Exam 4 Flashcards
Endocrine vs Exocrine in the Pancreas
- Endocrine: Islets of Langerhans
-Alpha Cells produce Glucagon
-Beta Cells produce insulin, C-peptide, proinsulin - Exocrine: Produces digestive enzymes
Role of Insulsin & Glucagon on BG
- Rising blood glucose –>beta cells are stimulated, release insulin into blood stream 1) Liver stores some glucose as glycogen 2) Cells take up glucose –>BG level declines to a set point, insulin release diminishes
- Dropping glucose levels (skipped a meal) –>Alpha cells of pancreas are stimulated to release glucagon into the blood -> liver breaks down glycogen and releases glucose into blood–> BG level rises to set point, stimulus for glucagon release diminishes
Four Types of DM
- DM I: Insulin Dependent (IDDM)
- Destruction of beta cells, severe or absolute insulin deficiency. Immune or idiopathic
- DM II: Non-insulin dependent (NIDDM)
-Metabolic syndrome. Combination of relative deficiency of insulin secretion with tissue insulin resistance - DM III: Other causes: drugs, pancreatitis
- DM IV: Gestational
-Hormones block insulin. Higher birth weight. Infant 30% more likely to develop DMII
Three cardinal signs of DM
- Polyuria
- Polydipsia
- Polyphagia
Describe the sorbitol pathway, and why it leads to peripheral neuropathy and blindness
Hyperglycemia leads to an increase in intracellular sorbitol. Sorbitol draws water into the cell, and then cannot leave the cell. This causes an increase intracellular osmotic pressure (typically in the eye lens, nerves, RBCs) and leads to permanent cell injury
Two Types of Diabetes Tests
- Fasting Blood Glucose- Blood glucose is taken after fasting overnight
- Glucose Tolerance Test- Patient fasts overnight, and then is required to drink a 10 oz surgery drink to see how their glucose levels respond
How the ATP-Gated K+ Channels work in the Beta Cells
Insulin is released from the beta cell and by sulfonylurea drugs. In a resting cell, ATP levels are low, and K+ diffuses down its concentration gradient through ATP-gated K+ channels maintaining Vrm.
If glucose concentration increases, ATP production increases –> K+ channels close, causing the cell to depolarize. Ca++ channels open in response to depolarization, and the increase in intracellular Ca++ results in an increase in insulin secretion.
Insulin Secretagogues
- Secretagogues increase insulin release: they work by closing the ATP gated K+ channels in the pancreatic beta cell
i. Glucose
ii. Amino Acids
iii. Hormones
iv. High concentrations of fatty acids- triglycerides
v. Incretins
vi. Drugs; sulfonylureas, beta-adrenergic agonists
What happens after glucose is brought into the cell?
Insulin Receptor Pathway
- After insulin has entered circulation, it diffuses into tissues and binds to specialized receptors.
- Insulin receptors consist of two covalently linked heterodimers each containing an extracellular Alpha subunit (recognition site) and a Beta subunit, a tyrosine kinase, that spans the membrane. Insulin binds to the alpha subunit–>receptor undergoes conformational change bringing the catalytic loops of the B subunits closer together –>facilitating mutual phosphorylation of tyrosine residues-»ultimately resulting in translocation of GLUT transporters (2, 4) to the cell membrane to increase intake of glucose, increase in glycogen formation, and multiple effects on protein synthesis, lipolysis, and lipogenesis, as well as the activation of DNA transcription factors.
i. GLUT 2- Located in beta cells, liver, kidney, gut
ii. GLUT 4- Muscle, adipose
Four Insulin Types and Examples
- Rapid Acting: Lispro, Aspart, Glulisine
i. Given w/ meals - Short Acting (Regular): Novolin, Humalin
i. Given BID; not tightly controlled - Intermediate Acting: NPH (Neutral protamine Hagedorn)
i. Given BID; not tightly controlled - Long Acting: Glargine, Detemir
i. Given once daily - Basal + Bolus is the best way to control, or use of an insulin-pump
Hypoglycemia
- S/S: SNS response symptoms; shakiness, sweating, palpitations. Blurred vision, slurred speech
- TX: 3-4 Glucose tabs, ½ soda, juice, 1mg Glucagon
Adjunctive Therapies w/ DM and pre-diabetes
- Diet, Exercise, Low-carb, low-fat, calorie restricted diet
- SBP <130mmHg
- ACE-I inhibitors are first line for HTN
- Dyslipidemia- statins, fiber, omega-3 fatty acids
- Antiplatelet agents like ASA
- Smoking Cessation, Eye exams, monitor kidney function
- Diabetic neuropathies- Regular foot exams
Treatment Plan for DMII
- Biguanide
- Biguanide + insulin or biguanide + secretagogue
- Biguanide + 2-3 other classes
- Intensive Insulin therapy
Biguanides
i. First line therapy in NIDDM
ii. Reduction in hepatic glucose production
iii. GI toxicities
iv. Metformin
Black box warning
Insulin Secretagogue-Drug form
i. Bind to K+ channel in beta cell causing depolarization
ii. Sulfonylureas (-ide), Meglitinide, Phenylalanine derivatives
iii. Black box warning: Increased risk of cardiovascular mortality
- Thiazolidinediones (TZD)
Risk of??
i. Decrease Insulin Resistance, Increase insulin signal transduction
ii. Risk of MI: If using insulin w/ nitrates, or Avandia
- A-Glucosidase Inhibitors
i. Block digestion of complex carbohydrates
ii. Flatulence, diarrhea, abdominal pain
- Bile Acid Sequestrant
i. Bind bile acids and prevent reabsorption
ii. GI upset
- Amylin Analogs
i. Suppresses glucagon release
ii. Decrease circulating glucose
iii. Use w/ insulin
Risk of what?
- Incretin-based therapies
i. GLP-1 -> stimulates insulin release
ii. Risk of pancreatic cancer
- SGLT2 Inhibitors
i. Prevents glucose reabsorption in PC
ii. Causes glucosuria, osmotic diuretic, weight loss, dehydration, genital necrosis
iii. -liflozin
Platelet Phases During Thrombogenesis
Platelets go through four phases:
a. Adhesion
b. Aggregation
c. Secretion of vasocontrictive factors (5-HT, ADP, TXA2)
d. Cross-linking of adjacent platelets
Thrombogenesis Pathway
Injury–> reactive proteins collagen & vWF exposed –> results in platelet adherence, activation, and secretion of 5-HT, TXA2, and ADP from platelet granules
–> vasoconstriction and platelet aggregation due to increased 5-HT –> fibrinogen cross-links platelets –> resulting in the formation of platelet plugs
Coagulation Cascade: Roles of Extrinsic, Intrinsic, Common Pathways
a. Extrinsic Pathway: Tissue damage exposes tissue factor. Exposed tissue factor interacts with Factor VII –->Factor VIIa–> Common pathway
b. Intrinsic Pathway: Platelets begin to interact with damaged endothelium
i. Factor XII –> XIIa, then activates factor XI –>XIa, then activates IX –> IXa, then activates VIII –>VIIIa –> Common pathway
c. Common Pathway: Both pathways meet at Factor X-
Factor X is activated by both VIIIa and VIIa. Factor Xa + Factor V (cofactor) cleaves Factor II (prothrombin) into thrombin. Thrombin then cleaves Factor I (fibrinogen) –>Factor Ia (fibrin) and fibrin clot is form
Red & White Thrombi, Thromboemboli
Red thrombi: Fibrin rich thrombi formed in low pressure veins that contain a large number of RBCs. Can detach and cause a pulmonary embolism
White Thrombi: Platelet rich thrombi formed in high pressure arteries with abnormal endothelium. Arterial clot formation can cause severe downstream ischemia
c. Thromboemboli: red thrombi that become dislodged
Inherited vs Acquired Risk Factors for DVT
Inherited:
i. Antithrombin III deficiency
ii. Protein C deficiency
iii. Protein S deficiency
iv. Sickle cell anemia
v. Activated protein C resistance
Acquired:
i. Bedridden
ii. Surgery/trauma
iii. Obesity
iv. Estrogen use
v. Malignancies
vi. Chronic venous insufficiency
DIC- Causes, Tx
Disseminated Intravascular Coagulopathy
i. Excessive consumption of clotting factors and platelets
ii. Spontaneous bleeding
iii. Causes: Massive tissue injury, malignancy, bacterial sepsis, abruptio placentae
iv. Tx: Plasma transfusions, treat underlying cause, up to 50% mortality
HIT- Causes, Tx
b. Heparin Induced Thrombocytopenia
i. Caused from using heparin
ii. D/C drug, give protamine
TTP- Causes, Tx
a rare, life-threatening blood disorder that causes blood clots to form in small blood vessels throughout the body.
Usually hereditary
Plasma-Exchange, large dose corticosteroids
Fibrinolysis
Fibrinolysis refers to the process of fibrin digestion
Precursor- Plasminogen circulates in its inactive form. Tissue factor plasminogen activator is released by endothelial cells in response to injury, converting plasminogen into plasmin –> plasmin releases fibrin degradation products and begin to digest the fibrin clot
Four Classes of Coagulation Modifying Drugs
a. Anticoagulants: Inhibit the action or formation of clotting factors & prevent clot formation. Heparin (IV), Warfarin (PO)
b. Antiplatelet: Inhibit platelet aggregation. ASA
c. Thrombolytic: Lyses existing clots. Streptokinase
d. Hemostatic/ Antifibrinolytic: Promote coagulation
-Vit K, Aminocaprioc, Tranxemic
-udins belong to which?
Indirect vs Direct Thrombin Inhibitors
Drugs in each class
Indirect Thrombin Inhibitors:
Enhances antithrombin activity
i. Inactivation of factor Xa
iii. Ex: Heparin, LMW heparin, fondaparinux
Direct Thrombin Inhibitors:
i. Bind to both active and substrate recognition sites of thrombin
ii. Hirudin
iii. Bivalrudin
iv. Bind only to thrombin active sites: Argatroban, Melagatran, Dabigatran
Heparin vs LMW Heparin vs Fondaparinoux
MOA
Heparin
i. Binds and activates antithrombin III (enhances the activity 1000x)
ii. High molecular weight/unfractionated
iii. Extracted from porcine intestinal mucosa & bovine lung
LMW Heparin- (Enoxaparin, Dalteparin, Tinzaparin)
i. More specific for factor Xa, less effective on antithrombin
ii. Less effective coagulation
Fondaparinux
i. Not as effective; selective for factor X
ii. Less bleeding risks
iii. Can give with HIT
Toxicity, Treatment, Contraindications for Heparin
Toxicity:
i. Reverse with Protamine (no effect on fondaparinux). Highly (+), binds to heparin and inactivates
ii. Bleeding- Elderly women and patients with renal failure more prone
iii. HIT
Contraindications:
i. Active bleeding/ Ulcers
ii. Hemophilia
iii. Thrombocytopenia
iv. Severe HTN
v. ICH
vi. Infective endocarditis
vii. Active TB
viii. Advanced hepatic disease
PT vs aPTT
What is it? And normal value
a. Prothrombin Time (PT):
i. Assesses the function of the extrinsic system and common pathway of coagulation cascade. Determines time to clot compared to INR
11-13.5 seconds
b. Activated partial thromboplastin time (aPTT):
i. Measures activity of the intrinsic system and common pathway
ii. Phospholipid is added to induce intrinsic pathway
Normal = 35-45 seconds
MOA, Therapeutic range, Drug Interactions
Warfarin
Reversal, Toxicity
Warfarin:
An anticoagulant that inhibits vitamin K epoxide reductase. blocking the formation of clotting factors II, VII, IX, X
ii. 8-12 hour delay in onset of action; bridge with Heparin
iii. Therapeutic range defined by INR. Normal : 0.8-1.2, Warfarin: 2-3
Drug Interactions:
1. Pharmacokinetic:
Enzyme induction, inhibition, and reduced plasma protein binding
2. Pharmacodynamic: Synergism, Competitive Antagonism, Altered vitamin K
Reverse w/ large dose vitamin K, FFP, factor IX
Toxicity: Hemorrhagic disorder in the fetus, birth defects, cutaneous necrosis
Factor Xa Inhibitors
MOA, reversal?
Eliquis, Xarelto, Bevyxxa, Pradaxa (Factor Xa inhibitors)
i. No reversal agent
ii. Inhibits factor Xa and thrombin
Three of them
Fibrinolytic Drugs
Streptokinase
i. Synthesized by streptococci
Urokinase
i. Lyses thrombus from within
Tissue plasminogen activator (TPA)
i. Preferentially activates plasminogen that is bound to fibrin
ii. Physiologic TPA confines fibrinolysis to the formed thrombus & avoids systematic activation. Pharmacologic TPA loses clot specificity
How are they different?
Anti-platelet Drugs
ASA, Plavix, Abciximab
ASA
i. Cox-1 selective
ii. Inhibits TXA2 formation inhibiting platelet aggregation
Plavix, Ticlid
i. Irreversibly inhibit ADP receptors on platelets reducing platelet aggregation
ii. Reduction in ischemic events by 8.7% compared to ASA
Abciximab- Monoclonal antibodies
i. Antiplatelet
ii. Targets IIb/IIIa receptor complex leading to inhibition of platelet aggregation
Aminocaprioc/TXA, Vitamin K, Plasma Fractions, Desmopressin
Tx of Bleeding Disorders
Aminocaprioc Acid/ Tranexamic Acid
i. Inhibitor of the fibronolytic system; competitively inhibits plasminogen activation
Vitamin K:
i. Precursor prothrombin and factors VII, IX, X
Plasma Fractions:
i. Used for deficiencies in plasma coagulation factors; diseases such as hemophilia and antithrombin III deficiency
ii. Concentrated plasma & plasma recombinant can be given to reduce bleeding
e. Desmopressin:
i. Tx for mild hemophelia A and von Willebrand disease
ii. Increases factor VIII activity
Tremor, Chorea, Ballismus, Athetosis, Dystonia
a. Tremor: Rhymic movement around a joint, repetitive
b. Chorea: Muscle jerks in various areas, quick
i. Ballismus: Violent abnormal movements
c. Athetosis: Slow, writhing, rotational
d. Dystonia: Abnormal posture
Explain the relationship between the basal ganglia, motor cortex, and thalamus; and describe the pathology in Parkinson’s & Huntington’s Disease
The basal ganglia, motor cortex, and thalamus work together to control movement. The basal ganglia help plan and coordinate movements, while the motor cortex sends signals to the muscles. The thalamus acts as a relay station, passing information between these areas.
The substantia nigra is a key player in movement control. It’s part of the basal ganglia and produces dopamine, a chemical that helps regulate movement.
In movement disorders this communication is disrupted. For example, in Parkinson’s, there’s less dopamine in the basal ganglia due to degradation of the substantia nigra, leading to tremors, stiffness
Huntingtons- Destruction of GABAnergic neurons; need to decrease dopamine
Occupations at risk
S/S of Parkinson’s, Cause, Risk Factors
And things that reduce risk
Idiopathic, progressive
Caused from dopaminergic neuron degradation and decreased dopamine levels
Rigidity, bradykinesia, tremor, postural instability, cognitive decline
Decreased risk: Cigarette smoke, coffee, anti-inflammatories, uric acid
Increased risk:
i. lead, manganese, vit D deficiency
ii. 60 or older
iii. Hereditary
iv. Men: Women 2:1
v. Occupation; teaching, healthcare, farming
vi. Toxin Exposure
Role of Alpha Synuclein in Parkinson’s
Alpha-synuclein is a protein involved in regulating neurotransmitter release in the brain.
In Parkinson’s disease, it clumps together to form Lewy bodies. These clumps disrupt brain cells, leading to cell death, particularly in the substantia nigra
Diseases Associated w/ Lewy Bodies
Alzheimer’s
Parkinson’s
Multiple System Atrophy
Prion Diseases- Mad Cow
Non-pharmacologic interventions for Parkinson’s
-Exercise
-Physical Therapy
-Speech Therapy
-Deep brain stimulation
-Lesional Ablation
-Stem cell therapy
i. Implantation of fetal substantia nigra
ii. Controversial
Levodopa, MOA, Role of Carbidopa
Also on-off phenomenom
a. Levodopa: L-Isomer of Dopa
i. Crosses BBB. Prodrug that is converted into dopamine as it crosses the BBB (1-3% of the drug makes it across). A lot of it is deactivated in the gut before reaching the bloodstream
b. Carbidopa prevents the breakdown of L-dopa by cOMT
c. Decreased effectiveness overtime
On-Off Phenomenon with long term use
i. Periods of increased mobility followed by marked akinesia
ii. Drug holiday- D/C drugs for a period of time
