Exam 4 Flashcards
1
Q
Endocrine vs Exocrine in the Pancreas
A
- Endocrine: Islets of Langerhans
-Alpha Cells produce Glucagon
-Beta Cells produce insulin, C-peptide, proinsulin - Exocrine: Produces digestive enzymes
2
Q
Role of Insulsin & Glucagon on BG
A
- 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
3
Q
Four Types of DM
A
- 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
4
Q
Three cardinal signs of DM
A
- Polyuria
- Polydipsia
- Polyphagia
5
Q
Describe the sorbitol pathway, and why it leads to peripheral neuropathy and blindness
A
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
6
Q
Two Types of Diabetes Tests
A
- 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
7
Q
How the ATP-Gated K+ Channels work in the Beta Cells
A
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.
8
Q
Insulin Secretagogues
A
- 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
9
Q
What happens after glucose is brought into the cell?
Insulin Receptor Pathway
A
- 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
10
Q
Four Insulin Types and Examples
A
- 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
11
Q
Hypoglycemia
A
- S/S: SNS response symptoms; shakiness, sweating, palpitations. Blurred vision, slurred speech
- TX: 3-4 Glucose tabs, ½ soda, juice, 1mg Glucagon
12
Q
Adjunctive Therapies w/ DM and pre-diabetes
A
- 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
13
Q
Treatment Plan for DMII
A
- Biguanide
- Biguanide + insulin or biguanide + secretagogue
- Biguanide + 2-3 other classes
- Intensive Insulin therapy
14
Q
Biguanides
A
i. First line therapy in NIDDM
ii. Reduction in hepatic glucose production
iii. GI toxicities
iv. Metformin
15
Q
Black box warning
Insulin Secretagogue-Drug form
A
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
16
Q
- Thiazolidinediones (TZD)
Risk of??
A
i. Decrease Insulin Resistance, Increase insulin signal transduction
ii. Risk of MI: If using insulin w/ nitrates, or Avandia
17
Q
- A-Glucosidase Inhibitors
A
i. Block digestion of complex carbohydrates
ii. Flatulence, diarrhea, abdominal pain
18
Q
- Bile Acid Sequestrant
A
i. Bind bile acids and prevent reabsorption
ii. GI upset
19
Q
- Amylin Analogs
A
i. Suppresses glucagon release
ii. Decrease circulating glucose
iii. Use w/ insulin
20
Q
Risk of what?
- Incretin-based therapies
A
i. GLP-1 -> stimulates insulin release
ii. Risk of pancreatic cancer
21
Q
- SGLT2 Inhibitors
A
i. Prevents glucose reabsorption in PC
ii. Causes glucosuria, osmotic diuretic, weight loss, dehydration, genital necrosis
iii. -liflozin
22
Q
Platelet Phases During Thrombogenesis
A
Platelets go through four phases:
a. Adhesion
b. Aggregation
c. Secretion of vasocontrictive factors (5-HT, ADP, TXA2)
d. Cross-linking of adjacent platelets
23
Q
Thrombogenesis Pathway
A
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
24
Q
Coagulation Cascade: Roles of Extrinsic, Intrinsic, Common Pathways
A
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
25
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
26
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
27
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
28
HIT- Causes, Tx
b. Heparin Induced Thrombocytopenia
i. Caused from using heparin
ii. D/C drug, give protamine
29
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
30
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
31
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
32
# -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
33
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
34
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
35
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
36
# 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
37
Factor Xa Inhibitors
| MOA, reversal?
Eliquis, Xarelto, Bevyxxa, Pradaxa (Factor Xa inhibitors)
i. No reversal agent
ii. Inhibits factor Xa and thrombin
38
# 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
39
# 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
40
# 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
41
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
42
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
43
# 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
44
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
45
Diseases Associated w/ Lewy Bodies
Alzheimer's
Parkinson's
Multiple System Atrophy
Prion Diseases- Mad Cow
46
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
47
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
48
# Which A/E does Carbidopa help? Which does it make worse?
Side Effects, Contraindications, Drug Interactions for Levodopa
a. N/V- decreased with carbidopa
b. Depression, anxiety, hallucinations and delusions worsen with carbidopa
-Can treat with Pimavanserin; antipsychotic
c. Tachycardia/ afib
d. Dyskinesias
Contraindications:
Psycosis, Glaucoma, Melanoma
Drug Interactions:
Vit. B6, MAOIS
49
MAO-B Antagonists, cOMT inhibitors, and dopamine receptor agonists
| For tx of Parkinsons- MOA, drug examples
a. MAO-B antagonists:
i. Specifically target dopamine. Increase dopamine in the substantia nigra
ii. Selegeline
iii. Rasagiline
b. cOMT Inhibitors
i. Inhibit cOMT, increasing circulating dopamine
ii. Tolcapone, Entacapone
c. Dopamine Receptor Agonists:
i. Pramipexole
ii. Ropinirole
iii. Rotigotine
iv. All less effective than levodopa, early disease tx
v. Reduced side effects
50
Essential Tremor, Benign Hereditary Chorea, Tardive Dyskinesia
| What are they?
a. Essential tremor
i. B1 receptor dysfunction; beta blockers
b. Benign Hereditary Chorea:
i. Autosomal dominant
ii. Childhood, typically no progression
iii. Dopamine-receptor blocker; tetrabenazine
c. Tardive Dyskinesia
i. Repetitive, involuntary movements
ii. Usually caused by antipsychotic drugs
51
Duchenne Muscular Dystrophy
| What is it? How to treat it? Gower's sign?
i. X linked recessive; typically affects males
ii. Results from the gene that encodes dystrophin (largest gene in our body) causing muscle degradation- skeletal, smooth, and cardiac
iii. Onset in early childhood, usually do not live past 20’s
iv. No cure. Maximize quality of life
i. Corticosteriods
ii. Beta- agonists
iii. Orthopedic braces
iv. Physical therapy
v. Assisted ventilation
v. Gower’s sign: Having a child do a “down dog” pose and then stand up. Gower’s sign is positive if the child needs to place hands on knees for support while standing up
52
Cerbral Palsy
| What is it? What causes it? Treatments?
-A non progressive motor disorder of the CNS resultin in alterations of movement or posture
a. Trauma at birth
b. Hemorrhage at birth
c. Anoxia while in utero or infection
d. Failure to meet developmental normal in the infant
e. No cure, maximize quality of life
i. Intrathecal baclofen pump
ii. Tendon release
iii. Botox
53
Huntington's Disease
| What causes it? Symptoms? Onset? Tx to reduce symptoms?
i. Autosomal dominant, chromosome 4
ii. Gene produces huntington protein- function unkown
iii. Losing GABAnergic neurons, overproduction of dopamine, reduction in choline acetyltransferase
iv. Tx: Tetrabenazine (reduces dopamine activity), speech therapy, PT/OT; Need to do genetic counseling
v. Onset in 30-40’s
i. Progressive loss of muscle control
ii. Chorea
iii. Dementia
iv. Death 15-20yrs after onset
54
ALS
| What is it? Treatment?
Rare, progressive neurological disorder characterized by loss of motor neurons
ii. Death 2-6 years after onset (40-60yrs)
iii. Improve quality of life-
i. Riluzole: Na+ channel blocker in damaged neurons
ii. Edaravone- antioxidant
55
Alzheimer's
| What is it? Signs? Treatmeant?
i. Can be familiar or nonheriditary
ii. Neurofibrillary tangles – twisted fragments of protein w/in nerve cells
iii. Senile plaques- products of dying nerve cells accumulate around protein
Insidious onset- forgetfulness, emotional upset, confusion, decline in problem solving and judgement
iv. Dx made by ruling out all other causes
v. More likely to get if you have a relative with it
Tx: ACh-esterase inhitors: tacrine
NMDAr Anatagonist: Memantine
56
Restless Leg Syndrome
Creeping discomfort in legs
Urge to move them
Sleep disorder, cause unknown
Increased in pregnancy and diabetics
Tx:
Dopamine agonists
Gabapentin
Benzodiazepines (Clonazepam)
Opiates
57
Inflammatory Response -mediators released
| Acute vs chronic inflammation
-Acute Inflammation:
Initial response to tissue injury
Mediated by autocoid group; 5-HT, Histamine, Bradykinin, Prostaglandins, Leukotrienes
-Chronic Inflammation:
Release of additional mediators such as: interleukins
58
Inflammatory Response Pathway & where drugs work
Stimulus--> leads to disruption of cell membrane and the release of phospholipids (Phospholipase inhibitors and corticosteroids work here)
This activates arachadonic acid which is then converted into Lipoxygenase and COX 1/2 --> (lipoxygenase inhibitors, nsaids work here)
-Signaling molecules such as prostaglandins, TXA2, and leukotrienes are released which results in inflammation
Leukotrienes also promote bronchoconstriction and vascular permeability
59
NSAIDS
| S/E for all of them?
Non-steroidal anti-inflammatory drugs
Inhibition of prostanglandin synthesis by inhibiting either Cox 1 or Cox 2
All are gastric irritants
All can cause nephrotoxicity and heptotoxicity
60
Cox 1 & Cox 2
Cox 1 is always active- helps maintain kidney function, protect the lining of the stomach, and produce thromboxane. Also plays a role in prostaglandin synthesis
Cox 2 is activated during inflammation and is responsible for the production of prostaglandins
61
Cox 1 Inhibitors- ASA
1200mg -1500mg TID for pain
Clot prevention dose 81mg-325mg
Anti-platelet effect takes 8-10 days
Gi upset, bleeding, increased incidence of gastric ulcers due to inhibition of GI protective prostaglandin
62
# Allergies & BB warning for Celebrex
COX 2 Selective Inhibitors
| Celebrex, Meloxicam
Celecoxib- Analgesic, antipyretic, anti-inflammatory
Sulfanomide (allergies), expensive, BB warning- serious risk of thrombotic events
Meloxicam- Less effective than celebrex
63
Other NSAIDS
| Ibuprofen, Ketorolac, APAP, Diclofenac, Indomethacin
Ibuprofen: Pain, inflammation. Less GI upset than ASA
Ketorolac: Used for severe pain in conjunction w/ opioids, good for sports medicine
APAP: Pain, fever, not anti-inflammatory, 15gm fatal dose
Diclofenac: Pain, inflammation, fever (GI upset 20%, decrease w/ misoprostol)
Indomethacin: Arthritis, gout, patent ductus arteriosus (GI upset 1/3rd of patients)
64
Glucocorticoids- Inflammation
| Acute vs Chronic Use
Acute use:
Supresses inflammation
Mobilize energy stores
Improve cognitive function
Salt and water retention
Chronic use of them affects:
Immunosuppresion
Diabetes, obesity, muscle wasting
Depression
HTN
65
Glucocorticoid Transcription
| How do they work? Annexin? IL-10? SLPI? NFkB?
Glucocorticoids bind to receptors inside the cell, forming a complex that enters the nucleus. This complex binds to DNA, influencing the transcription of specific genes.
This decreases the synthesis of Annexin-1; which decreases phospholipase A2 and inhibits leukocyte response
Inhibits nuclear factor kappa pathway
Increases synthesis of IL-10, an immunosuppresive enzyme, but also helps to reduce inflammation
Increases levels of SLPI- protects tissue from damage by inhibiting enzymes that break down proteins during inflammation
Inh-NFkB
66
# reduce inflammation rate by decreasing..
DMARDs
| General MOA & drugs
Disease Modifying Anti-Rheumatic Drugs
-Initially targeted to join disorders
-Reduce inflammation rate, by decreasing sedimentation rate, c-reactive protein, and rheumatoid factor
-Decreases damage to bones and joints
Often given w/ NSAIDS
Drugs: MTX, Cyclophosphamide, Cyclopsorine
Biologic: Orencia, Rituximab, Humira
67
# Chronic exposure to inflammation leads to what 4 things?
Tumor Promoting Inflammation
| Cytokines activate....
Chronic exposure to inflammatory mediators is a risk for cancer and can cause:
Cell proliferation
Mutagenesis
Oncogene activation
Angiogenesis- creating new blood supply to support tumor growth
Cytokines from tumor-infiltrating immune cells activate key transcription factors (NF-kB/ STAT 3) in premalignant cells inducing production of cyclins, cdks, growth/division proteins
68
Fibers for Transmission of Sensation
a. A-beta fibers; Non-noxious mechanical stimuli
b. A-delta fibers: Noxious heat, mechanical stimuli (sharp pain, produces reflex response)
c. C-fibers: Un-myelinated, slower. Noxious, chemical, heat, slow/burning pain
d. A-fibers can suppress pain from C-fibers
69
Noxious Stimuli
Harmful substances that cause pain-
Histamine
Tissue Damage- Bradykinin, PKA, PKC
Arachadonic Acid Pathway: Cox & Lox Pathway --> prostaglandins
70
Spinothalamic, Spinoreticular, Spinomesencephalic Pathways
| PAG - "Gate Control Theory of pain"
a. Spinothalamic (Primary): Spinal Cord --> Pons -->Thalamus
-->Somatosensory cortex
b. Spinoreticular (Limbic System): Spinal Cord-->Reticular formation of medulla --> reticular formation of pons --> Thalamus --> Somatosensory cortex
c. Spinomesencephalic: Spinal cord -->Pons -->Periaqueductal grey of the midbrain. PAG initiates the descending inhibitory pathway
71
# MOA: Bind to receptors where? Modulate release of which NT?
Pharmacokinetics/dynamics- Opioids
| ADME
A: Well absorbed (IM, SQ, ORAL)
i. Nasal, patch can avoid first pass
ii. Codeine has a low first pass
D: Highly perfused tissues- accumulation
i. Brain, heart, kidney, liver
ii. Skeletal muscle; reservoir
M: Varies
i. Morphine- phase II to active forms (M3G, M6G)
ii. Esters (heroin) – converts to morphine
E: Mainly in urine
MOA: Bind to receptors in brain and spinal cord: modulate pain, reduce neurotransmitter release (glutamate, ACh, NE, 5-HT, substance-P), hyperpolarize post-synaptic neurons
72
Effects on organ systems- opioids
| CNS, CV, GI
i. CNS: Analgesia, euphoria, sedation, respiratory depression (brainstem), cough suppression, miosis (always), hyperthermia (mu), hypothermia (kappa)
ii. CV: Most have no direct effects. Bradycardia from brainstem stimulation, Demerol causes tachycardia
iii. GI: Constipation
73
Uses for Opioids
Analgesia: Severe, constant (chronic), terminal illness, OB, renal or biliary colic in infants. Not as effective for sharp, intermittent pain
Acute Coronary Syndrome: MONA
Acute Pulmonary Edema: Reduce preload, afterload, and anxiety; Lasix is a better option
Cough
Diarrhea
Post-op shivering
Anesthesia adjunct
74
Opioid Toxicity
Usually an extension of therapeutic effects
a. Dysphoric reactions- restlessness, tremor
b. Respiratory depression
c. N/V
d. Increased ICP
e. Postural hypotension
f. Constipation
g. Urinary retention
h. Itch (mast cell degranulation)
75
# Tolerance builds quickly due to? 3 things
Opioid Tolerance vs Dependence
| Degrees of tolerance, withdrawal symptoms
a. Tolerance develops quickly through multiple mechanisms (receptor phosphorylation, cAMP, uncoupling w/ G-Proteins)
b. Dependence
i. Physically dependent -->withdrawal symptoms if discontinuation -->can lead to addiction
W/D symptoms: Rhinorhhea, lacrimation, yawning, chills, N/V/D, hyperthermia, muscle aches
Degrees of tolerance:
-High Degree of Tolerance: Analgesia, euphoria, dysphoria, mental clouding, sedation
-Moderate degree of tolerance: bradycardia
-Minimal or no degree of tolerance: Miosis, constipation, convulsions
76
Opioids- Strong Agonists
| Phenanthrenes, Phenylheptylamines, Phenylpiperidines
i. Phenanthrenes: Morphine, dilaudid, heroin (UK)
ii. Phenylheptylamines: Methadone (morphine tolerance, chronic opioid use)
iii. Phenylpiperidines: Fentanyl, meperidine
77
Opioids- Moderate Agonists
| Phenanthrenes, Phenylpiperidines
i. Phenanthrenes: Codeine, Oxycodone (more effective in combination with APAP or ASA)
iii. Phenylpiperidines: Tramadol, Loperamide
78
Opioid Antagonists
i. Naloxone, naltrexone, naloxegol
ii. Reverse opioid effects in 1-3 minutes
79
Gram (+) and Gram (-) Bacteria
| Difference between the two
Gram (+)
i. Special stain; stains purple
ii. Thicker peptidoglycan cell wall, causes the blue dye to stain purple
Gram (-)
i. Stains pink- very thin peptidoglycan wall
ii. Two plasma membranes; outer membrane contains lipopolysaccharides release endotoxins when destroyed in the body
iii. Want to slow down growth rather than kill bacteria
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# Gram + or -
1. Inhibition of Cell Wall Synthesis
| MOA- Beta Lactam ring does what?, Drugs?
MOA- Beta-lactam antibiotics attach to the enzymes that cross-link peptidoglycans and prevent cell wall synthesis
i. Penicillin, cephalosporins, carbapenems, vancomycin
ii. Selectively damage gram (+) cocci
iii. Contain B-Lactam Ring
81
# Broad or narrow spectrum? More resistant to what?
Cephalosporins
| alternative to which abx?
-More resistant to beta-lactamase
-Broad spectrum, better gram (+)
-First Generation, alternative to PCN if allergy
82
Hypersensitivty to PCN & Cephalosporins
Hypersensitivity
i. Most common drug allergy
ii. Anaphylactic shock, hemolytic anemia, interstitial nephritis, rash
83
Vancomycin
a. Gram (+), supposed to be “last resort:
b. Resistant to beta-lactamase
c. 10% have adverse reactions
d. Irritating to tissues
e. Chills, fever, red man syndrome
f. Ototoxicity, nephrotoxicity
84
# Gram + or -
2)Disruption of Cell Membrane Function
i. Act as detergents, bind to phospholipids
ii. Especially effective against Gram (-) that have an outer membrane
iii. Polymixin, Daptomycin
85
# Bind to what? And that inhibits...?
3) Inhibition of Protein Synthesis
i. Widest spectrum of activity
ii. Bind to bacterial ribosomes and inhibit protein synthesis. Attack bacterial cells without significantly damaging animal cells;however, destroy normal microbiota, bone deposition disorder
iii. Tetracyclines, macrolides, aminoglycosides
86
Macrolides
Prototype- Erythromycin
Clarithromycin
Azithromycin
Mostly Gram (+)
MOA: Inhibit protein synthesis
87
4) Inhibition of Nucleic Acids
| Rifamycin, Quinolones
Differentiate between the enzymes used by bacterial cells and animal cells
Rifamycin disrupts mRNA synthesis
Quinolones (Cipro, Levaquin, Floxin)- Inhibit DNA gyrase in bacteria
Excellent gram (-)
Good gram (+)
UTI, RTI, bone and joint infections
88
5) Inhibition of Folic Acid Synthesis
| Sulfas, use, toxicity
-Sulfonamides
-Treat pneumocystitis, toxoplasmosis
Use w/ trimethoprim (Bactrim Septra)
-Toxicity: Allergic rxns, may precipitate urine, hematopoetic disturbances
89
Effects of Premature Termination of Abx Tx
Stopping antibiotics early can lead to incomplete infection clearance, allowing bacteria to survive, and become highly resistant to the antibiotic given.
This highly resistant organism can also spread to other hosts, causing more drug-resistant infections
90
Aquisition of Resistance- Abx
| R plasmids are what?
Bacteria become resistant through natural selection, chromosomal mutations or acquiring extrachromosomal resistance genes from other bacteria
R plasmids are small DNA molecules in bacteria that carry genes for antibiotic resistance. These can be transferred between bacteria, spreading resistance
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Unique Properties of Viruses
| Particles, Active or Alive, Do they need a host? Lyso/lytic
-Infectious particles that are active or inactive
Not an organism that is alive or dead
Obligate intracellular parasites:
Cannot multiply unless they invade a specific host
Must instruct the machinery of the host to make and release new viruses
i. If host cell is kept alive- lysogenic cycle (prolonged/chronic)
ii. If host cell is killed; “bursts”: Lytic cycle (acute)
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Capsid/Naked Viruses, Envelope, Spikes
i. Naked: Capsid (protein shell) with a viral spike (targets cell proteins)
ii. Enveloped: Additional lipid membrane- Takes part of the host cell’s cell membrane, and creates an envelope around itself
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Chain Termination of Acyclovir
| How is Acyclovir makeup similar to HSV?
Mimics a DNA building block (dGTP) and gets incorporated into viral DNA during replication.
Virus mistakes acyclovir for dGTP and it prevents further DNA elongation, causing irreversible chain termination
Acyclovir- similar to HSV virus makeup, missing an OH group
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# HIV viral spike protein targets what?
Antiretrovirals
HIV/HBV
Viral spike protein (gp120) specifically targets our CD4+ cells (T-Cells)
-AZT- Zidovudine, Azidothymidine
i. Reverse transcriptase inhibitor
ii. HIV Cocktail- HAART; Highly Active Antiretroviral Therapy
c. Lamivudine
i. Inhibits HBV polymerase and HIV reverse transcriptase
95
Viruses & Interferon
Interferon is a naturally occuring human cell product
Used with some success in preventing and treating viral infections
-Hep C
96
Influenza A & B
Influenza A:
i. Human cell surface antigens determine subtypes
ii. Three main human hemagglutinins: H1, H2, H3- role in viral attachment to cells
iii. Two main types Neuraminidases: N1, N2- role in penetration into cells
iv. Cause moderate to severe illness
Influenza B:
i. Primarily has an impact on adolescents and schoolchildren
ii. Affects humans and seals
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Antivirals- Flu tx
a. Oseltamivir
i. FDA approved for early tx (first 48hrs)
ii. BID x 5 days
iii. Targets N1, N2
b. Zanamivir (Relenza)
i. Targets N1, N2
ii. Must be taken when exposed to flu, not when symptoms appear
c. Baloxivir Marboxil (Xofluza)
i. Targets polymerase
ii. Not for pregnant women, breast feeding mothers, may shorten flu by about a day
98
Covid-19 Tx
Vaccination
FDA approved meds:
i. Paxlovid- 2 antivirals combined, approved for emergency use
ii. Remdesevir- chain terminator
iii. Mabs- Block covid entry into the cell
iv. Dexamethasone- targets cytokine storm
99
# Chemical makeup of triglycerides? Form what if there's excess?
Triglycerides vs Cholesterol
| Cholesterol is a precursor to what? Mevalolate pathway?
Triglycerides:
i. Consist of glycerol esters (3) combined with free fatty acids
ii. Form adipose tissue and are the main storage form of fats in the human body
iii. Stored triglycerides can be catabolized into free fatty acids and used for energy during fasting or between meals
Cholesterol:
i. Important precursors to steroid hormones, cell membranes, Vit D, bile salts
ii. Produced via dietary intake (20%), or De Novo Synthesis (made in liver)
iii. Acetyl-Coa is converted by HMG-CoA into Mevalolate --> Cholesterol
100
Free vs Esterified Cholesterol
a. Free cholesterol is not attached to any other molecules, and can move in cell membranes and is important for structure and fluidity
b. Esterified cholesterol is attached to a fatty acid, forming an ester bond. These are stored for energy or transported into the bloodstream
101
# Chylomicrons, VLDL, LDL, HDL
Lipoproteins
| Transported to?
Chylomicrons:
i. Formed in intestine
ii. Carry triglycerides and cholesterol through the lymphatic system, then the blood stream, to the liver
VLDL
i. Secreted by the liver, transported to peripheral tissues
ii. Converted into IDL, LDL
LDL
i. “Bad” cholesterol. Transported to cells from liver
ii. In excess, deposited into arteries
HDL
i. “Good” cholesterol
ii. Scavenges cholesterol from other cells and lipoproteins
iii. Low HDL associated with atherosclerosis
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Target levels of cholesterol- Total, LDL, HDL, Triglycerides.
LDL/HDL Cholesterol Risk Ratio
a. Total: <200
b. LDL: < 130
c. HDL: >40 Men, >50 Women
d. Triglycerides <120
1.00- One half the average
3.5- Average
6- Twice the average
8- Three times the average
103
# Decreases LDL how much?
Statins
| MOA, A/E
a. Statins- HMG-CoA Reductase Inhibitors. Decrease cellular cholesterol synthesis (LDL) significantly, increases HDL. Decreases LDL 65% when combine with Mab
i. Muscle Pain
104
# Works by reducing the transport of....
Niacin
b. Niacin- Reduces transport of VLDL from liver; Decrease LDL, decrese triglycerides, ***increases HDL***
i. Flushing
105
Fibrates
c. Fibrate: PPAR mediated lipolysis in liver (increases the breakdown of fatty acids and reduces triglyceride levels in the blood); decrease VLDL, LDL, increase HDL
i. GI Upset- Rare
106
# Two possible A/E?
Cholesterol Absorption Inhibitors
e. Absorption Inhibitors- Inhibit intestinal cholesterol absorption (LDL)
i. Ezetimbe
ii. Possible hepatotoxicity
iii. Promoting arterial wall thickening?
107
Mabs- PCSK9 Inhibitors
PCSK9 inhibitors are drugs that help lower cholesterol levels. They block the PCSK9 protein, which normally tags LDL receptors for destruction. By inhibiting PCSK9, more LDL receptors remain on liver cells to remove LDL cholesterol from the blood.
PCSK9 increase in circulation after long-term statin use
108
Atherogenesis
-process of forming atherosclerotic plaques in arteries. It begins with damage to the artery wall, leading to the accumulation of lipids and inflammatory cells.
Macrophages begin to engulf LDL that is stored in the arterial wall, and that causes the formation of foam cells. These begin to accumulate and contribute to plaquestion formation
109
Echinacea
St. John's Wort
-Stimulation of immune system, anti-inflammatory
-Anti-depressant (cyp450)
110
Garlic
Ginkgo
-HMG CoA Reductase inhibitor- reduces cholesterol
-Improved blood flow, free radical scavenger
111
Ginseng
Milk thistle
-Memory, immune, analgesia
-Reduction in hepatotoxicity
112
Saw Palmetto
Kava Kava
Kombucha
- BPH
- Anxiety, muscle relaxant, sedative
- Yeast and bacteria
113
Alkylating Agents
| Four groups
● Largest and most diverse class (CCNS)
● Either alkylate DNA or interfere by crosslinking (platinum compounds)
● Groups:
○ Nitrogen Mustards
■ Cyclophosphamide, chlorambucil
○ Nitrosoureas- cross BBB
■ Carmustine, lomustine, streptozocin
○ Alkyl Sulfonate
■ Busulfan
○ Platinum Analogs
■ Cisplatin, Carboplatin
114
Cisplatin
| MOA, Excretion, BBB? Uses, A/E
MOA: Enters cells, forms highly reactive platinum complexes, damages DNA with intrastand and interstrand crosslinks, inhibits cell proliferation
Highly bound to plasma proteins
Concentrates in kidney, intestine, testes
● Poorly penetrates BBB
● Slowly excreted in urine
● Uses
○ Testicular cancer (85% - 95% curative)
○ Ovarian cancer
○ Other solid tumors: lung, esophagus, gastric
● Adverse effects
○ Emesis
○ Nephrotoxicity
○ Peripheral neuropathy
○ Ototoxicity
Alternative:
● (Carboplatin – better tolerated)
115
MTX
| MOA, Cytotoxic & immunosuppresive actions
-inhibits the enzyme dihydrofolate reductase (DHFR). This blocks the synthesis of DNA, RNA, and proteins, affecting rapidly dividing cells.
-Cytoxic actions:
Predominant on bone marrow
Ulceration of intestinal mucosa
Cross placenta, fetal malformations & death
Immunosuppressive action:
Prevents clonal expansion of B & T lymphocytes
Anti-inflammatory
116
# Cancer drugs
Antimetabolites
Plant-based
Antibiotics
| Drugs
-6-MP, 5-FU
Vincristine, Paclitaxel
Dantinomycin, Doxorubicin, Bleomycin
117
# Cancer drugs
Hormonal Agents
Misc.
Corticosteroids, Tamoxifen, Fulvestrant
-Imatinib, Trastuzumab, Rituximab
118
GRASE
Generally recognized as safe and effective
