Worksheet 2/3

Diuretics and Ototoxicity

• Loop diuretics are associated with ototoxicity
• Loop diuretics inhibit the Na/K/2Cl co-transporter in the ascending limb of the Loop of Henle

Thiazide Diuretics

• Thiazide diuretics inhibit the Na/Cl co-transporter in the distal convoluted tubule
• Thiazides inhibit reabsorption and increase excretion of Na and H2O
• Thiazides increase the reabsorption of Calcium
• Thiazide diuretics can cause an increase in blood glucose
• Thiazide diuretics can cause an increase in hyperuricemia and ammonia

Spironolactone

• Spironolactone works by blocking the aldosterone receptor

Triamterene

• Triamterene blocks the Na channel directly in the endothelial ENAC inhibitor

Potassium-Sparing Diuretics

• Potassium-sparing diuretics primarily work in the collecting duct in the nephron

Dopamine and Receptor Activation

• Activation of D1 receptors by dopamine increases the formation of cyclic AMP
• Higher doses of dopamine agonists activate D1 adrenergic receptors, increasing inotropy and cardiac output
• Higher doses of dopamine agonists activate B2 adrenergic receptors, causing vasoconstriction

Electrolyte Changes with Diuretics

Perioperative Kidney Injury

• Age is a patient risk factor for perioperative kidney injury
• CHF is a patient risk factor for perioperative kidney injury
• Surgical procedure being in peritoneum is a patient risk factor for perioperative kidney injury

Nephrotoxic drug classes

• Aminoglycosides are a common nephrotoxic drug class
• Cephalosporins are a common nephrotoxic drug class

Cell Cycle Phases

• The four major phases of the cell cycle are G1, S, G2, and Mitosis
• The G0 phase is considered a "resting" cell phase with no cellular division

Mitosis phases explained

• Prophase: Chromatin condenses into distinct chromosomes, which migrate towards the center of the cell. The nuclear envelope breaks down, and spindle fibers form
• Metaphase: The nuclear membrane disappears, the spindle develops, and chromosomes align
• Anaphase: Paired chromosomes (sister chromatids) separate, and spindle fibers lengthen the cell
• Telophase: Chromosomes are sectioned off into two distinct new nuclei with equal genetic content. Cytokinesis (division of the cytoplasm) begins after anaphase and finishes after telophase, forming two new cells

Cancer

• Malignant cells escape normal mechanisms for control of cellular division and growth
• Malignant cell migration and invasion of other tissues = Metastasis
• p53 is an important tumor suppressor

Telomeres

• Telomeres are the name for DNA “end caps” (lead to cellular aging)

Chemotherapy Toxicity

• Chemotherapy toxicity side effects are often related to rapidly dividing cell targets affecting normal cells such as hair follicles and mucosal cells

Immunosuppressed Patients

• Anesthetic considerations for the immunosuppressed cancer patient carries include aseptic methods and prophylactic antibiotics

Alkylating Agents

• Alkylating agents work in no specific cell-cycle phase
• Two pulmonary side effects of alkylating agents can be pneumonitis and fibrosis, which leads to decreased diffusion capacity
• Alkylating agents inhibit the activity of plasma cholinesterase, affecting anesthetic drugs by way of cardiotoxicity, specially cyclophosphamide

Platinum Complexes

• Platinum complexes such as the Platins work on solid tumors in a non-cell cycle-specific manner
• Platinum complexes crosslink DNA, disrupting replication and division to cause an alkylating-like effect
• Cisplatin can cause nephrotoxicity and Ototoxicity, also peripheral neuropathy, nausea and vomiting, myelosuppression, or hypersensitivity reaction
• Antimetabolites mimic cellular nutrients like Folic acid and inhibit enzymes like nucleobases.
• Antimetabolites work on the S Phase
• Dermatitis, pigmentation changes, nail changes, alopecia (hair loss) and photosensitivity are dermatologic side effects of antimetabolite drugs
• Bone marrow suppression, pulmonary toxicity, GI toxicity, nephrotoxicity, hepatotoxicity, and CNS effects are other side effects

Topoisomerase Inhibitors

• Topoisomerase inhibits DNA action from the S phase through early G2, which leads to DNA breakage as well as cardiotoxicity via free radicals
• Free radicals disrupt critical cardia proteins and cell membrane components

Bleomycin

• Bleomycin can cause pulmonary toxicity
• Anesthetics containing crystalloids instead of colloids and high FiO2 increase the risk of pulmonary toxicity in patients taking bleomycin

Microtubule Inhibitors

• Microtubule inhibitors are active in the M phase
• The two main drug classes are Vinca Alkaloids and Taxanes
• Three neuromuscular side effects are sensory-motor neuropathy, areflexia, paresthesia's, skeletal weakness, skeletal muscle pain, and ataxia

Edema and Effusions

• Dexamethasone treats edema and effusion

Muscle Blockers

• Residual musculoskeletal blockage is treated with sugammadex, not neostigmine

Regional Anesthesia

• Regional anesthesia can worsen neuropathy when combined with microtubule inhibitors

Tumor Treatment

• Signal transduction modifier hormones disrupt growth factor-receptor interaction or target overexpressed antigens
• Signal transduction modifier (monoclonal) antibodies target autoimmune disease, specific cancer antigens, or receptors
• Monoclonal antibodies also treat multiple sclerosis and rheumatoid arthritis
• Anti-estrogens like Tamoxifen are associated with an increased risk of thromboembolic and stroke
• Vaccines are given in cancer or at-risk populations to decrease the risk of having cancer

Key Side Effects of Chemotherapy Drugs

• Bleomycin is toxic to the lungs, causing endothelial and epithelial damage leading to pulmonary fibrosis, resulting from free radical production

  • The recommended O2 limit is below 30% when possible to avoid exacerbating pulmonary fibrosis damage

• Cisplatin can lead to nephrotoxicity, peripheral neuropathy, nausea/vomiting, hypersensitivity reactions, myelosuppression, and ototoxicity

• Doxorubicin is known for cardiotoxicity

Antimicrobials: Chlorhexidine

• Chlorhexidine and other topical antiseptics put patients at risk for corneal toxicity

Antibiotics: Vancomycin

• Vancomycin is given preoperatively in a dose of ~15mg/kg IV

Antibiotics: Macrolides

• Macrolides are used for inflammation and respiratory infections but can prolong QTc intervals

Antibiotics: Ciprofloxacin

• Ciprofloxacin may be used off-label for surgical prophylaxis within 2 hours of incision

Antibiotics: Aminoglycosides

• Aminoglycosides may cause nephrotoxicity and ototoxicity

Timing IV Antibiotics

• Most antibiotics should be administered within 1 hour of surgical incision

Bacteria Resistance

• Bacterial resistance is a term for a variety of conditions which reduce the effectiveness of antimicrobials
• Cefazolin or Metronidazole are highly effective against gram-negative, anaerobic, and other organisms usually in the GI tract
• A bacterial structure, Beta Lactam, is highly susceptible to the antimicrobial, Cefazolin (1st Gen.)
• Beta-lactamases are enzymes that provide bacterial resistance for beta-lactams

Vancomycin

• The antibiotic vancomycin should be infused within 2hrs hours before incision

Post-Op Antibiotics

• Antibiotics should be discontinued within 24hrs hours after surgery

Surgical Site Infections

• Endogenous risk factors for surgical site infections include: corticosteroid use, preop skin prep, prolonged hospital stays, extremes of age, malnutrition, obesity, diabetes, tobacco use, current infections, altered immunity, and/or radiotherapy
• There are three types of surgical site infections: superficial incisional, deep incisional, and organ/space
• Clean contaminated wounds usually affect the respiratory, gastrointestinal (GI), and genitourinary (GU) tracts

Cefazolin

• Cefazolin is an antibiotic and the first-generation drug of choice for surgical prophylaxis
• A 135 kg patient is administered 3g IV, which is the dose of cefazolin given to patients weighing more than 120 kg
• First-generation cefazolin has skeletal muscle weakness because it can give calcium that poses a high risk to myasthenia gravis patients

Clindamycin

• Clindamycin (Cleocin) is a common perioperative antibiotic that is classified as a lincosamide
• Clindamycin should be infused over 10-60 minutes but is recommended for 30 minutes

3 Topical Antiseptics

• Chlorhexidine, Povidone-lodine, and lodine

Red Man Syndrome

• Erythema, pruritus, and hypotension are symptoms of "red man syndrome"

Metronidazole

• Abdominal disturbances, nausea, vomiting, headache, and flushing are the side effects from administering metronidazole with alcohol

Gentamicin Mechanisms and Toxicity

• Gentamicin is an aminoglycoside that binds to the 30S ribosomal subunit of bacteria, resulting in the inhibition of protein synthesis
• Ototoxicity and Nephrotoxicity are toxicities that this drug class can cause

HIV Replication and Management

• Entry inhibitors block viral entry into cells
• Zidovudine (AZT) treats HIV in pregnant patients and also inhibits the enzyme
• A boosting agent is required of a certain class of antiretrovirals

Airway Disorders

• Airway fibrosis, alveolar destruction, and mucus hypersecretion is a common effect in respiratory disorders
• Using bronchodilators may be required during light anesthetic use when inflammatory airway disease
• Albuterol can cause skeletal muscle stimulation
• Cromolyn sodium blocks degranulation of inflammatory cells
• Beta-2 receptor agonism leads to relaxation of vascular and bronchial smooth muscle
• The inhaled corticosteroid fluticasone decreases inflammation
• Nitric oxide directly increases guanylyl cyclase & relaxes bronchial smooth muscle

Respiratory Drug Mechanisms

• Theophylline blocks phosphodiesterase
• Montelukast blocks conversion of arachidonic acid to LTs
• Pre-oxygenation with 100% O2 removes & replaces nitrogen in the alveoli

Key Values

• Theophylline > 20 for toxicity

Other Respiratory Information

• Positive end expiratory pressure and other ventilator settings can improve lung capacity
• Compliance in a lung refers to the relationship between a change in airway pressure for a given change in lung volume
• General anesthesia causes partial alveolar closure/collapse known as atelectasis
• Moderate and severe COPD patients have elevated Paco2 levels
• Ipratropium may cause cardiovascular side effects
• Ristrictive airway disease is characterized by a normal FEV1/FVC ratio and decreased forced expiratory volume

Bronchodilators

• Propofol and ketamine cause bronchodilation
• Beta-2 agonists increase intracellular cAMP levels in smooth muscle causing vasodilation, Broncodilation, and Tachycardia

Muscarinic Antagonists

• Muscarinic antagonists block the M3 receptor which is attached to Gq protein

Asthma Characterizations

• Inflammatory airway disease, bronchospasm, edema, mucus secretion, and smooth muscle cells characterize asthma

Low FiO2 Delivery

• A nasal canula, non-rebreather, or simple face mask are low-flow oxygen delivery options

High FiO2 Delivery

• A vent Uri mask, High-flow NC, or trach are high-flow oxygen delivery options

Normal Vagal Tone in Airways

• Vagus nerve uses ACH to activate M3 receptors causing Bronchial smooth muscle constriction

Physiological dead space

• Alveoli that does not participate in gas exchange

Physiological Effects of Beta-2 Agonism

• Vasodilation
• Bronchodilation
• Tachycardia

Beta Agonists: Side Effects

• Tachycardia
• Tremor
• Hypotension

Albuterol Dose

• 4-6 puffs (90 mcg per puff every 15 mins)

Methylxanthines

• Methylxanthines can be used for a post-dural puncture headache
  • Caffeine
  • Theophylline
  • Theobromine

Airway Waveform changes in bronchospasm

• An expected finding for the capnographic waveform is a shark fin due to prolonged respiratory phase

cGMPs

• 3 mechanisms for cGMP-mediated smooth muscle relaxation: Ca Inhibition, K hyperpolorization, Activate MLCK

Antihypertensive Drugs

• Sildenafil is a PDE5 inhibitor which is often used as a treatment of pulmonary hypertension
• Epoprostenol increases prostacyclin hormone targets IP receptors - Gs protein – increase cAMP – smooth muscle relaxation = vasodilation

Hyperkinetic vs Hypokinetic

• Bradykinesia is defined as slow and decreased movement in relation to Parkinson's Disease.

Neurotransmitter Depletions

• Parkinson Disease is characterized by bradykinesia, unstable gate, shuffling gate, ridged elbows, knees in flexion, and masked face
• Dopamine is the neurotransmitter depleted in patients with Parkinson's Disease leading to an imbalance and excess of excitatory activity from Acetylcholine
• Parkinsonian patients are rigid & bradykinetic of respiratory and pharyngeal muscles.

Antiemetics in Parkinson’s

• Ondansetron does not affect dopamine and can be used as an antiemetic in Parkinson’s

The Motor System

• Extrapyramidal system is involved in involuntary movements, posture, and reflexes

MAO-B

• MAO-B drugs antagonize MAOB's from breaking down Dopamine

Levodopa

• Give Levodopa, IV fluid, and Supportive care to treat Parkinsonism-hyperpyrexia syndrome
• Levodopa is the natural physiologic precursor to dopamine, with side effects of Orthostatic Hypotension, Tachycardia, Arrhythmia, Skin flushing, and increased inotropy due to dopamine, epinephrine, and norepinephrine activation
• Levodopa is a dopamine precursor and crosses the blood brain barrier

Anti-Parkinson

• B-Blockers are avoided during intraoperative tremor tests
• To balance Dopamine and Acetylcholine effect give anti-cholinergics to PD patients

Antileptic Drug Actions

• Keppra blocks the alpha 2 delta subunit of voltage-gated calcium channel, can cause hypertension, as well as decreased alertness and sedation
• Phenytoin is an enzyme inducer requiring an increased maintenance dosage for non-depolarizing neuromuscular blocker
• Patients taking antiepileptic drugs may require higher doses of propofol, Midazolam, Opcodes, and NDMR, and benzodiazepines
• The effect of BZs (benzodiazepines) is enhanced through GABA-inhibition.
• Carbamazepine keeps sodium channels in the inactive phase
• Seizures in older patients are caused by tumors

Three Symptoms Seen With a Seizure:

- Altered awareness
- Convulsions
- Loss of motor control

Seizure Risk Factors

- Hypoglycemia
- Hyperventilation
- Hypoxia

Two Indicators for Benzos During a Seizure:

- Acute Sz
- Status Epilepticus

Anesthetic Drugs

- Down-regulate the release of catecholamines
- Vasopressors include
    - Phenylephrine
    - Epinephrine
    - Vasopressin

• Doxapram can be used to stimulate the medulla

Epileptic Concerns

• Status epilepticus describes sustained seizures that do not return to baseline
• Seizures in older adults may suggest of tumor

Anesthesia and Liver concerns regarding Valproic Acid

• Causes hepatic dysfunctions in young/peds populations

Anesthetics for Patients on Pysch Meds:

• Avoid dropping Sodium concentrations while treating patients on Lithium
• Lithium may prevent the nervous system from sending signals

CNS Stimulants

• Chronic use results in down-regulation of endogenous catcholamines

Post-Dural Puncture

• Caffeine can treat dural punctures