Acid-Base Pathophysiology: Causes

Acid-Base Pathophysiology Causes

• Respiratory acidosis results from carbon dioxide accumulation, leading to a blood pH decrease (typically 7.3-7.4).
  • Pulmonary dysfunction (COPD, asthma) is a cause.
  • Decreased neurologic respiratory drive (medulla) can lead to respiratory acidosis.
  • Renal dysfunction may cause respiratory acidosis.
  • Increased metabolism (hyperinflammation, sepsis) may contribute.
• Metabolic acidosis involves reduced bicarbonate levels.
  • Increased AGMA leads to metabolic acidosis due to elevated inorganic acid levels, categorized by "MUDPILES."
    • Methanol increases formic acid accumulation, causing blindness due to optic nerve inflammation.
    • Uremia indicates elevated sulfuric acid, common in patients with CKD and renal impairment .
    • Diabetic ketoacidosis and related ketoacidosis causes result in high levels of beta-hydroxybutyrate, acetoacetic acid and acetone.
      • Acetone presence causes fruity breath in DKA patients.
    • Propylene Glycol (lactic acid), parenteral nutrition and IV fluids can cause metabolic acidosis.
    • Isoniazid (lactic acid) can lead to B6 deficiency.
      • Pyridoxine normally converts glutamate to GABA; without it, glutamate accumulates and converts to lactic acid, causing acidosis.
    • Iron supplementation and hyperinflammation/sepsis can cause lactic acidosis.
    • Ethylene Glycol (antifreeze) causes glycolic acid accumulation, a primary acidosis driver and oxalic acid combines with calcium, forming kidney stones.
      • Suspect ethylene glycol toxicity when metabolic acidosis occurs with kidney stones.
    • Salicylate toxicity can present with AGMA and respiratory alkalosis.
• Non-anion gap metabolic acidosis stems from direct bicarbonate loss.
  • Excessive parenteral nutrition (hyperalimentation), carbonic anhydrase inhibitors (Acetazolamide), and zona glomerulosa insufficiency (Adrenal Insufficiency) can cause it.
    • Aldosterone deficiency, hyperkalemia, hyponatremia (NAGMA) are indications of adrenal insufficiency.
  • Diarrhea causes potassium and bicarbonate loss.
  • Spironolactone can result in hyponatremia, hyperkalemia, and hypotension.

Pulmonary Unit

• Obstructive lung diseases include COPD, asthma, and emphysema.
  • Reduced FEV1/FVC ratio causes carbon dioxide retention
  • Avoid giving oxygen if saturation is above 88%.
• Delivering excessive oxygen creates homeostatic imbalance; the medulla reduces breathing drive, causing respiratory failure.

COPD vs Asthma

• COPD is commonly caused by smoking, leading to irreversible scarring of Type II alveoli and emphysema.
  • COPD management mirrors asthma and definitively requires corticosteroids.
  • CAP (Streptococcus pneumoniae) treatment involves azithromycin.
• Asthma is deeply rooted in genetics and driven by inflammation associated with IgE, mast cells, basophils, eosinophils, histamine, and serotonin, leading to bronchoconstriction.
  • Asthma is managed by reducing bronchoconstriction.
    • SABA (albuterol) and LABA (salmeterol) are used for this.
    • Anticholinergics (Tiotropium, Ipratropium) may also provide relief.
• Restrictive lung disease presents with normal FEV1/FVC due to reduced lung expansion availability.
  • Iatrogenic causes of pulmonary fibrosis include drugs like Methotrexate, Bactrim, Amiodarone, Nitrofurantoin and Cyclophosphamide.
  • Chemical exposures like Coal Worker’s Pneumoconiosis (coal miners), Berylliosis (glass, electronic plants), Silicosis, and Asbestosis can cause pulmonary fibrosis.
  • Chronic autoimmune diseases like SLE and Rheumatoid Arthritis can lead to pulmonary fibrosis.

Dermatologic Unit

• The epidermis layers (from superficial to deep) are: Stratum Corneum, Stratum Lucidem, Stratum Granulosum, Stratum Spinosum, and Stratum Basale. Use the mnemonic "CHEETAHS LOVE GOOD SPAGHETTI, BRO"
• In skin, keratin is produced from keratinocyte apoptosis.
• Atopic dermatitis (eczema) involves a Type I HS reaction and IgE, mast cells, basophils, eosinophils, and Th2 CD4 T cells (releasing IL-4, IL-5, IL-13).
  • Symptoms manifest rapidly (minutes to an hour), and management includes topical corticosteroids (Bethamethasone, Triamcinolone, Hydrocortisone), systemic corticosteroids (ONLY in severe cases), Tacrolimus, and Dupilumab.
• Contact dermatitis involves a Type IV HS reaction and macrophages, CD8 T cells, NK cells, IFN-gamma, and TNF-alpha.
  • Symptoms can take days to weeks to appear.
  • Management is similar to atopic dermatitis but excludes Dupilumab.

Neuropathology of Parkinson’s Disease

• Parkinson's is caused by substantia nigra (pars compacta) destruction, which lowers dopamine production.
• Reduced dopamine leads to decreased thalamic activation and motor cortex input.
  • D1 receptors are stimulatory, while D2 receptors are inhibitory.
• Clinical signs involve bradykinesia, tremors during movement, and late-stage Parkinsonian dementia.
• Treatments include Carbidopa-Levodopa, Dopa-Decarboxylase inhibitors to help dopamine enter the brain, D2 agonists such as Ropinorole and Pramixpexole and MAO-B inhibitors such as Selegiline and Rasagiline.
  • AVOID dopamine medication with wines, cheeses, deli meats, or pickles.
• Huntington's Disease results from CAG trinucleotide repeats.
  • Excess glutamine residues lead to abnormal Huntingtin protein, affecting the caudate and putamen.
    • More repeats mean earlier onset and greater disease severity.
  • Displays choreiform movements and hyperkinetic movements and late stages show Parkinsonian-like phenotypes.
  • Early management: Tetrabenazine and D2 antagonists
    • Late stage management follows Parkinson's disease protocols.

Resting Membrane Potential & Neurotransmitters

• The resting membrane potential of neurons in the CNS is -70 millivolts.
• Glutamate binds to AMPA receptors, allowing sodium entry into the post-synaptic neuron, associated with focal seizures.
• Glutamate binds to NMDA receptors, allowing calcium entry into the post-synaptic neuron, associated with generalized seizures.
  • Magnesium typically blocks NMDA receptors; glutamate and neuronal depolarization remove the block.
• GABA binds to:
  • GABAA receptors, on post-synaptic neuron only to open chloride channels causing hyperpolarization, and they are targeted by benzodiazepines.
  • GABAB, pre and post-synaptically, using GPCR mechanisms; having a smaller role in seizures, inhibiting voltage-gated ion channels, decreasing synaptic vesicle docking, as well as neurotransmitter release, and opening potassium efflux channels, causing hyperpolarization.

Seizures

• Seizures can result from glutamate over-activation.
  • This increases glutamatergic release and AMPA/NMDA receptor expression post-synaptically.
• Decreased inhibition due to reduced GABAergic effects also can cause seizures
  • Decreased GABA release and GABAA expression can lower the seizure threshold
• Neuronal firing synchronization can significantly increase the likelihood of depolarization and seizure-like activity.
• Metabolic or electrolyte abnormalities, notably hyponatremia and/or hypoxia and mitochondrial dysfunction, can lower the seizure threshold.
• Focal seizures start in one location and may spread, causing motor or nonmotor symptoms, without necessarily causing unconsciousness.
  • Clinical findings are lobe-specific:
    • Frontal lobe involvement shows focal motor findings,
    • Parietal affects primary somatosensory cortex,
    • Occipital causes visual auras,
    • Temporal is most common, the hippocampus is often affected.
    • Subcortical areas such as the thalamus and amygdala (inducing fear/aggression).
    • Brainstem involvement relates to consciousness loss.
• Generalized seizures involve both hemispheres without a specific focus, affecting subcortical areas (thalamus, basal ganglia, and brainstem), causing loss of consciousness followed by a post-ictal state.
  • Tonic-clonic seizures: Patient becomes stiff (tonic), falls, loses consciousness, then experiences jerking movements (clonic) for 2-5 minutes, with no recollection afterward.
  • Absence seizures cause patients to appear to stare into space, with no post-ictal phase, and are common in childhood.

Status Epilepticus

• Status epilepticus involves continuous seizure activity lasting longer than 5 minutes or recurrent seizures without consciousness recovery, requiring immediate medical intervention with three primary subtypes.
  • Generalized convulsive: Persistent tonic-clonic seizure, hyperthermia, hypertension, tachycardia.
  • Non-convulsive: No motor manifestations, but EEG shows epileptiform activity, staring, and unresponsiveness.
  • Focal: Predictable motor/sensory/visual symptoms, based on the affected lobe, with potential progression to generalized seizure.
• Management involves ABC's and tiered pharmacologic interventions.
  • First-line: IV Benzodiazepines (Ativan, Midazolam, Diazepam).
  • Second-line: Long-acting anticonvulsants (Phenytoin, Valproic Acid, Levitiracetam). Other options are Phenobarbitol or general anesthesia (propofol).

Illicit Drugs and Seizures

• Illicit drugs like amphetamines, cocaine, and MDMA can increase glutamate release, causing hyperexcitability.
• Ketamine uniquely causes seizures in an NMDA-independent manner.
• Ketamine, though an NMDA receptor antagonist, increases norepinephrine and dopamine release, especially in the thalamus, leading to seizures.

Prescription Drugs and Seizures

• Bupropion is commonly prescribed for smoking cessation.
• Bupropion acts as a dopamine-norepinephrine reuptake inhibitor but also increases sodium permeability, lowering the seizure threshold, and increasing neuronal excitability.
• Flumazenil is a benzodiazepine reversal agent and a GABAA antagonist.
• Isoniazid, used for tuberculosis, can cause B6 deficiency.
• Isoniazid-induced Pyridoxine deficiency reduces GABA production and increases glutamate.
• Other antipsychotics such as clozapine are used in the management of schizophrenia which can increase glutamate.

Benzodiazepine & Alcohol Withdrawal Seizures

• Benzodiazepine withdrawal results in decreased GABA transmission, increasing CNS excitability through increased sympathetic NS activity.
• Short-acting benzodiazepines (Alprazolam, Lorazepam) show quicker symptom onset.
• Long-acting benzodiazepines (Chlordiazepoxide, Diazepam) can have symptoms that last for weeks.
  • Symptoms: Anxiety, insomnia, sweating, tremors, heart palpitations, and late symptoms of seizures, hallucinations, paranoia, severe autonomic instability (hypertension, tachycardia), cardiac arrest, and hyperthermia.
  • Management: Use short-acting benzodiazepines like Lorazepam, Midazolam, or Diazepam.
  • Also, manage ABC's and autonomic instability; severe cases may need general anesthesia.
• Alcohol Withdrawal: Alcohol increases GABAA transmission, promoting hyperpolarization.
  • Chronic alcohol use leads to downregulation of GABAA receptors and desensitization.
  • Sudden alcohol withdrawal results in acute loss of GABA transmission, reducing inhibition, increasing glutamate activity, and causing CNS hyper-reactivity.
    • Symptoms include anxiety, tremors, insomnia, heart palpitations, and in chronic alcoholics, severe nausea.
• Delirium tremens: A life-threatening condition presenting with seizure, autonomic instability, paranoia, and aggression 48-96 hours after drinking.
• Management: IV Lorazepam, with further long-acting benzodiazepines to help restore GABA sensitivity and other treatments following anesthesia if severe.

Neurotransmitters & Pharmacology

• The 5-HT1A receptor in the emotional centers of the brain are stimulatory, promotes rational decision making, and establishes emotional memory.
• 5-HT1A and 5-HT2A receptors in the emotional centers of the brain promote DECREASED serotonergic activity
• Dopamine Deficiency: affects the motivation, pleasure, and attachment to emotional events.
• Brain-Derived Neurotrophic Factor (BDNF): Stimulates neurogenesis, enhances neuroplasticity for strengthened response to stimuli and decreases inflammation of the brain.

Pharmacological Interventions for Depression

• Selective Serotonin Reuptake Inhibitors (SSRIs): First-line treatment that inhibits 5-HT1A and 5-HT2A receptors to increase serotonin availability .
  • Examples are Sertraline, Fluoxetine, Citalopram and Escitalopram.
• Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs): Increase both serotonin and norepinephrine availability
  • Examples are Venlafaxine and Duloxetine.
• Dopamine and Norepinephrine Reuptake Inhibitors (DNRIs): Increase dopamine & norepinephrine availability.
  • Bupropion is used used for smoking cessation.
    • Bupropion has a black box warning for increased seizure risk, due to increasing membrane permeability to sodium.
• Tricyclic Antidepressants: Reserved for treatment-resistant depression due to side effects (cardiotoxicity); function as SNRIs.
  • Amitriptyline is often used.
• Monoamine Oxidase Inhibitors (MAOIs): Patients must avoid tyramine-containing foods to prevent severe hypertension and increased stroke risk.
  • Selegiline is a MAO-B inhibitor.
  • Phenelzine is an MAO-B and MAO-A inhibitor.
• Other antidepressants includes Mirtazapine (SNRI, increasing DA release) and Trazodone which is a serotonin receptor/NE antagonist and a H1 receptor antagonist that promotes sleep.

Serotonin Syndrome

• Serotonin syndrome is hyperstimulation of serotonergic receptors that leads to - autonomic instability (hypertension, tachycardia, diaphoresis) - Neuromuscular hyperreactivity (myoclonic jerking, hyperreflexia) and altered mental state.
  • Symptoms occur within hours, and treatment includes ABC's and IV Benzodiazepines as well as cooling.

Schizophrenia

• Environmental factors predisposing schizophrenia: childhood trauma, adolescents who abuse cannabis and history of imprisonment.
• Schizophrenia (Positive Symptoms): Hallucinations, delusions, paranoia, abnormal motor behavior, thought disorder.
  • Dopamine hyperactivity in the brain induces the positive symptoms.
• Schizophrenia (Negative Symptoms): Apathy, anhedonia and cannot stay motivated.
  • Decreased serotonergic function causes negative symptoms.
• Social withdrawal
  • This can last for days to weeks
  • This is associated with pathophysiological causes, such as decrease in function or decreased secretion of serotonin in the brain stem.

Schizophrenia: Pharmacological Treatments

• First Generation Antipsychotics are Haloperidol, Fluphenazine and Chlorpromazine.
  • Reserved for non-compliant patients with high doses lasting for months at a time
  • Large side effects of Pseudo Parkinson's disease, hyperprolactinemia and cardiotoxicity
• Second Generation Antipsychotics are Risperidone, Olanzapine, Quetiapine, Aripiprazole and Clozapine.
• First Line consolidation.
• MUCH better side effects.
• Increased risk of Metabolic Syndrome and weight gain
• Clozapine is EXTREMELY STRONG for treatment resistance - Must monitor for AGRANULOCYTOSIS - For suicidal ideations.

Cannabis/Cannabinoid MOA in Neuroaxis

• Cannabis and Cannabinoids are partial agonists of CB1 receptors
  • Partial agonism = more euphoria; this decreases depression
  • Impure products release NE

Methamphetamines (Neuroaxis)

• Mimic the effects of Norepinephrine/Epinephrine, which increase dopamines.
  • Causes hallucinations (tactile)
  • Severe paranoia
  • Aggression
  • Insomnia (For days)
    • Rx = Lorazepam + Midazolam
      • Atypical

Ketamine/PCP (Neuroaxis)

• Nmda receptor antagonist.
  • Decreases releases in GABA with thalamic and DA involvement but a lot of lobes are affected.
    • Out of body experiences

Pharmacology: MDMA (Ecstasy)

• Sympathomimetic, highly Dopaminergic
• Hallucinations ( tactile)
  • Sensitive to touch.
    • Vasoconstriction or fever, hyponatremia which causes seizures from overcompensating for polydipsia

Upper GI and the Pathophysiology

• Dysgeusia: Is the term technical or LOS/dysfunction in taste.
• Candidal Esophagitis:
  • Most common cause esophageal in immuno deficiency
  • From fever or dysphagia and pain.
  • The disease is known to occur fungal bloodstream.
• Severe cases
• NORMALLY: Lower esophagus has Stratified squamous epithelium; In GERD
• Normal repetitive Acid (exposure/damage) Metaplasia = Goblet calls in Simple Columnar Cells
• Barretts Esophagus = esophageal Adenocarcinoma*

GERD: What are some RISK FACTORS?

• Obesity: Sedentary life-High Adiposity index
• Weak lower sphincter from smoking or food with too much spice; Citrus food, caffeine, alcohol or Fats. Other: asthma; calcium blockers or nitrates
• Tx = Pranzole drugs and H2 blockers - Histamine is decreased camp production. - Tidines
• Alkaline Agents = For rapid relief* - May cause Tachyphylaxis. Magnesium Hydroxide of Calcium Carbonate
• Bismuth is bad during pregnancy.

Additional GERD facts

• Metoclomperamide can cause Parkinson like symptoms that increase sphincter activity.
• Sucralfate must be taken last for PH Balance.

Hormonal Factors that Promote Acid Production

• Gastrin receptor activation -H2 histamine activation pathway
• Vagous nerve activation

Peptic Ulcers

• Hematemesis = Vomiting blood due to a dark or bright ulcer

Celiac Disease

• The body cannot digest wheat and is lost through stool
• Gliadin interacts with transglutaminase activating glutamate which is immunostimulatory.
• The body produces 2 antibodies
• TTG catalyses Deamination from Glutamate on Gliadin molecules - This stimulates anti -TTG Bodies

Antibodies are key diagnostic Fatigue and peripheral neuropathy may occur as a result of the disease.

CD: Additional Conditions That May Occur

• Szeizures = B Def. and hyponatremia
• Steatorrhea - Abdominal pain
• Dermatitis in elbows and butt.
• Common associations

Forms of IBD

• Ulcerative Colitis - Engorged blood
• Chrons Disease - Cobblestone
• These diseases affect two traits of the GI Tract*

Other Facts for UC and Chrons

• UC has a normal GI tract vs. CHRONS which can skip segments.
• Fistulas and obstructions are known to occur*
• Use Hematocherzia to diagnose blood

UC and CD Treatment

• 5 ASAs =Mesalamines. for MILD to moderate cases.
• Steroids for Aute Flaire Ups
• Immunosuppressant which have Puring and pyrindine effects
• Biologics = - TNF - Check First

Diarrhea

• Viral = Norovirus and rotavirus - Mostly in cruises and cruise ships may cause severe watery
  • Adeno. is common in children under 2 from water or fever.

Bacterial Causes

• E.Coli = from raw meat
  • Mexico and leads to mild fever with diarrheas. - EHEC - - Shiga 4 kids can cause kidney failure.

Other Diarrhea Facts

• Salmonella can cause limited cramps from milk or eggs.
• Campy - Can effect barreners syndrome.

Infections

• C DIFF due to disrupt antibiotics leads to MegaColon. - Manage with Vancomycin.

Fungal causes

• Candida from oral infection and is treated will fluconazole.
• Always suspect birds of OHIO*

Weird DI FACTS!

• Hyperthyroidism causes Basal metabolic rates to rise.
• Hypercalcemia causes diarrhea.
• Lack of B7 and fat absorption, which may be caused by Celiacs.

Treatment

• Loperamide; which must bypass through 1 more barrier or Diphen, which has atropine and helps slow intestional motility !