for intracellular fluid
• Sodium is the major cation extracellular
• Proteins and large Macro prevent move across fluid compartments

Assessment of Fluid Status

• Central Venous Pressure and Urine Output assess fluid status
• Elevated Dynamic Pressures indicates Fluid responsiveness and Dehydration

Crystalloids

• LR is a balanced crystalloid
• Strong Ion Difference (SID), normal values is 40+
• Decreased SID results in Chloride Levels leads to high Chloremic Metabolic Acidosis
• Isotonic remain 20% intravascular
• NS and D5W fluid shifts

Hypertonics

• Hypertonics (saline) water moves out the cell
• Albumin are synthetic Colloids

HES

• Is an synthetic colloids that causes harm and death to Critical, kidney, heart CABG patients
• Sodium causes neuron and action
• Potassium is critical for clotting

Protein

• Protein levels affect pregnancy issues
• Calcium is higher is Calcium Chloride

Blood and Blood Products

• RBC immune response
• Agglutinin is antibody
• Clotting in clumping blood
• Reduced ATP means clotting

Blood Fluids

• Avoid LR and D5W
• Plasma is great in first 24 hours
• Platelets, Fibrinogen, and Cryo (factors)
• Not mix with Platelets.
• Leukoreduction (remove WBC) prevent antibody development
• TACO develops from cardiogenic
• Lung injury for TRALI
• Hypothermia worsens blood health
• TEG detects Thrombo (clotting)
• Calcium and Magnesium replaces
• 10units mean massive blood
• Platelets, plasma and red cells mixed 1:1:1

Anticoagulants & Procoagulants

• The mechanisms of primary hemostasis are Adhesion, Activation, and Aggregation
• Platelet adhesion requires exposure to the subendothelial vascular basement membrane and the attachment factor vWF to collagen receptors
• Recruited platelet aggregates are ADP and Thromboxane 2
• Fibrinogen via GP IIb & GP IIIa links holds platelets linking each other
• Clot linked by Fibronogen
• Vitamin K factors II VII IX X are clotting
• Thromboplastin is Extrinsic coagulation for Tissue Factor
• Damage means intrinsic cascades from Factor XII
• Calcium factors 3 and activated then is Factor V and Factor II to the fibrin clot
• Final mesh contains Factor XIII
• Pro Extrinsic 11-14
• Instrinsic is 28-35

Intrinsic vs Extrinsic Pathway

• Inhibit Heparinization or Protamine-Antagonization (measure)
• Common and intrinsic tested
• Inhibits Factor 3 a1000 fold with antithrombin is used
• Unfractured =4 hours shut in
• Hit aggregates platelets then release IGg
• Low Weight Heparin is high hemoptysis
• Vitamin K prevent activate clot
• Measure =INR
• Warfarin on is 3-5
• Bind Prothrombin bivalirudin
• Reversal-Xarelto and Apixaban
• Stroke is reduced during clots

More Agents

• Aspirin Clopidgrel is on 7 days shut day
• Block or reduce blood product administration during axial anasthesia for 2 days
• Anti Three clot prevent
• Reduce fibrin break with tPA
• Reduce clot breakdown with caprio
• TXA - high dose
• Act fast and Acidic block with protamine
• LMWH still reduce flow with this
• High blood pressure during protamine
• Demospressin at 15 mins for factor VII
• The test to memorize include 7 factors

Anti-Parkinsonian Medications

• Resting Tremor and Stiffness are traits
• Less Dopamine in Parkinson leading to Acetylcholine Excesss in Muscles
• Muscles affected with breathing bradykinesia
• Beta need not be used
• Liver must have function
• Muscles, tremors are side effect cause
• Hyper pyrexia needs Liver support quickly
• MAO slows CNS

Antiemetic Meds

• Anticholinnergic help block fluids
• Seizure drugs
• Awareness decreased
• Sleep, imbalances causes
• BZ (anti E)

GABA Agonists

• Anxiolytics increase GABA and inhibit with decrease doses
• Withdrawal syndrome leads to increased muscle response
• Benz increase to fix pain
• NMJ blocker with long-term therapy is a drug

Stimulants and Headaches

• NMDA block pain and ACH is side effect
• Depleted Epinephrine
• Doxapram
• adenosine stops headaches and methyls help with after surgery

Psychopharma and Nerves

• Serotonin affects aggression platelet genital
• Blocks depression mood and serotonin
• Suilide-Child is side effect
• Serotonin - low BP and Tachycardia

Nerve Receptors

• TCAs stop serotonin which increases HR while orthostatic changes and inhibits alpha.
• NE not created if they are stopped
• Lithium increase GABA
• Altered body
• D stop dopamine

Antipsychotics

• Tardine means is the muscles altered
• Activity affected is akathsia
• Larynx affected in acute dystonia
• Paralyzed muscles indicate drug side effect
• NMS AND EXTRA is what meds use
• Neuro transmitters like dopamine can be a problem.

Chemotherapeutics

• GO growth stage of the cells
• Tumors develop fast
• P53 gene for mutations
• Resistance from the bad genetics
• Toxicity effects are cells dividing
• Ask for immunosuppesion side effects

Pulmonary Agent Side Effects

• Alkylating, Platinum, Antimeta, Topoiso, Micro (all used here agents to stop replication process)

Bleomycin

• Bleo affects heart and lung functions most and cause cell death
• Always vaccinate the ill

Antimicrobials

• Three kinds of SSIs or Soft Sites injuries
• Nutrition or Immune
• Pro Skin Prep
• Respira, GU, GI have site for wounds
• 2hours prior to antibiotic, or not give.

Beta Lactams

• Break down the good cells
• Most all cell have beta effects
• First is cefazolin to stop gut, skin flours
• MRNA interfered causes problems by aminoglycosides
• Drug toxicity to Kidney and Inner Ear
• Lincosamide (Clindamycin is not rapid to administer)
• Anafilaxia for Red-Syndrome
• Not use alcohol with drug treatments
• Iodine used in site treatments