Acid-Base Pathophysiology Causes

• A summary of the different causes of acid-base pathophysiology

Respiratory Acidosis

• Respiratory acidosis involves the accumulation of carbon dioxide (CO2), leading to a decreased blood pH (usually 7.3-7.4)
• Pulmonary dysfunction (COPD, asthma)
• Decreased neurologic respiratory drive (medulla) causes respiratory acidosis
• Renal dysfunction
• Increased metabolism (hyperinflammation, infection in the bloodstream leading to systemic effects [sepsis])

Metabolic Acidosis

• Metabolic acidosis involves a decrease in bicarbonate levels
• Increased AGMA leads to metabolic acidosis due to increased inorganic acid levels

"MUDPILES"

• MUDPILES: a list of causes behind increased AGMA levels
• Methanol can cause increased formic acid accumulation
• Methanol accumulation can cause optic nerve inflammation and blindness
• Uremia causes increased presence of sulfuric acid
• Sulfuric acid is found in patients with CKD and renal impairment
• Diabetic Ketoacidosis and other causes of ketoacidosis can cause metabolic acidosis
• Beta-hydroxybutyrate is present
• Acetone is responsible for the fruity breath in DKA patients
• Oxaloacetic acid /Acetoacetate
• Propylene Glycol (lactic acid)
• Parenteral nutrition
• IV fluids
• Isoniazid (lactic acid)
• Pyridoxine deficiency
• Pyridoxine normally converts glutamate to GABA
• Without pyridoxine, glutamate accumulates to toxic levels
• Glutamate converts into Lactic acid, leading to acidosis
• Iron supplementation
• Lactic acidosis
• Lactic acidosis can be caused by hyperinflammation and sepsis
• Ethylene Glycol (antifreeze)
• Glycolic acid functions as the primary driver for acidosis in Ethylene Glycol poisoning
• Oxalic acid combines with calcium, forming calcium oxalate kidney stones
• Metabolic acidosis and kidney stones indicate ethylene glycol toxicity
• Salicylate Toxicity can present with AGMA + respiratory alkalosis
• Non-Anion Gap MA occurs due to direct bicarbonate loss
• Hyperalimentation causes excessive parenteral nutrition
• Acetazolamide functions as a carbonic anhydrase inhibitor
• Adrenal Insufficiency can cause zona glomerulosa insufficiency
• Zona glomerulosa insufficiency results in aldosterone deficiency
• Aldosterone deficiency causes hyperkalemia and hyponatremia, resulting in NAGMA
• Diarrhea results in potassium and bicarbonate loss from stool
• Spironolactone can cause hyponatremia, hyperkalemia, and hypotension

Pulmonary Unit

• Obstructive and Restrictive Lung Disease are the two general classes of lung diseases

Obstructive Lung Disease

• COPD, Asthma, and Emphysema are types of obstructive lung diseases
• Decreased FEV1/FVC ratio leads to carbon dioxide retention
• Keep oxygen saturation above 88%
• Delivery of excessive oxygen creates a homeostatic IMBALANCE
• Medulla decreasing breathing drive and respiratory failure are also involved

COPD vs Asthma

• SMOKING is the cause of COPD
• Irreversible scarring of Type II alveoli causes emphysema
• The COPD management is the same as asthma cases
• Use corticosteroids for treatment
• Treat CAP with streptococcus pneumoniae
• Use Azithromycin

Asthma

• Asthma is rooted in genetics and driven by inflammation
• IgE, mast cells, basophils, and eosinophils, histamine, and serotonin are involved in the inflammatory process
• Bronchoconstriction!
• Management involves decreased bronchoconstriction
• Use SABA (albuterol) or LABA (salmeterol)

Restrictive Lung Disease

• Normal FEV1/FVC occurs due to decreased availability of lung expansion
• Iatrogenic causes of pulmonary fibrosis are Methotrexate and Bactrim, Amiodarone, Nitrofurantoin, and Cyclophosphamide
• Chemical Exposures that can lead to lung disease are Coal Worker’s Pneumoconiosis (coal miners), Berylliosis (glass, electronic plants), Silicosis (electronic plants), and Asbestosis (ship yards, abandoned/old houses)
• Chronic autoimmune diseases like SLE and Rheumatoid Arthritis can cause lung disease

Dermatologic Unit

• CHEETAHS LOVE GOOD SPAGHETTI, BRO: mneumonic for remembering layers of epidermins
• Stratum Corneum
• Stratum Lucidum
• Stratum Granulosum
• Stratum Spinosum
• Stratum Basale

Keratin Formation

• Keratinocyte apoptosis produces keratin as a byproduct

Atopic Dermatitis (Eczema)

• Type I HS reaction
  • IgE, mast cells, basophils, and eosinophils
  • Th2 CD4 T cells (which release IL-4, IL-5, and IL-13)
• Symptoms occur within minutes-1 hour
• Management is
  • Topical Corticosteroids (Bethamethasone, Triamcinolone, Hydrocortisone
  • Systemic Corticosteroids are ONLY USED IN SEVERE CASES with SYSTEMIC CIRCULATION
  • Tacrolimus
  • Dupilumab

Contact Dermatitis

• Type IV HS reaction
  • Macrophages, CD8 T cells, NK cells
  • IFN-gamma and TNF-alpha
• Manifests in days or weeks
• Management options match cases of atopic dermatitis, but do not use Dupilumab!

Neuropathology of Parkinson’s Disease

• Substantia nigra (pars compacta) destruction causes decreased dopamine production
• Decreased dopamine production and release leads to decreased thalamic and motor cortex activation
  • D1 is stimulatory
  • D2 is inhibitory
• Bradykinesia is a clinical finding (slow movements)
• Tremors during movement can be a clinical sign
• Parkinsonian dementia is a late-stage symptom
• Carbipoda-Levodopa Dopa-Decarboxylase inhibitors
  • Promotes isomeric dopamine entry into the brain and decreases the activation of receptors in the periphery
• D2 agonists: Ropinorole, Pramixpexole, bromocriptine
• MAO-B inhibitors: Selegiline, Rasagiline
  • AVOID using with wines, cheeses, meats (deli meats), pickles

Huntington’s Disease

• CAG trinucleotide repeats cause excessive glutamine residues and abnormal Huntingtin protein
• The protein impacts the caudate and putamen nuclei of the striatum
• More CAG repeats lead to increased disease severity and earlier onset
• Movement Disorder symptoms involve Choreiform movements (“dancing”) and Hyperkinetic (fast) uncontrollable movements
• Late stages have Parkinsonian-like phenotypes due to substantia nigra destruction
  • EARLY cases: tetrabenazine which inhibits DA packaging and D2 antagonist

Resting membrane potential

• Resting membrane potential of most neurons in the CNS is -70 millivolts

Glutamate Receptors

• AMPA receptor allows for sodium entry into the post-synaptic neuron
  • Highly associated with focal seizures
• NMDA receptor allows for calcium >>> sodium entry into post-synaptic neuron
  • Magnesium blocks NMDA receptor under normal conditions, this block is removed with glutamate binding + post-synaptic neuronal depolarization
  • Highly associated with generalized seizures

GABA Receptors

• GABAA receptor is only post-synaptic
  • Binds GABA, opening chloride channels for intracellular movement
  • Leads to hyperpolarization and ionotropic functions
  • Common target for benzodiazepines (agonists)
• GABAB receptor is presynaptic and postsynaptic
  • Metabotropic receptor
  • Utilizes GPCR (G-protein coupled receptor based signal transduction) mechanisms
  • Slightly smaller role with seizures
  • Presynaptic Inhibition of voltage-gated ion channels
  • Decreases synaptic vesicle docking + neurotransmitter release
  • Post-synaptic opening of potassium efflux channels
  • Results in potassium efflux and hyperpolarization

Seizures

• Excessive Activation by Glutamate

  • Increased glutamatergic release and increased AMPA/NMDA receptor expression post-synaptically

• Decreased Inhibition caused by a decreased

  • GABAergic effect leading to decreased GABA release and decreased GABAA expression

• Synchronization of Neuronal Firing

  • Neurons fire together to increase the likelihood of other nerve networks in the brain becoming depolarized simultaneously, causing seizure-like activity

• Metabolic/Electrolyte Abnormality: hyponatremia

• Hypoxia +/- mitochondrial dysfunction

Seizure Types

• Focal Seizures: abnormal hyperexcitability in one location

  • Can stay localized or spread

  • Causes motor +/- nonmotor symptoms

  • Does not always results in loss of consciousness/awareness

  • Clinical findings reflect the lobes affected:

    • Frontal Lobe: impacts primary motor cortex, supplemental motor areas
    • Parietal Lobe: impacts Primary somatosensory cortex
    • Occipital Lobe: impacts Primary Visual Cortex
    • Temporal Lobe: most common epileptiform focus!

  • Hippocampus: most highly affected subcortical area (deep to the temporal lobe) responsible for induction of fear and aggression

  • Brainstem: responsible for the loss of consciousness

• Generalized Seizures: affect both hemispheres and subcortical areas (thalamus, neuronal projections from the thalamus/basal ganglia to cerebral lobes of the brain, brainstem)

  • Causes loss of consciousness

  • Followed by a post-ictal state (fatigue and confusion)

    • Generalized tonic-clonic seizures causes muscles to stiffen and patient falls to the ground with complete loss of consciousness, after about 45-60 seconds, muscles jerk uncontrollably for 2-5 minutes.
    • Absence Seizures shows patients staring into space without significant clonus/tonic movements are rare common in childhood

Status Epilepticus

• Pathophysiologic state longer than 5 minutes or when recurring for longer without recovery between seizures
  • MEDICAL EMERGENCY
  • Generalized Convulsive Status Epilepticus is MOST COMMON; involves persistent tonic-clonic seizure, hyperthermia, hypertension, tachycardia Non-Convulsive Status Epilepticus shows no motor manifestations Electroencephalogram (EEG) evidence can show epileptiform activity, staring into space, unresponsiveness

Focal Status Epilepticus:

• Predictable focal motor/sensory/visual symptoms related to the affected lobe

  • Uses ABC’s (airway, breathing, circulation) + TIERED PHARMACOLOGIC MANAGEMENT:

  • IV Benzodiazepines (Ativan, Midazolam, Diazepam) are the FIRST LINE of defense

  • Long-Acting Anticonvulsant like Phenytoin, Valproic Acid, Levitiracetam

• Phenobarbitol can be administered if Pheno isn’t on hand/available

• General Anesthesia (propofol)

Illicit and pharmaceutical drugs that increase the risk of seizures

• Amphetamines, Cocaine, MDMA (ecstasy, Molly)

  • Increase glutamate release, resulting in hyperexcitability

• Ketamine causes seizures in an NMDA-independent manner

• Ketamine is NORMALLY an NMDA receptor ANTAGONIST

  - However, ketamine ALSO potentiates (promotes) increased norepinephrine and dopamine release from subcortical areas, especially the thalamus with cortical neuron hyperexcitability
  

Medical treatment

• Bupropion: used in smoking cessation BupropionDNRI increases dopamine and norepinephrine

Flumazenil

• Benzodiazepine reversal agent that causes GABAA antagonism

Isoniazid

• Seizures occur secondary to pyridoxine deficiency- Decreased GABA production and increased glutamate accumulation causes glutamate toxicity and neuron hyperexcitation thus seizure

Benzodiazepine and Alcohol Withdrawal

• In patients who abuse benzodiazepines chronically, acute cessation of benzodiazepines with decreased GABA transmission causes high CNS hyper-excitability and sympathetic NS activity

  • Short-acting benzodiazepines (Alprazolam, Lorazepam) causes quicker onset of symptoms

    • Long-acting benzodiazepines (Chlordiazepoxide, Diazepam) causes symptoms to last WEEKS

Alcohol withdrawal seizures

• Alcohol potentiates GABAA transmission, promoting hyperpolarization; chronic alcohol use causes downregulation of available GABAA receptors and resulting in desensitization
• Sudden loss of GABA transmission and decreased receptor sensitivity causes decreased inhibition, resulting activity in the CNS. Patients may experience anxiety, tremors, insomnia, heart palpitations, and n severe nausea
  • Delirium Tremens is life-threatening with autonomic instability, paranoia + aggression for around 48-96 hours after last drink - SEVERE agitation leads to Hallucinations, death and autonomic instability ###Management - IV Lorazepam helps restore GABA sensitivity and a physiologic response in general anesthesia

• The emotional centers of the brain
• 5-HT1A post-synaptic receptor promote emotional stability, rational decision making, and memory
• 5-HT1A: autoreceptor that induces serotonin reuptake
• 5-HT2A: inhibitory receptor leading to issues in depression
  • Decreased goal-motivated behavior and response to rewarding stimuli shows DA deficiency
• Normal physiologic functions of brain-derived neurotrophic factor(BDNF) causes neurogenesis
  • Neuroplasticity-synaptic connections to promote response

Pharmacologic Interventions for Depression

• SSRI’s and SNRI’s are FIRST LINE drugs used here
  • SSRI's inhibit presynaptic receptor and 5-HT2A receptor
  • SNRIS increases the availability of BOTH serotonin and NE

SN RIS

• Venlafaxine, Duloxetine

• Black Box warning for Bupropion: lowers seizure threshold

Amitriptyline:

• Mostly tricyclic antidepressants are reserved for difficult cases with side effects. The medication also functions as an SRI

• MAOI’s must avoid tyramine with aged cheeses and foods high in yeast

Treatment of MAOI’s:

Mirtazapine:

-SNRI- enhance medication release while requiring weight gain -Trazodone- SNI: serotonin and norepinephrine release to promote sleep -Serotonin syndrome can occur with autonomic hypertension

Serotonin syndrome:

1. hypertension diaphoresis with neuroplasticity; symptoms can occur within hours of use

Treatment

• Benzodiazepines (Lorazepam)

Schizophrenia

• History of abuse can cause trauma
• History of Cannabis abuse in teenage years can cause schizophrenia
• Hallucinations and disorganized thinking leads to negative symptoms like positive hallucinations in schizophrenia -Dopamine hyperactivity with lack of serotonergic function -
• The negative symptoms in schizophrenia is treated through apathetic behavior First-generation drugs cause side effects of carpal tunnel, -

###Risperidone: The class of medication used is Agranulocytosis - cannabinoids

• The increase of function leads to euphoria

Treatment for methamphetamine-

• Symptoms: increase paranoia Use second atypical generation of medications

Norovirus and E. coli

• Both causes is common

What decreases intestinal absorption?

Deficiency of lactose is broken down by fatty acids

What is treatment for Imodium?

Treatment with an opiod

• Diophenoxylate + antrophine