Psychoactive Drugs Overview

Psychoactive Drugs

• Lithium: Used to treat manic-depressive illness (bipolar disorders) and prevent chronic cluster headaches.

• Lithium inhibits thyroid hormone synthesis and release, causing hypothyroidism.

• Lithium is a cationic metal that does not bind to proteins.

• Lithium is absorbed rapidly and completely via PO administration.

• Distribution is uniform throughout body water and is reabsorbed.

• When given with Demeclocycline, it inhibits the action of ADH on the kidneys.

• Therapeutic range: 0.8-1.2 mmol/L.

• Toxic effects at levels >2 mmol/L include severe dehydration, nephrotoxicity, hypothyroidism, apathy, lethargy, speech difficulties, seizures, muscle rigidity, and coma.

• Elimination: Renal filtration.

• Tricyclic Antidepressants (TCAs): Used to treat depression, insomnia, extreme apathy, and loss of libido.

• PO administration absorption is variable (85-95%).

• Highly protein-bound.

• Examples: Imipramine, Amitriptyline, Doxepin, Nortriptyline, Trazodone.

• Elimination: Hepatic metabolism.

• Peak Serum Concentration: 2-12 hours.

• Therapeutic level: 100-300 ng/mL.

• Major metabolite: Desipramine.

• Toxic effects include drowsiness, blurred vision, memory loss, seizures, cardiac arrhythmias, Parkinsonian syndrome, and unconsciousness.

• Fluoxetine: Blocks the reuptake of serotonin in central serotonergic pathways.

• Used for the treatment of obsessive-compulsive disorder (OCD).

• Therapeutic level: 90-300 ng/mL.

• Toxic effects include attempted suicide, decreased libido, and decreased sexual function.

Bronchodilator

• Theophylline is a methylated xanthine.
• It relaxes bronchial smooth muscle.
• It inhibits the release of histamine and other proinflammatory agents.
• It's used in the treatment of asthma and chronic obstructive pulmonary disease (COPD).
• It's also used for primary apnea of prematurity.
• Administration: 1st IV and 2nd orally; 50% protein bound.
• Crosses the placenta and may be teratogenic in pregnant females.
• Blood level is the best predictor of toxicity.
• Elimination: Renal filtration and hepatic metabolism.
• Therapeutic level: 10-20 µg/mL.
• Toxic level: >20 µg/mL.
• Toxic effects include GI bleeding, seizures, tachycardia, and syncope.

Immunosuppressive Drugs

• Cyclosporine: Inhibits cellular immune response by blocking IL-2 production and is used to prevent organ transplant rejection.

• Also used for acute graft-versus-host disease (GVHD).

• Used for heart, liver, and pancreas transplants, requiring high dose (300 ng/mL).

• High affinity with RBC (temperature dependent).

• PO administered (5-50% absorption).

• Elimination: Hepatic and metabolized whole blood.

• Toxic level > 500 ng/mL.

• Toxic Effects: Including renal, GI disturbances and hematologic dyscrasia

• Tacrolimus (FK-506): A macrolide lactone abx, 100x more potent than cyclosporine.

• GIT uptake varies, elevated in patients with cholestasis.

• Specimen of choice is whole blood.

• Elimination: Hepatic metabolism.

• Toxic Effects: Including Thrombus formation, nephrotoxicity and neurotoxicity

• Rapamycin: Similar to tacrolimus.

• Major Side Effects: Lipid abnormalities and Thrombocytopenia

• Mycophenolate mofetil: Decreases renal allograft rejection.

• Leflunomide: Inhibits lymphocyte proliferation.

• Used for the treatment of Rheumatoid Arthritis.

Antineoplastic Drugs

• Methotrexate: Effective therapy for various neoplastic conditions and immunosuppression.

• Inhibits DNA synthesis by blocking dihydrofolate reductase.

• Leucovorin is a rescue drug for methotrexate toxicity.

• Toxic Drug Level: 0.01 umol/L.

• Toxic Effects: Leucopenia, GI ulceration, thrombocytopenia, and cirrhosis.

• Busulfan: An alkylating agent used prior to bone marrow transplantation for leukemias and lymphomas.

• Overdosage can cause Hepatic Occlusive Disease.

Anti-inflammatory/Analgesics

• Salicylates/Aspirin: Direct stimulator of the respiratory system; inhibitor of Krebs' cycle; and antiplatelet.

• Decreases TXA and PG.

• Acute aspirin intoxication is a common cause of fatal drug poisoning in children.

• Side Effects: includes GI disturbances, and interference with platelet aggregation.

• Therapeutic Level: 5 mg/dL (treatment of HA).

• Toxic Level: >30 mg/dL, and can cause mixed acid-base disturbance (Met. Acidosis and Resp. Alkalosis) and Reye’s syndrome.

• Methods: Trinder Assay, Enzymatic Assay (Salicylate hydroxylase), and HPLC

• Acetaminophen: Inhibits PG metabolism, analgesic, and antipyretic.

• Overdosage leads to hepatotoxicity.

• Toxic Doses: Acute single ingestion levels of 140 mg/kg.

• Very High Doses (with suicide attempts) can cause fulminant hepatic failure and maximum liver damage.

• Not apparent until 2-4 days after ingestion.

• Severe Poisoning: CNS stimulation followed by CNS depression, vascular collapse, shock, total seizure, coma, and death.

• Chronic Abuse: Chronic toxicity and death, anemia, renal damage, Gastroenterintestinal disturbance.

• NAC treats toxic effects of Acetaminophen/APAP.

• Therapeutic Levels: 25 µg/mL.

• Toxic levels: 100-300 µg/mL (hepatic cirrhosis).

• Toxic effects: Cyanosis due to methemoglobinemia, CNS depression, seizures.

• Methods: HPLC

• Ibuprofen: Analgesic/Anti-inflammatory, lower risk of toxicity than salicylates and acetaminophen.

• Toxic effects include nausea/vomiting, blurred vision, abdominal pain, and edema.

• Therapeutic level: 10-50 µg/mL.

• Toxic level: >100 µg/mL..

Neuroleptics (Antipsychotic Major Tranquilizers)

• Blocks dopamine and serotonin in the limbic system.
• Used in schizophrenia treatment.
• Difficult to monitor in the serum due to abundant metabolites.
• Extensive hepatic metabolism.
• Toxic effects: Cholestasis, Orthostatic hypotension, and Aplastic Anemia, Muscle rigidity.

Carbohydrates

• Glucose: The only carbohydrate used for energy or stored as glycogen that does not enter muscle cells freely.
• The brain completely depends on blood glucose for energy production.
• Two-thirds of glucose utilization occurs in the CNS.

Reducing and Non-reducing Sugars

• Reducing sugars: Glucose, Maltose, Fructose, Lactose, and Galactose.
• A double bond and a negative charge in the enol anion makes glucose an active reducing substance.
• Non-reducing sugars: Sucrose.
• Do not contain an active ketone or aldehyde group.

Pancreas

• Islet of Langerhans containing:
  • Beta cells: Secrete insulin and amylin.
  • Alpha cells: Secrete glucagon.
  • Delta cells: Secrete somatostatin.
  • F cells: Secrete pancreatic polypeptide..
• Endocrine gland: Secrets insulin, glucagon, and somatostatin from different cells in the pancreatic islets of Langerhans.
• Exocrine gland: Secretes amylase responsible for the breakdown of ingested complex carbohydrates.

Insulin

• Primary hormone for glucose entry into cells.
• Promotes Glycogenesis, Lipogenesis, and Glycolysis.
• Suppresses Glycogenolysis.

Glucose Measurement

• Patient preparation: No MTV/Supplements 12 hours prior to collection.
• Sample requirement: Serum.
• Reference values: 2.6-24.9 mIU/mL.

Glucagon

• Hyperglycemic agent.
• Released during stress and fasting states.
• Enhances catabolic functions during fasting periods and promotes glycogenolysis.
• FP Glucagon = 25-50 pg/mL

Other Hormones That Tend to Increase Blood Glucose Concentration

• Cortisol and Corticosteroids (Glucocorticoids).
• Catecholamines.
• Growth Hormone (Somatotrophic).
• Thyroid Hormones.
• Adrenocorticotropic Hormone (ACTH).
• Somatostatin.

Clinical Conditions Related to Carbohydrate Metabolism

• Hyperglycemia: Toxic to beta-cell function, impairs insulin secretion. Causes: Stress, severe infection, dehydration, pregnancy, pancreatectomy, hemochromatosis, and FPG deficiency.
  • FPG ≥126 mg/dL.
• Hypoglycemia: Imbalance between glucose utilization and production. Warning signs and symptoms related to low blood glucose concentration. Whipple's Triad.

Interpretation of Plasma Glucose Values

• 65-70 mg/dL: Glucagon and other glycemic hormones are released into the circulation.
• 50-55 mg/dL: Observable symptoms of hypoglycemia appear.
• ≤50 mg/dL: Considered low value; further diagnostic test needed.
• <50 mg/dL: Impairment of cerebral function starts.

Symptoms of Hypoglycemia

• Neurogenic: Tremors, palpitations, anxiety, and diaphoresis.
• Neuroglycopenic: Dizziness, tingling, blurred vision, confusion, and behavioral changes.

Classification of Hypoglycemia

• Drug-induced
• Critical illnesses
• Hormonal deficiency
• Endogenous hyperinsulinism
• Autoimmune hypoglycemia
• Non-beta cell tumors
• Hypoglycemia of infancy and childhood
• Alimentary (reactive) hypoglycemia

If Px is suspected of Endogenous Hyperinsulinism

• Measure: Plasma glucose, Insulin & Proinsulin, C-peptide, Beta-hydroxybutyrate, Insulin antibodies, and Oral hypoglycemic drugs.

Clinical Hypoglycemia

• Plasma/serum glucose concentration is low enough to cause symptoms/signs of impairment of brain function.

Factitious Hypoglycemia

• Intentional attempt to induce low blood glucose levels.
• Results from exogenous self-administration of insulin/insulin-secretagogues.
• More common in women in their 30s-40s.

Diabetes Mellitus (DM)

• Hyperglycemia due to defects in insulin secretion or insulin receptors.
• FPG = ≥126 mg/dL.
• Glucosuria: Excessive glucose excretion in urine.
  • Plasma glucose >180 mg/dL with normal renal function.
• Ketosis: Excessive synthesis of Acetyl-CoA leading to formation of Ketone Bodies.
  • Severe β-hydroxybutyrate to acetate ratio 6:1.

Laboratory Findings in DM

• Increased glucose found in plasma and urine; increased urine specific gravity.
• Positive ketones in the serum and urine.
• Acidosis in blood and urine.
• Electrolyte imbalance (low sodium, increased potassium, and low bicarbonate).
• High serum osmolality.

Classification of DM

• Type 1 DM (T1DM)
• Type 2 DM (T2DM)
• Gestational Diabetes Mellitus (GDM)
• Other Types (OTODM)

Type 1 DM

• Insulin-dependent diabetes mellitus (IDDM).
• Juvenile onset diabetes mellitus.
• Brittle diabetes.
• Labile diabetes.
• Ketosis-prone diabetes.
• Results from cellular-mediated autoimmune destruction of beta cells in the pancreas.
• Insulinopenia (absolute insulin deficiency) due to loss of pancreatic B-cells.
• Prone to Ketoacidosis

Latent Autoimmune Diabetes of Adulthood (LADA)

• Type 1a or 1.5 DM.
• Slow immune-mediated DM.
• Slowly progressive insulin-dependent type 1 DM (SPIDDM).
• Characterized by moderate hyperglycemia with gradual autoimmune destruction of pancreatic beta cells
• Common among adults, shares immunological features with both T1DM and T2DM.
• Distinguishing features include (+) single specific islet cell autoantibody (GAD, IA-2A, ZnT8).
• Predisposing factors: Low birth weight, advanced age, and family history of autoimmune disease.

Fulminant Type 1 Diabetes (FT1D)

• Formerly idiopathic type 1 DM or type 1b.
• Strongly inherited and associated with the absence of B-cell autoantibodies.
• Characterized by remarkably rapid and complete B-cell destruction.
• Aggressive progression of hyperglycemia and ketoacidosis.

Type 2 DM

• Non-insulin-dependent diabetes mellitus (NIDDM).
• Adult type/maturity onset diabetes mellitus.
• Stable diabetes.
• Ketosis-resistant diabetes.
• Receptor-deficient diabetes.
• Hyperglycemia due to insulin resistance and defective insulin secretion.
• Strong genetic predisposition; not related to autoimmune disease.
• Patient at risk for macrovascular and microvascular complications.
• Risk factors: Obesity, family history, advanced age, hypertension, lack of exercise, and gestational diabetes (GDM).

Gestational Diabetes Mellitus (GDM)

• Impaired ability to metabolize carbohydrates.
• Deficiency of insulin, metabolic, and hormonal.
• Occurs during pregnancy and disappears after delivery.
• Screening and diagnosis: 2-hour OGTT.
• Diagnostic tests: one-step and two-step methods.
• Diagnostic criteria: Fasting blood sugar (FBS) ≥92 mg/dL, 1-hour sample ≥180 mg/dL, and 2-hour sample ≥153 mg/dL.

Other Types of DM

• Due to pancreatic disorder (pancreatogenic DM/Type 3c DM).
• Related to endocrine disorders (Cushing's syndrome, pheochromocytoma, acromegaly, aldosteronoma, and hyperthyroidism).
• Caused by genetic syndromes (Down syndrome, Klinefelter's syndrome, Rabson-Mendengall syndrome, Leprechaunism, Huntington's chorea, and Turner syndrome).
• Associated with other exocrine diseases (cystic fibrosis, neoplasia, and hemochromatosis).

DM due to Pancreatic Disorders

• Chronic pancreatitis.
• Pancreatic malignancy (pancreatic CA).
• Pancreatectomy.

DM related to Endocrine Disorders

• Cushing's syndrome.
• Pheochromocytoma.
• Acromegaly.
• Aldosteronoma.
• Hyperthyroidism.

Other Clinical Findings

• Down syndrome, Klinefelter's syndrome, Rabson-Mendenhall syndrome, Leprechaunism, and Huntington's chorea.
• Turner syndrome.

Samples for Glucose Measurement

• Random blood sugar (RBS).
• Fasting blood sugar (FBS).
• Two-hour post-prandial blood sugar (2-HPPBS).
• Glucose tolerance test (GTT).
• Glycosylated hemoglobin (HbA1c).
• Fructosamine.
• 1,5-anhydroglucitol (1,5-AG).

Lipids and Lipoproteins

• Major functions of lipids: Primary sources of fuel, provide stability to cell membranes, and sources of hormones.
• Major lipids in plasma: Phospholipids, cholesterol, triglycerides, fatty acid, and fat-soluble vitamins (ADEK).
• Phospholipids (conjugate lipid): Most abundant lipid derived from phosphatidic acid; produced from conjugation of two fatty acids and a phosphorylated glycerol; reference value is 150-380 mg/dL
• Cholesterol (3-hydroxy-5,6-cholestene): Unsaturated steroid alcohol; synthesized in the liver and is found on the surface layer of lipoproteins; does not serve as a source of fuel/energy; transport and excretion are promoted by estrogen
• Ref. values: <200 mg/dL; 200-239 mg/dL borderline; ≥240 mg/dL = high cholesterol.

Diagnostic Significance of Cholesterol

• Evaluates the risk for atherosclerosis, myocardial, and coronary arterial occlusions.
• Direct relationship with MI, used in thyroid, liver, and renal function tests, and DM studies to aid in diagnosis and management of lipoprotein disorders.
• Monitors the effectiveness of lifestyle changes and stress management.

Increased Cholesterol

• Hyperlipoproteinemia types II, III, IV.
• Biliary cirrhosis.
• Nephrotic syndrome.
• Poorly controlled DM.
• Alcoholism.
• Primary hypothyroidism.

Decreased Cholesterol

• Severe hepatocellular disease.
• Malnutrition.
• Severe burns.
• Hyperthyroidism.
• Malabsorption syndrome.

Triglyceride/Triacylglycerol (Neutral Fat)

• Very hydrophobic and water-insoluble.
• Main storage lipid in humans (adipose tissue).
• Used as a source of energy during fasting states and between meals.
• Low caloric intake = low TG levels.
• Function: When TAGs are metabolized, FAs are released into the cells and converted into energy; provides excellent insulation.
• Breakdown is facilitated by epinephrine, cortisol, and lipoprotein lipase.
• Reference range <150 mg/dL.
• Interpretation: 150-199 mg/dL = borderline, 200-499 mg/dL = high, > 500 mg/dL = Very High.
• Diagnostic Significance: Evaluates suspected atherosclerosis and measures the body’s ability to metabolize fat.

Fatty Acids

• Consist of constituents of phospholipids or TAGs in plasma.
• Bound to albumin.
• Polyunsaturated and cis-monosaturated FAs are not associated with elevated serum LDL cholesterol.
• Reference range: 9-15 mg/dL.
• Function: Very important sources of energy.
• Provides substance for conversion to glucose (gluconeogenesis).

Lipoproteins (LPPs)

• Large macromolecular complexes of lipids with Apoproteins.
• Main purpose: Transport TAGs and cholesterol to sites of energy and storage utilization.

Apolipoprotein

• Keeps lipids in solution during blood circulation. Aids in solubilization and transfer from GIT to the liver.
• Facilitates uptake of LPPs into cells.
• Maintains structural integrity of the LPP complex.

Properties of ApoA-I and ApoB

• ApoA-I and ApoB: Considered differential factors of atherosclerotic disease.
• ApoA-II: Relates to insulin resistance and increased body fat.
• ApoB: Nonexchangeable apolipoprotein, predictor of artery disease, found in VLDL and LDL.

Major Lipoproteins

• Chylomicron (CM).
• Pre-beta lipoprotein/Very-low-density lipoprotein (VLDL).
• Alpha lipoprotein/High-density lipoprotein (HDL).
• Beta lipoprotein/Low-density lipoprotein (LDL).

Minor Lipoproteins

• Intermediate density lipoprotein (IDL).
• Lipoprotein (a)/Lp(a).

Abnormal Lipoproteins

• Lipoprotein X.
• B-VLDL (Floating B lipoprotein).
• Oxidized HDL.

Chylomicron

• Largest and least dense lipoprotein.
• Produced in the intestine from dietary fats.
• Completely cleared within 6-9 hours.
• Transports exogenous dietary TAGs to liver, muscles, and fat depots.
• Major composition: 90% TAG +1-2% Protein and ApoB-48; Density <0.95 kg/L.

VLDL

• Secreted in the liver.
• Transports TAGs from the liver to muscle, fat depots, and peripheral tissues.
• Prolonged high fat diet = elevated TAG in VLDL.
• Major composition: 65% TAG + 6-10% Protein + 16% Cholesterol Ester; Major apolipoprotein = ApoB-100; Density 0.95-1.006 kg/L.

HDL

• Smallest and most dense lipoprotein.
• Produced in the liver and small intestine.
• Transports excess cholesterol from the tissues, and returns it to the liver, where it is reused or excreted as bile (reverse cholesterol transport).
• Antiatherogenic property (concentration inversely related to CVD).
• Protects cardiomyocytes against oxidative stress.
• Anti-inflammatory effects on the myocardium.
• Cigarette smoking reduces HDL-C.
• Reverse cholesterol transport & Reduce HDL-C.
  • Forms: HDL1, HDL2, & HDL3.
• Major composition: 30% phospholipid + 45-50% Protein + 20% Cholesterol Ester.
• Major apolipoprotein: apoA-1.
• Density: 1.063-1.21 kg/L.
• Reference Range: 40 mg/dL; <40 mg/dL = low risk; <35mg/dL = highest risk for CHD; ≥60 mg/dL = high HDL = protective level.

LDL

• Synthesized in the liver; major end product of VLDL catabolism.
• Constitutes 50% of total LPP in plasma.
• Transports cholesterol to the peripheral tissues.
• Most cholesterol-rich and most atherogenic.
• Passes through the intima layer of vascular beds and be taken up by macrophages to become foam cells..

CRP and Atherogenesis

• CRP is a primary target for cholesterol-lowering therapy.
• Primary marker for clinical events in CHD.
• Cigarette smoking, hypertension, low HDL, familial CHD history, and advanced age are major CHD risk factors.

NCEP Classification of Total and LDL-Cholesterol in Children and Adolescents

• Desirable: <170 mg/dL total cholesterol, <110 mg/dL LDL cholesterol.
• Borderline: 170-199 mg/dL total cholesterol, 110-129 mg/dL LDL cholesterol.
• High: ≥200 mg/dL total cholesterol, ≥130 mg/dL LDL cholesterol.

IDL

• Product of VLDL catabolism = "VLDL remnant".
• Converted to LDL.
• Major lipids: Endogenous TAG and cholesterol ester.
• Major apolipoprotein: ApoB-100.

Lipoprotein (a)

• Synthesized in the liver; density & composition = same as LDL.
• Increased levels may indicate premature CHD, stroke, and are independent risk factors for atherosclerosis.
• Not lowered by many LDL-lowering treatments.
• Distinct feature: Apo(a), a carbohydrate-rich protein attached to ApoB-100.
• Major lipids: Cholesterol ester and phospholipid.
• Major apoliproteins: ApoB-100 and Apo (a).
• Density: 1.045-1.080 kg/L.
• Reference range <20 mg/L to 500 mg/L.

Lipoprotein X

• Abnormal lipoprotein found in obstructive jaundice and LCAT deficiency, sensitive indicator of cholestasis.
• High content of phospholipid (90%) and free cholesterol,.
• Contains ApoC and albumin.

ß-VLDL (Floating β lipoprotein)

• Abnormally migrating ß-VLDL, due to defective VLDL catabolism.
• Found in Type 3 Hyperlipoproteinemia or Dysbetalipoproteinemia.
• Accumulation of IDL because of the failure to fully convert VLDL to LDL.
• Density <1.006 kg/L.

Oxidized HDL

• Commonly considered as dysfunctional HDL.
• Native HDL protects against atherosclerosis.

This quiz explores essential aspects of psychoactive drugs, focusing on lithium and tricyclic antidepressants (TCAs). You will learn about their uses, effects, absorption, and elimination processes. Test your understanding of these critical medications used for mental health disorders.