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PHRM 100 – APPP > APPP: Final Review > Flashcards

APPP: Final Review Flashcards

1
Q

What are the 4 different currents of the AP in the SA node? (4)

A
  • pacemaker current: If – Na+ influx/depolarization
  • transient calcium current: ICa(T) – open for short time
  • depolarizing current: ICa(L) – slow Ca2+ influx
  • repolarizing current: IK – K+ efflux
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2
Q

How is heart function regulated?

A

when stimulated, ATP is converted to cAMP (which increases PKA)

  • cAMP helps open Ca2+ channels, and Ca2+ enters cell and then SR
  • cAMP also activates HCN channel in SA node, and Na+ current increases (higher heart rate)
  • PKA increases rate of Ca2+ uptake into SR, which enhances relaxation
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3
Q

What pumps are involved in heart contraction? (2)

A
  • Na+/Ca2+ exchanger
  • Na+/K+ ATPase
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4
Q

How does pain transduction occur?

A
  • nociceptors detect noxious stimuli from somatic and visceral tissues
  • painful stimuli is converted to energy (neuronal AP)
  • stimulus sends an impulse across peripheral nerve fibres
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5
Q

Transduction: Nociceptor Activation

Globulin and Protein Kinases

A
  • released by damaged tissues
  • ie. kallikrein cleaves kininogen to release bradykinin
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6
Q

Transduction: Nociceptor Activation

Arachidonic Acid

A
  • released by damaged tissues
  • metabolized into prostaglandin and cytokines
  • prostaglandin blocks K+ outflow from nociceptors via G-protein and PKA cascade, increasing their sensitivity
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7
Q

Transduction: Nociceptor Activation

Histamine

A
  • released by mast cells when tissue is damaged
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8
Q

Transduction: Nociceptor Activation

Nerve Growth Factor (NGF)

A
  • released during inflammation or tissue damage
  • binds to TrkA receptors on nociceptors
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9
Q

Transduction: Nociceptor Activation

Substance P (SP) and Calcitonin Gene-related Peptide (CGRP)

A
  • released due to injury
  • causes vessel dilation, which spreads swelling around the injury
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10
Q

Transduction: Nociceptor Activation

Other Substances released during tissue damage

A
  • serotonin
  • acetylcholine
  • low pH solutions
  • ATP
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11
Q

What are the 3 principle opioid receptors?

A

(all members of GPCR family)

  • μ (mu)
  • Κ (kappa)
  • 𝛿 (delta)
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12
Q

What is the result of opioid receptor activation? (3)

A
  • reduced cAMP (and PKA): coupled to inhibitory Gi protein
  • reduced neuronal cell excitation and transmission: Ca2+ channels close, neurotransmitter release stops, and K+ efflux
  • euphoria: dopaminergic pathways
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13
Q

What are the 2 pathways underlying properties of opiates?

A
  • MOR (mu opioid receptor) agonists reduce excitability and transmitter release
  • opiates induce inhibition in VTA on GABAergic interneurons OR reduce GABA-mediated inhibition in NAc and increase outflow from VP – positive reinforcing state
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14
Q

What mediates NSAID inflammatory activity?

A

inhibition of prostaglandin biosynthesis

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15
Q

Describe how pain is modulated in the body?

A
  • excitatory neurotransmitter (ie. glutamate, substance P, CGRP) mediates synaptic transmission in dorsal horn
  • inhibitory neurotransmitter (ie. GABA, glycine, enkephalin, dynorphin, noradrenaline) hinder pain transmission
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16
Q

What factors does successful hemostasis depend on? (3)

A
  • vessel wall
  • circulating platelets
  • plasma-coagulation protein
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17
Q

Compare how arterial thrombi vs. venous thrombi result.

A
  • arterial: adherence of platelets to arterial wall
  • venous: activation of clotting/coagulation system (therefore made of RBC and fibrin), develop in areas of stagnated blood flow
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18
Q

Compare the characteristics of arterial thrombi vs. venous thrombi.

A
  • arterial: pale, granular, lower cell count
  • venous: soft, gelatinous, deep red, higher cell count
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19
Q

Compare the management strategy for arterial thrombosis vs. venous thrombosis.

A
  • arterial: anti-platelet strategies
  • venous: anti-coagulation strategies
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20
Q

What does clot formation in arterial thrombosis require?

A
  • platelet adhesion, activation, and aggregation
  • formation of thrombin, which catalyzes the production of fibrin to stabilize the clot
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21
Q

Arterial Thrombosis

A
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22
Q

Why don’t platelets normally adhere to healthy arterial walls (endothelium)?

A

have coated glycoproteins that carry negative charges, which repels against negative charge of endothelial cell coated glycoproteins

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23
Q

Why can platelets adhere to arterial walls upon injury?

A

injury exposes collagen and other tissue (sub-endothelium), which has positive charges that attract platelets

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24
Q

What receptors are involved in direct platelet adhesion to collagen?

A
  • GPVI – main glycoprotein receptor
  • α2β1-integrin
  • GPIa
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25
Q

What receptors are involved in indirect platelet adhesion to collagen?

A
  • GPIb – binding via von Willebrand factor (vWF) glycoprotein that is released from injured endothelial cells and platelets
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26
Q

How does platelet activation occur?

A
  • after platelet adhesion, Ca2+ from intracellular stores are mobilized into the cytoplasm
  • Ca2+ promotes platelet shape change, and contractile proteins in platelets allow for movement of granules and release of second-wave agonists (TXA2 and ADP)
  • TXA2 and ADP enhance platelet activation by binding to their receptors (P2Y12 and TP) to increase intracellular Ca2+, OR activate TXA2 and ADP receptors on other secondary platelets to increase intracellular Ca2+
  • increase in Ca2+ stimulates cyclooxygenase to promote synthesis of thromboxane A2
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27
Q

How is thromboxane A2 synthesized?

A
  • Ca2+ activates phospholipase A2, which cleaves platelet membrane phospholipids and liberates arachidonic acid
  • in the presence of cyclooxygenase, arachidonic acid forms prostaglandin H2 (PGH2)
  • thromboxane synthase facilitates PGH2 metabolism to produce TXA2
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28
Q

What promotes platelet aggregation?

A

second-wave chemical mediators

  • expose platelet surface receptors that are normally inactive on resting platelets, but undergo conformational transformation when there is an increase in Ca2+
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29
Q

What is the predominant receptor for platelet aggregation and how does it act?

A

GPIIb/GPIIIa

  • facilitates contact with circulating proteins – mainly fibrogen, but also vWF
  • then fibrinogen can act as a bridge between two platelets with its 2 amino acid RGD recognition sequences
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30
Q

What is critical for platelet aggregation?

A

interaction between fibrinogen and GPIIb/GPIIIa

  • these linkages rapidly enlarge the (primary) platelet plug
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31
Q

What is primary hemostasis?

A

platelet plug formation at site of injury that occurs within seconds and is key to stopping blood loss

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32
Q

What is secondary hemostasis?

A

local activation of plasma coagulation factors (ie. thrombin) forms a fibrin clot that strengthens the primary plug

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33
Q

What does each stage of the coagulation cascade involve?

A

conversion of precursor protein (synthesized in liver) to active protease by cleavage

  • non-enzymatic protein co-factor (reaction accelerator)
  • Ca2+
  • organizing surface (ie. phospholipid surface of activated platelets in vivo)
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34
Q

What are the coagulation proteases of the coagulation cascade?

A
  • HMWK (high molecular weight kallikrein)
  • prekallikrein
  • factors XII, XI, IX, X, VII, and II (prothrombin)
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35
Q

What are the non-enzymatic protein co-factors of the coagulation cascade?

A
  • factors V, VIII
  • tissue factor (TF or thromboplastin) – glycoprotein receptor found on the surface of a number of cells surrounding blood vessels, present on extravascular tissue
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36
Q

How is the intrinsic system of coagulation initiated?

A
  • clotting factors are present inside blood vessels
  • activation of factor XII on contact with a negatively charged surface or prolonged exposure to negative charges on endothelial cells
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37
Q

How is the extrinsic system of coagulation initiated?

A
  • initial stimulus (tissue factor) is present outside blood vessels
  • damage to blood vessels exposes TF-containing cells from underlying layers to the bloodstream
  • with Ca2+ present, TF (receptor) can then bind to factor VII (in blood)
  • this sets off sequential protease activations
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38
Q

Where is tissue factor (TF) expressed?

A
  • proposed to be a cell surface, membrane-bound glycoprotein
  • leukocytes (under pathological conditions)
  • activated endothelial cells (under pathological conditions)
  • microvesicles (MVs)
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39
Q

What happens when the intrinsic and extrinsic pathways converge into a final common pathway?

A

generates thrombin, fibrinogen, and formation of insoluble fibrin

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40
Q

What happens when thrombin binds to thrombomodulin on endothelial cell surfaces?

A
  • prevents it from cleaving fibrinogen
  • instead cleaves and activates protein C (in the presence of protein co-factor Va), which inhibits clotting by cleaving and inactivating factor Va and VIIIa (pro-coagulant factors)
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41
Q

What is protein C and what is its function?

A
  • natural plasma protein
  • with co-factor protein S (which results in activated protein C), it degrades factors Va and VIIIa – provides natural anticoagulation by inhibiting activation of factor X and prothrombin
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42
Q

How do valves in veins affect venous thrombosis?

A

turbulent flow and reduced oxygenation of the valve endothelium, which may activate endothelium and allow thrombus to form

  • valve pocket sinus can lead to surface expression of adhesion proteins due to its tendency to become hypoxic
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43
Q

What is P-selectin glycoprotein ligand-1 (PSGL-1)?

A
  • expressed by leukocytes
  • secretes microvesicles that express PSGL-1 and tissue factor
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44
Q

Venous Thrombosis

A
  • leukocytes and microvesicles binds to activated endothelium via PSGL-1
  • leukocytes become activated and express tissue factor
  • TF binds to factor VII (and activate it to VIIa) to form TF-FVIIa complex, which activates factor X to Xa
  • this initiates coagulation, where lots of thrombin is generated
  • local activation of the coagulation cascade overwhelms the protective anticoagulant pathways and triggers thrombosis
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45
Q

What are the functions of the pharynx? (3)

A
  • passageway for food and air
  • resonating chamber for sound/voice production
  • houses tonsils for immune response
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46
Q

What structures does the larynx contain? (2)

A
  • epiglottis – prevents food/liquid from travelling into trachea and airways
  • vocal cords – creates sound
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47
Q

What are the 2 structural changes that occur during branching of the bronchial tree?

A
  • mucous membrane goes from ciliated to non-ciliated
  • incomplete C rings of cartilage become plates of cartilage, then no cartilage (smooth muscle instead)
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48
Q

What is Boyle’s Law?

A

volume of a gas varies inversely with its pressure

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49
Q

What is minute ventilation?

A

respiratory rate x tidal volume

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50
Q

What is inspiratory capacity (IC)?

A

tidal volume (TV) + inspiratory reserve volume (IRV)

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51
Q

What is functional residual capacity (FRC)?

A

residual volume (RV) + expiratory reserve volume (ERV)

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52
Q

What is vital capacity (VC)?

A

inspiratory reserve volume (IRV) + tidal volume (TV) + expiratory reserve volume (ERV)

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53
Q

What is total lung capacity (TLC)?

A

vital capacity (VC) + residual volume (RV)

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54
Q

What is Dalton’s Law?

A

each gas in a mixture of gases exerts its own pressure as if all other gases were not present (partial pressure)

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55
Q

What is Henry’s Law?

A

quantity of a gas that will dissolve in a liquid is proportional to the partial pressure of the gas and its solubility

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56
Q

What does the binding of O2 to Hb depend on? (5)

A
  • partial pressure of O2: lower PO2 → less O2 combined with Hb
  • acidity/pH: low pH → less O2 combined with Hb
  • partial pressure of CO2: higher PCO2 → low pH → less O2 combined with Hb
  • temperature: higher temperature → less O2 combined with Hb
  • 2,3-biphosphoglycerate (BPG): higher BPG → less O2 combined with Hb
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57
Q

What is the chloride shift?

A

(transport of CO2)

  • blood picks up CO2 and HCO3- accumulates in RBCs, creating a high to low concentration gradient
  • HCO3- moves out of blood plasma and Cl- moves into RBCs
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58
Q

What is asthma?

A

chronic inflammatory disease of the airway

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59
Q

What is chronic obstructive pulmonary disease (COPD)?

A

progressive lung disease

  • emphysema and chronic bronchitis are the most common conditions
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60
Q

What is cystic fibrosis?

A

inherited disorder that affects cells that produce mucus, sweat, and digestive fluids

  • leads to severe damage to lungs, digestive system, and other organs
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61
Q

What is acute inflammation and what does it cause?

A

tissue injury caused by physical or chemical agent or pathogenic microorganism

  • capillary widening → increased blood flow
  • increased capillary permeability → release of fluid
  • attraction of WBCs → migration of WBCs to injury
  • systemic response → fever and proliferation of WBCs
  • all result in heat, redness, tenderness, swelling, and pain
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62
Q

What are the stages of acute inflammation?

A
  1. recognition of danger
  2. vasodilation and increase vascular permeability
  3. chemotaxis
  4. systemic response
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63
Q

Stages of Acute Inflammation

  1. Recognition of Danger
A
  • tissue resident immune cells (mast cells of macrophages) recognize damage signals through PRRs (such as toll-like receptors)
  • recognize pathogen factors (PAMPs) and cells in stress (DNA, heat shock proteins)
  • mast cells release stored histamine and NO
  • platelets release serotonin
  • inflammatory response is initiated
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64
Q

Stages of Acute Inflammation

2a. Vasodilation

A
  • dilation of blood vessels from arteriole → capillary → venule
  • stasis occurs when enlarged vessels pack with cells – assists leukocyte migration along vessel endothelium (blood normally flows too fast for directed leukocyte movement)
  • increased blood flow to wound sites causes local tissue erythema (redness) and warmth, swelling, painfulness
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65
Q

Stages of Acute Inflammation

2b. Increase Vascular Permeability

A
  • contraction and retraction of endothelial cells allow protein-rich exudate to cross into interstitial tissue
  • results in reduced osmotic pressure in blood, and increased osmotic pressure in interstitial space
  • leakage of fluid out of blood vessels leads to edema
  • when infection is present, edema can spread to nearby lymph channels and lymph nodes (lymphadenopathy)
  • increased delivery of immune cells and mediators, and clotting factors
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66
Q

Stages of Acute Inflammation

  1. Recruitment of Immune Cells – Chemotaxis

What are the WBC migration steps? (3)

A
  • rolling: loose, intermittent contact with endothelium
  • adhesion: tight, constant contact with endothelium
  • transmigration: WBCs cross endothelial layer through gaps created by contracted endothelial cells
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67
Q

Stages of Acute Inflammation

  1. Recruitment of Immune Cells – Chemotaxis

Leukocytes are recruited to the site of insult in different phases. What are these 2 phases?

A

6-24 hours post-injury:

  • dominated by neutrophils – first responders, fast arrival
  • phagocytes, apoptosis after response

24-48 hours post-injury

  • finds monocytes (→ macrophages, APC)
  • finds lymphocytes (sometimes eosinophils)
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68
Q

What are the 4 pre-formed acute inflammation mediators released by mast cell degranulation?

A
  • histamine
  • cytokines: TNF-a, IL-1, IL-6
  • chemokines for neutrophils and eosinophils
  • enzymes: tryptase, chymase, cathepsin
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69
Q

Acute Inflammation Mediators

What are the 2 secondary mediators synthesized and secreted upon mast cell activation?

A
  • eiconsanoids: leukotrienes, prostaglandins, and thromboxanes
  • Th2 cytokines: Il-4, IL-5, IL-13, GM-CSF
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70
Q

Acute Inflammation Mediators

What do eiconsanoids do?

A
  • increase vascular permeability
  • platelet aggregation
  • bronchiole constriction
  • slower reacting substances, but longer-lasting effects
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71
Q

What are the 6 types of inflammatory exudate and their biological content?

A
  • serous – cell-free plasma (ie. skin blisters, pericarditis)
  • fibrinous – with increased fibrinogen for wound repair (ie. adhesions following surgery)
  • mucinous – thick clear gel-like mucous provides physical barrier and aid targeting of infectious materials (ie. runny nose with common cold)
  • purulent – thick, coloured pus containing WBCs (ie. abscesses, boils, cellulitis)
  • sanguineous – fresh bleeding (ie. hematoma)
  • mixed types – mixture of the above (ie. serosanguineous, mucopurulent)
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72
Q

Describe the steps of the inflammatory response.

A
  1. bacteria and other pathogens enter wound
  2. platelets form blood release blood-clotting proteins at wound site
  3. mast cells secrete factors that mediate dilation and constriction of blood vessels – delivery of blood, plasma, and cells to injured area increases
  4. neutrophils secrete factors that kill and degrade pathogens
  5. neutrophils and macrophages remove pathogens by phagocytosis
  6. macrophages secrete cytokines, which attract immune system cells to the site and activate cells involved in tissue repair
  7. inflammatory response continues until the foreign material is eliminated and the wound is repaired
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73
Q

Mast cells are the source of which mediators of inflammation?

A

histamine, others

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74
Q

Macrophages are the source of which mediators of inflammation?

A

cytokines, others

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75
Q

Endothelium is the source of which mediators of inflammation?

A

NO, cytokines, others

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76
Q

What plasma proteins are sources of mediators of inflammation?

A
  • complement
  • clotting factors and kininogens
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77
Q

What are the 4 outcomes of acute inflammation?

A
  • resolution
  • abscess formation
  • fibrosis (scar) formation
  • chronic inflammation
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78
Q

Outcomes of Acute Inflammation

Resolution

A
  • damaging agent removed and damages repair
  • organ regeneration and full function restored (normal function)
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79
Q

Outcomes of Acute Inflammation

Abscess Formation

A
  • walled off collection of pus (neutrophils and necrotic tissues)
  • may need reabsorption or necrosis
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80
Q

Outcomes of Acute Inflammation

Fibrosis (Scar) Formation

A
  • excessive or abnormal connective tissue (fibrosis)
  • hard, non-functional tissue, no organ regeneration (loss of function)
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81
Q

What is septic shock?

A
  • most severe form of sepsis with bacteria/infectious agents in blood
  • end organ damage + hypotension
  • typically leads to death
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82
Q

What are the 2 types of chronic inflammation mediators?

A
  • macrophages
  • lymphocytes
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83
Q

What are the macrophage chronic inflammation mediators? (5)

A
  • proteases
  • cytokines: TNF, IL-1 (activates lymphocytes)
  • NO
  • eicosanoids
  • angiogenesis and growth factors: platelet derived growth factor (PDGF)
  • fibroblast growth factor (FGF)
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84
Q

What are the lymphocyte chronic inflammation mediators? (2)

A
  • cytokines: interferon 𝛾 (activates
    macrophage)
  • angiogenesis and growth factors: transformation growth factor beta (TGF𝛽), platelet derived growth factor (PDGF), fibroblast growth factor (FGF)
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85
Q

What are granulomas?

A

accumulations of mononuclear WBCs (macrophage and lymphocytes), epithelioid cells, and multi-nucleated giant cells in injured/damaged tissues

  • associated with mycobacterial (TB) or fungal infections
  • chronic injury caused by foreign agents such as silica
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86
Q

What are the 5 mediators of tissue repair?

A
  • epidermal growth factor (EGF)
  • vascular endothelial growth factor (VEGF)
  • platelet derived growth factor (PDGF)
  • fibroblast growth factor (FGF)
  • transformation growth factor beta (TGF𝛽)
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87
Q

What does epidermal growth factor (EGF) do?

A

stimulates granulation tissue formation

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88
Q

What does vascular endothelial growth factor (VEGF) do?

A

stimulates formation of blood vessels

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89
Q

What does platelet derived growth factor (PDGF) do?

A

promotes growth of fibroblasts and smooth muscle cells

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90
Q

What does fibroblast growth factor (FGF) do?

A

stimulates formation of blood vessels and wound repair

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91
Q

What does transformation growth factor beta (TGF𝛽) do?

A

promotes collagen deposition and ECM growth

92
Q

What are the steps in tissue repair?

A
  1. injury occurs and inflammation
  • clotting caused by clotting proteins and plasma proteins occurs, and scab is formed
  • removal of damaging agents (neutrophils/WBC)
  • removal of dead tissues (macrophages and others)
  1. new (granulation) tissue formation
  • deposition of extracellular matrix (fibroblasts)
  • formation of new blood vessels (endothelial cells) restores vascular supply
  • production of extracellular matrix (ie. collagens)
  1. tissue remodeling
  • maturation and reorganization of fibrous tissues – restored epithelium thickens
  • wound contracture
93
Q

What is first intention wound healing?

A
  • wound has clean edges
  • close proximity of margins
  • minimal tissue disruptions
  • outcome: no tissue loss, little or no scar
  • ie. surgical incision, clean cuts
94
Q

What is second intention wound healing?

A
  • wound has unclean, wide edges
  • extensive tissue disruption and necrosis
  • large, more prominent scar
  • ie. pressure ulcers, trauma that affects large areas
95
Q

Describe the wound healing timeline.

A
  • injury occurs and acute inflammatory response is induced
  • repair starts within 24 hours of onset of acute inflammation
  • 3-5 days: granulation tissues form, collagen deposition continues to week 2, edema and inflammatory cells disappear
  • 1 month: all inflammatory infiltrate is gone, scar consists of mature collagen
96
Q

What is granulation tissue?

A

contains fibroblasts, ECM, newly formed blood vessels by ECs, immune cells (mostly macrophages)

  • occurs in all wounds
  • formed during initial process of wound healing (first 24-72 hours), but also in chronic inflammation
97
Q

What are the 6 factors that delay/impair wound healing?

A
  • infection
  • necrotic debris
  • poor tissue perfusion and hypoxia
  • nutritional deficiency
  • physical trauma
  • drugs (glucocorticoids, immunosuppressives)
98
Q

Type I Hypersensitivity

A
  • IgE mediated
  • classic allergy
  • onset in minutes
99
Q

Type II Hypersensitivity

A
  • IgG/IgM mediated
  • cytotoxic reaction
  • onset in hours to days
100
Q

Type III Hypersensitivity

A
  • IgG/IgM
  • immune-complex diseases
  • onset in hours to weeks (1st encounter)
101
Q

Type IV Hypersensitivity

A
  • T cell
  • delayed type hypersensitivity
  • onset in 2-3 days
102
Q

How does degranulation during an allergic response occur?

A
  1. allergen binds IgE/FceR1 on mast cell surface
  2. cross-links of two IgE activates degranulation signal with tyrosine phosphorylation
  3. Ca2+ influx
  4. degranulation and release of inflammation mediators
  • granule contents include histamine, proteases, chemotactic factors (ECF, NCF)
103
Q

What is the immediate phase event in the allergic response?

A
  • release of histamine and cytokines by mast cells
  • occurs within minutes following exposure to allergens
104
Q

What is the late phase event in the allergic response?

A
  • induction and continuing synthesis of eicosanoids, cytokines, and chemokines
  • immune cells infiltrate (eosinophils and others)
  • smooth muscle contraction, edema
  • may last hours to days, and lead to chronic inflammatory reaction
105
Q

What is the effector stage of the allergic response?

A
  • high affinity IgE receptor (FceR1) found on mast cells, basophils, and activated eosinophils
  • after sensitization, an increasing number of mast cells are primed with IgE on surface
106
Q

What are the candidate polymorphic genes related to atopy? (5)

A
  • IL-4 receptor
  • IL-4 cytokine (promoter region)
  • FceRI: high affinity IgE receptor
  • class II MHC (present peptides promoting Th2 response)
  • inflammation genes
107
Q

What is Type II hypersensitivity (cytotoxic) mediated by?

A

inappropriate binding of antibodies (IgG or IgM) to a tissue cell surface antigen, including:

  • extrinsic antigens presented on cell surface following infection
  • chemical that modifies a cell surface component (ie. penicillin binding to RBC, and quinine binding to platelet)
  • self antigen (auto-immune disease)

through classical complement pathway MAC or immune cell mediated ADCC

108
Q

What are some Type II hypersensitivity reactions? (3)

A
  • ABO hemolytic anemia – clinical mistakes in blood transfusions
  • autoimmune hemolytic anemia
  • Guillain Barre Syndrome – autoimmune reaction following viral infections
109
Q

What are special Type II hypersensitivity reactions?

A
  • known as Type V in UK
  • associated with cell surface receptors targeting antibodies
110
Q

What are the 3 phases of Type III hypersensitivity (immune-complex)?

A

phase 1:

  • antigen presentation and antibody (IgG or IgM) production
  • formation of antigen-antibody complexes in circulation (soluble)

phase 2:

  • deposition of antigen-antibody complexes in tissues
  • frustrated phagocytes unable to clear these complexes

phase 3:

  • inflammation and tissue injury where antigen-antibody complexes are deposited (kidney, endothelial cells, joints)
111
Q

When are immune complexes formed in Type III hypersensitivity?

A

when clusters of antibodies (mostly IgG, but also IgM) interlock after binding to a soluble (not cell surface) foreign or tissue antigen

  • found in circulation, in body fluids, and deposited in tissue
112
Q

How are immune complexes normally removed and what happens if they aren’t?

A
  • normally rapidly removed through actions of phagocytic cells
  • when not effectively removed, they can become trapped in local tissues and cause degranulation of phagocytes
  • activation of complement system is also implicated in tissue injury caused by precipitated/trapped IC
113
Q

What are some immune complex conditions (Type III hypersensitivity)?

A
  • glomerulonephritis following streptococcal infection
  • rheumatoid arthritis (autoimmune)
  • systemic lupus erythematosus (autoimmune)
114
Q

How does systemic lupus erythematosus occur?

A
  • antibodies against dsDNA from apoptotic cells form immune complexes
  • these complexes are deposited in kidney’s glomerular structures and in blood vessels
  • immune complex deposition/formation eventually leads to immune-mediated tissue inflammation and damage
115
Q

What are the 2 phases of Type IV hypersensitivity (delayed type)?

A
  • sensitization phase: initial contact with antigen
  • effector phase: secondary contact with antigen
116
Q

What are some other haptens? (2)

A
  • heavy metals (nickel, cobalt, chromium, zinc)
  • latex
117
Q

How does delayed type hypersensitivity (Type IV DTH) occur?

A
  • soluble protein antigens are presented by macrophages or dendritic cells to TH1 helper T-cells
  • in the classical TH1-macrophage feedback, TH1 cells secrete cytokines to recruit mononuclear cells and form granulomas
  • at the epidermis, Langerhans cells (dendritic cells specific to skin and mucosa) act as APC – small molecules bind to normal cellular proteins following skin contact, and present as modified epidermal antigens to elicit immune activation of cytotoxic T cells
118
Q

How does contact dermatitis occur (Type IV hypersensitivity)?

A
  • during sensitization, small molecules act as haptens and complex with skin proteins to be taken up by APCs and presented to Th1 cells
  • during secondary exposure, Th1 memory cells become activated by cytotoxic T cells to cause DTH
119
Q

What are some Type IV hypersensitivity disorders?

A
  • contact dermatitis (effector phase is cytotoxic T cell mediated)
  • tuberculin formation in tuberculosis (effector phase is TH1-macrophage)
120
Q

What causes autoimmune disorders? (3)

A
  • breakdown in immune tolerance against self-antigens
  • molecular mimicry of infectious microbe’s antigens resembling self-antigen
  • neo-antigen creation through hapten binding to cellular proteins, as well as somatic mutations that alter protein structures
121
Q

What are the risk factors in autoimmune disease? (4)

A
  • genetics: polymorphic forms of MHC II allotypes
  • sex: hormonal, X-inactivation, and micro-chimerism roles
  • infections in susceptible individuals (see mimicry above)
  • age: immunosenescence and loss of immune system self-regulatory capacity
122
Q

What hypersensitivity type is Graves Disease?

123
Q

What hypersensitivity type is Myasthenia Gravis?

124
Q

What hypersensitivity type is celiac disease?

125
Q

What hypersensitivity type is multiple sclerosis?

126
Q

What hypersensitivity type is type I diabetes?

127
Q

What are the functions of cholesterol? (3)

A
  • critical component of cell membranes
  • precursor of aldosterone
  • precursor of estrogens, androgens, testosterone
128
Q

What is HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase?

A

key enzyme in the hepatic synthesis (major source) of cholesterol

129
Q

What do hepatic LDL receptors do?

A

facilitates clearance and uptake of plasma LDL cholesterol

130
Q

What happens when there is adequate cholesterol available (due to receptor-mediated uptake)?

A
  • rate of synthesis of LDL receptors is reduced
  • critical enzyme (HMG-CoA reductase) is inhibited and cholesterol is not synthesized
131
Q

What do LDLs do?

A

carry cholesterol to peripheral tissues

132
Q

What do HDLs do?

A

remove cholesterol from cells and macrophages and deliver to liver

  • HDL directly binds to hepatic docking receptors
  • or is indirectly transferred to acceptor lipoproteins
133
Q

What does extracellular lipoprotein lipase (LPL) do?

A
  • degrades triglycerides into free fatty acids, which are then used for energy by skeletal muscle
  • synthesize triglyceride and store in adipose tissue and liver
  • present in adipose tissue, skeletal muscle, and heart capillaries
134
Q

How is IDL and LDL generated?

A

lipoprotein lipase (LPL) action on triglycerides in VLDL

135
Q

Why are small dense LDL more likely to cause heart disease?

A
  • decreased affinity for LDL receptor
  • longer residence in plasma
  • easier entry into arterial wall
  • greater retention in arterial intima
  • greater susceptibility to oxidation
  • increased endothelial cell dysfunction – increased production of plasminogen activator inhibitor 1 (clot is not dissolved), and TXA2 (increases platelet aggregation)
136
Q

Why is HDL protective against atherosclerosis?

A

reverse cholesterol transport

  • HDL is secreted from liver, takes up cholesterol from tissues and plaques, and recirculates it to the liver for excretion in bile
137
Q

Where are LDL receptors predominantly present? (3)

A
  • hepatocytes
  • adrenal cells
  • adipocytes
138
Q

How do LDL receptors work?

A
  1. receptor binds to LDL particles and endocytoses them
  2. vesicles containing LDL fuse with lysosomal enzymes that degrade LDL
  3. LDL receptors are recycled
  4. once internalized, cholesterol inhibits HMG-CoA reductase (decreases gene transcription and enzyme activity) and LDL receptors
139
Q

What is PCSK9 (proprotein convertase subtilisian/kexin type 9)?

A

enzyme that binds to LDL receptor to promote its internalization, and escorts receptor for lysosomal degradation – prevents recycling of LDL receptor

140
Q

What are the 3 layers of the artery wall?

A
  • intima – endothelial cell layer
  • media – thickest layer with smooth muscles
  • adventitia – loose connective tissue, small blood vessels, and nerve fibres
141
Q

How does atherosclerosis initially develop?

A
  • small lesions in vascular endothelium or increase in endothelial permeability allows leakage of blood into vascular wall
  • infiltration of plasma lipoproteins (including LDL)
142
Q

Mechanism of Atherosclerosis

A
  1. increased LDL infiltration into intima with potential oxidative modification yields modified Ox-LDL
  2. Ox-LDL causes endothelial cells to express MCP-1, which attracts monocytes (phagocytic) to adhere to injured endothelium and migrate through intima (transmigration)
  3. Ox-LDL also promotes differentiation of monocytes into macrophages, resulting in expression of receptors that uptake Ox-LDL
  4. macrophages release cytokines (TNF-a)
  5. cytokines activate endothelial cells to express adhesion molecules (VCAM-1) that bind monocytes, making them available for recruitment of additional circulating monocytes into the intima
  • Ox-LDL accumulates within macrophages to form foam cells
  1. engorgement of foam cells causes release of more cytokines and proteolytic enzymes, and eventually cell death (necrotic core)
  • proteolytic enzymes cause degradation, allowing smooth muscle from media to integrate into intima, proliferate, and secrete fibrous connective tissue (collagen) to make the lesion harder and form fibrous cap
  • rupture of lesions is responsible for angina and myocardial infarct
  • dislodging the clot blocks artery near plaque and causes occlusion
  • if damage to myocardium is severe, heart pumping will be impaired, resulting in congestive heart failure or cardiac death
143
Q

What is the periosteum?

A
  • fibrous covering that contains blood and lymphatic vessels, nerves
  • inner layer contains osteoblasts that form bone
144
Q

What is hyaline cartilage (or articular cartilage)?

A

where joint forms

145
Q

What is the endosteum?

A

osteoclast layer in marrow cavity

146
Q

What are the steps of bone remodeling?

A
  • bone resorption by osteoclasts
  • bone resorption by mononuclear phagocytes
  • recruitment of osteoblast precursors
  • secretion of new matrix by osteoblasts
  • continued secretion of matrix, with initiation of calcification
  • completion of mineralization of new matrix
147
Q

What are the 3 major forms of cartilage?

A
  • hyaline (glassy) cartilage – most common
  • elastic cartilage
  • fibrocartilage
148
Q

Describe the structure and components of cartilage.

A
  • chondrocytes – produce collagen and proteoglycans
  • lack blood vessels, lymphatics, nerves
  • surrounded by perichondrium
149
Q

What are the 2 main cell types in the synovial membrane?

A
  • macrophage-like type A cell – remove debris, regulate inflammatory events
  • fibroblast-like type B cell – produce synovial fluid
150
Q

What is the sliding theory of muscle contraction?

A
  1. depolarization of muscle membrane
  2. release of Ca2+ from internal stores (SR)
  3. binding of Ca2+ to actin
  4. sliding of myosin along actin
151
Q

How are APs generated in muscle fibres at the neuromuscular junction?

A
  1. transmission of motor neuron signal
  2. increased permeability of Ca2+ at neural ends of a synapse
  3. release of ACh from synaptic vesicles and binding to nicotinic receptors
  4. Na+ influx
  5. change endplate potential and depolarization
  6. muscle fibre action
  7. propagation of signal OR turn off signal (degradation of ACh by acetylcholinesterase)
152
Q

What are the 2 types of proprioceptors?

A
  • muscle spindle afferents
  • mechanoreceptors from skin and joints
153
Q

What is myasthenia gravis?

A

autoimmune disorder of neuromuscular transmission

  • produce antibodies against nicotinic ACh receptor
  • abnormal immune response results in decreased activity and number of ACh receptors, causing failed nerve transmission at certain neuromuscular junctions

symptoms:

  • dropping of one or both eyelids (ptosis)
  • blurred or double vision (diplopia) due to weakness of the muscles that control eye movements
  • change in facial expression
  • difficulty swallowing
  • shortness of breath
  • impaired speech (dysarthria)
  • weakness in arms, hands, fingers, legs, and neck
154
Q

What are some peptide hormones?

A
  • oxytocin (activates GPCR)
  • anti-diuretic hormone (ADH)/vasopressin (activates GPCR)
  • human growth hormone (activates JAK/STAT)
  • all hormones secreted by hypothalamus, pituitary glands, digestive tract, and pancreas
  • insulin
155
Q

What are some amino acid hormones?

A
  • thyroid hormones (activates nuclear hormone receptors)
  • melatonin (GPCR)
  • epinephrine/norepinephrine (GPCR)
156
Q

What are some hormones derived from fatty acids?

A

(arachidonic-acid-derived hormones)

  • prostaglandins (activates GPCR)
  • leukotrienes (activates GPCR)
  • thromboxanes (activates GPCR)
157
Q

What are some steroid hormones?

A

(these are all ligands that bind to and activate transcription factors)

  • estrogen (estrogen receptor)
  • progesterone (progesterone receptor)
  • testosterone (androgen receptor)
  • cortisol (glucocorticoid receptor)
158
Q

Which hormones can pass through the cell membrane?

A
  • amino acid hormone
  • steroid hormone
159
Q

How do nuclear hormone receptors work?

A
  1. steroid hormone enters cells due to their chemical properties and high partition coefficient
  2. find and bind to soluble hormone receptors
  3. receptor changes conformation, allowing recognition and binding of specific DNA elements (that are hormone responsive)
  4. binding recruits transcriptional co-activator (enhance) or transcription co-repressor (reduce), leading to change in expression of gene products
160
Q

Where is the hypothalamus?

A

below thalamus and right above brainstem

161
Q

Where is the pituitary?

A

at the base of the brain, connected to hypothalamus, and rests within a hollowed out area of the sphenoid bone called the sella turcica

162
Q

What are the functions of the pineal body?

A
  • synthesizes melatonin
  • inhibits reproductive function
  • protects against damage by free radical
  • sets circadian rhythms
163
Q

What is the function of oxytocin?

A

(activates GPCR)

  • females: causes contraction of the uterus and ejection of breast milk
  • males: stimulates contraction of the prostate and vas deferens during sexual arousal
164
Q

What is the function of antidiuretic hormone (ADH/vasopressin)?

A

(activates GPCR)

  • stimulates kidneys to conserve water
  • vasoconstriction
165
Q

Describe the action and regulation of growth hormones.

A
  • GH release from anterior pituitary is regulated by GHRH (+) and somatostatin (-)
  • GH regulates protein synthesis, particularly in skeletal muscle
166
Q

What are the direct actions of growth hormones? (2)

A
  • stimulate fat breakdown – switch to fatty acid as energy source
  • glycogen to glucose (gluconeogenesis)
167
Q

Hypothalamic Hormone

Growth-Hormone-releasing Hormone (GHRH) (+)
Somatostatin (-)

  • anterior pituitary hormone
  • primary target organ and their hormones
  • primary functions at target organ(s)
A
  • growth hormone (GH) binding causes dimerization and JAK-STAT activation
  • liver, bone, muscle, kidney, and others – IGF-1
  • stimulates increase in size of muscles and bones
168
Q

Hypothalamic Hormone

Thyrotropin-releasing Hormone (TRH) (+)
Somatostatin (-)

  • anterior pituitary hormone
  • primary target organ and their hormones
  • primary functions at target organ(s)
A
  • thyroid-stimulating hormone (TSH)
  • thyroid – thyroxine, triodothyronine
  • stimulates thyroid gland
169
Q

Hypothalamic Hormone

Corticotropin-releasing Hormone (CRH) (+)

  • anterior pituitary hormone
  • primary target organ and their hormones
  • primary functions at target organ(s)
A
  • adrenocorticotropic hormone (ACTH)
  • adrenal cortex – cortisol
  • stimulates adrenal cortex
170
Q

Hypothalamic Hormone

Gonadotropin-releasing Hormone (GnRH) (+)

  • anterior pituitary hormone
  • primary target organ and their hormones
  • primary functions at target organ(s)
A
  • follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
  • gonads – estrogen, progesterone, testosterone
  • stimulates sexual development in males and females
171
Q

Hypothalamic Hormone

Dopamine (-)

  • anterior pituitary hormone
  • primary target organ and their hormones
  • primary functions at target organ(s)
A
  • prolactin
  • breast
  • stimulates milk production
172
Q

What do follicular cells do?

A

produce thyroid hormone

  • thyroxine (T4)
  • triiodothyronine (T3)
173
Q

What do parafollicular or C cells do?

A

produce calcitonin (peptide hormone)

174
Q

How are both T4 and T3 transported?

A

by binding to thyroid-binding globulins (TBG) and albumin

175
Q

What is the effect and mechanism of thyroid hormones on the heart?

A
  • chronotropic and inotropic
  • increased number of beta-adrenergic receptors, enhanced responses to circulating catecholamines, increased proportion of alpha-myosin heavy chain (with higher ATPase activity)
176
Q

What is the effect and mechanism of thyroid hormones on adipose tissue?

A
  • catabolic
  • stimulated lipolysis
177
Q

What is the effect and mechanism of thyroid hormones on muscle?

A
  • catabolic
  • increased protein breakdown
178
Q

What is the effect and mechanism of thyroid hormones on bone?

A
  • developmental
  • promote normal growth and skeletal development
179
Q

What is the effect and mechanism of thyroid hormones on the nervous system?

A
  • developmental
  • promote normal brain development
180
Q

What is the effect and mechanism of thyroid hormones on the gut?

A
  • metabolic
  • increased rate of carbohydrate absorption
181
Q

What is the effect and mechanism of thyroid hormones on lipoprotein?

A
  • metabolic
  • formation of LDL receptors
182
Q

How is thyroid hormone release regulated?

A
  1. TSH (produced by anterior pituitary) binds to receptor (GPCR), which increases expression of thyroid hormone biosynthesis enzymes
  2. hormone synthesis and release increases
  3. T4 exerts negative feedback on TSH release at anterior pituitary
183
Q

What is the most sensitive index for measurement of thyroid function?

A

serum TSH levels

184
Q

What is Hashimoto disease?

A

autoimmune disease that leads to hypothyroidism

185
Q

What are the clinical features of hypothyroidism?

A
  • goiter
  • slow heartbeat
  • dry skin
  • cold intolerance
  • weight gain
186
Q

What are the clinical features of hyperthyroidism?

A
  • bulging eyes
  • unblinking stare
  • goiter
  • rapid heartbeat
  • increased sweating
  • heat tolerance
  • unexplained weight loss
187
Q

What are the 2 types of cells in the parathyroid gland?

A
  • oxphil cells
  • chief cells – produce PTH when Ca2+ decreases
188
Q

What are the primary positive regulators of extracellular Ca2+ levels in healthy adults?

A
  • parathyroid hormone
  • calcitrol – produced in kidney, activates nuclear hormone receptor
189
Q

How does the endocrine system respond when Ca2+ in blood is too high?

A

thyroid produces calcitonin, which decreases blood Ca2+ by:

  • increasing excretion of Ca2+ by kidneys
  • increasing Ca2+ deposition in bones
  • stopping osteoclasts
190
Q

How does the endocrine system respond when Ca2+ in blood is too low?

A

parathyroid glands produce PTH, which increases blood Ca2+ by:

  • releasing stored Ca2+ from bones
  • stimulating production of calcitrol in the kidney, which increases absorption of Ca2+ by digestive system
  • enhancing reabsorption of Ca2+ by kidneys
191
Q

What are the 3 regions of the adrenal cortex and what do they secrete?

A
  • zona glomerulosa – secretes mineralocorticoids (controls salt reabsorption)
  • zona fasciculata – secretes glucocorticoids (sugar)
  • zona reticularis – secretes adrenal androgens (sex)
192
Q

What steroid hormone does each region of the adrenal cortex produce?

A
  • zona glomerulosa – produces aldosterone
  • zona fasciculata – produces cortisol (stress response)
  • zona reticularis – produces DHEA, DHEAS
193
Q

Zona Glomerulosa

Describe mineralocorticoid actions.

A
  1. aldosterone enters kidney’s principle (P) cells and binds to mineralocorticoid receptor (MR)
  2. MR activation increases expression responsive genes
  • epithelial Na+ channel (ENaC – slower effect)
  • serum glucocorticoid-regulated kinase 1 (SGK-1) that promotes ENaC activity (fast effect)
  1. both cortisol and aldosterone can bind to MR – in mineralocorticoid target tissues, expression of 11βHSD2 (11β-hydroxysteroid dehydrogenase 2) converts cortisol into inactive metabolite to ensure MR endocrine signaling is restricted to aldosterone
194
Q

What tissues express the mineralocorticoid receptor (MR)?

A
  • kidney
  • sweat gland
  • colon (GI)
  • heart (CVS)
  • hippocampus (CNS)
195
Q

How does the renin-angiotensin-aldosterone system (RAAS) work?

A
  • when renal blood flow is reduced, juxtaglomerular cells in kidney convert precursor prorenin (already present in blood) into renin and secrete it directly into circulation
  • plasma renin converts angiotensinogen (released by liver) to angiotensin I
  • angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE) found on surface of vascular endothelial cells (mostly lungs)
  • angiotensin II causes vasoconstriction and increases blood pressure
  • angiotensin II secretes aldosterone, which causes renal tubules to increase reabsorption of Na+ (and therefore water) into blood and also increases blood pressure
196
Q

Zona Fasciculata

How are glucocorticoid receptors activated?

A
  1. transcriptional activation of target genes
  • glucocorticoids exert their effects through ligand-activated transcription regulation of protein expression
  • unliganded (no hormone) receptor is sequestered by heat shock proteins (Hsp) in cytoplasm
  • hormone binding causes change in conformation and translocation to nucleus
  • binding of hormone-GR to DNA glucocorticoids response elements (GRE) in promoter of target genes induces their transcription
  1. activation of MAPK for fast effects by liganded GR
197
Q

Zona Fasciculata

What are the 3 main actions of glucocorticoids?

A
  • regulate all aspects of metabolisms, stress response
  • mediate organogenesis in different stages of development
  • potent immunosuppressive activity
198
Q

Zona Fasciculata

What are the 3 anti-inflammatory actions of glucocorticoids?

A

(through genomic actions)

  • inhibit activation and proliferation of key immune cells (T-lymphocytes and B-lymphocytes, dendritic cells, macrophages, eosinophils, and mast cells)
  • inhibit expression of inflammatory cytokines in immune cells as well as in target tissues
  • inhibit production of antibodies (including both auto- and neutralizing antibodies)
199
Q

Zona Fasciculata

How is glucocorticoid release regulated?

A
  • trauma via nociceptive pathways, afferent from NTS, emotion via limbic system, and circadian rhythm affect CRH
  • HPA corticotropin-releasing hormone (CRH) from hypothalamus regulates release of adrenocorticotropic hormone (ACTH)
  • homeostasis levels of ACTH release follows circadian rhythm in irregular bursts, with highest concentration in early mornings
  • increased ACTH secretion occurs in response to stress and injury
  • glucocorticoids exert negative feedback on ACTH secretion, both at pituitary and hypothalamus
  • prolonged treatments with anti-inflammatory glucocorticoids may lead to adrenal atrophy and loss of endogenous glucocorticoid output – gradual cessation is necessary
200
Q

Zona Fasciculata

Describe the actions of corticosteroids in the acute and chronic stress responses.

A
  • HPA axis is key regulatory pathway in maintenance of physiological homeostatic processes – end product (cortisol) is secreted in pulsatile pattern, with changes in pulse amplitude creating a circadian pattern, with cues from light-dark cycles
201
Q

Zona Fasciculata

What happens to cortisol levels during acute stress?

A

both epinephrine and cortisol levels rise

  • acute elevations in these factors are beneficial to promoting survival of the fittest as part of the fight or flight response
202
Q

Zona Fasciculata

What happens to cortisol levels during chronic stress?

A

cortisol levels remain raised

  • long-term cortisol exposure becomes maladaptive, which can lead to a broad range of problems including metabolic syndrome, obesity, cancer, mental health disorders, cardiovascular disease, and increased susceptibility to infections
203
Q

Zona Reticularis

What controls the secretion of adrenal androgens?

204
Q

Zona Reticularis

What is dehydroepiandrosterone (DHEA)?

A
  • the major form of adrenal androgens
  • is converted into androstenedione (A)
205
Q

Zona Reticularis

What is androstenedione (A)?

A
  • a form of adrenal androgens, produced in a small amount
  • precursor for testosterone and estradiol in peripheral tissue (ie. adipose tissue)
206
Q

What is the follicular phase of the menstrual cycle?

A
  • selection and maturation of a dominant follicle
  • continued production of sex hormone (E2) by two cell types (granulosa and theca) within the follicle
207
Q

What is the ovulation phase of the menstrual cycle?

A

occurs mid-way (d14) in the cycle following the LH surge

208
Q

What is the luteal phase of the menstrual cycle?

A
  • corpus luteum continues production of sex hormones (P4 and E2) in anticipated support for fertilization
  • continue production of P4 and E2 suppresses LH and FSH release
209
Q

Describe the process of the ovarian synthesis of estradiol.

A

two-cell, two-gonadotropin principle of ovarian steroid hormone production

  • LH controls theca cell production of androstenedione, which diffuses into adjacent granulosa cells and acts as precursor for estradiol biosynthesis
  • granulosa cell capacity to convert androstenedione to estradiol is controlled by FSH

(theca cell: cholesterol to progesterone to androstenedione)
(granulosa cell: androstenedione to estrone to estradiol)

210
Q

Describe the hormonal and endometrial changes during the menstrual cycle.

A
  1. menstrual cycle begins with gradual increase in FSH, promoting follicle development
  • increasing follicular estradiol (F2) secretion inhibits LH and FSH production
  1. at E2 secretion peak, LH surge (and increased FSH, to a lesser extent) causes decrease in E2 and starts production of progesterone (P4)
  • LH surge also results in ovulation

3, following ovulation, corpus luteum took over production of E2 and P4, which inhibits FSH and LH

  1. uterine lining (endometrium) corresponding go through proliferative (growth) phase during follicular development (follicular phase)
  • P4 release with formation of corpus luteum (luteal phase) will induce endometrial differential and gland secretion to prepare for fertilization
  1. in absence of fertilization, corpus luteum regression leads to reduced E2 and P4 levels
  • shedding of endometrium occurs (menstruation)
  1. fall of E2 and P4 levels releases negative feedback on FSH/LH production
  • cycle repeats
211
Q

What effect does estrogen have in the ovary?

A

mitotic effects on granulosa cells

212
Q

What effect does estrogen have in the liver?

A

metabolic modulation

213
Q

What effect does estrogen have in the CNS?

A

neuroprotective

214
Q

What effect does estrogen have in bone?

A

antiresorptive

215
Q

What effect does estrogen have in the CVS?

A

cardioprotective

216
Q

What are the 5 effects of progesterone?

A
  • anti-estrogenic effects in uterus
  • pro-estrogenic effects in breast
  • pro-thyroid effects
  • anti-inflammatory effects
  • metabolic effects
217
Q

What are the 3 anti-estrogenic effects of progesterone in the uterus?

A
  • decreased uterine motility
  • development of secretory endometrium
  • thickened cervical mucous
218
Q

What are the 2 pro-thyroid effects of progesterone?

A
  • increased body temperature
  • increased appetite
219
Q

What is the anti-inflammatory effect of progesterone?

A

depressed T-cell function

220
Q

What is the metabolic effect of progesterone?

A

anti-insulin – switch to use fat for energy

221
Q

What are the 2 main cells of the testes?

A
  • Leydig cells – in interstitial space surrounding seminiferous tubules
  • Sertoli cells – in seminiferous tubules
222
Q

Where is the circulating testosterone in males produced?

A
  • majority produced in testis’ Leydig cells
  • small amount produced from adrenal cortex (zona reticularis)
223
Q

What is testosterone converted into?

A
  • within target cells, converted by enzyme 5-alpha-reductase into dihydrotestosterone (DHT) – which has higher affinity to androgen receptor
  • small amounts are converted to estrogen through action of aromatase (CYP19)
224
Q

How is testosterone metabolized and excreted?

A

metabolized in liver to inactive forms, and excreted through kidney

225
Q

Mechanism of Testosterone Action

A
  1. hormone binding results in conformational changes of androgen receptor and relocation to nucleus
  2. in nucleus, hormone-bound receptor interacts with androgen response element of target genes
    - recruitment of co-activators results in altered gene expression
226
Q

Androgen Feedback Regulation

A
  1. LH stimulates Leydig cell secretion of testosterone, while FSH stimulates Serotoli cells for sperm production
  2. testosterone exerts androgenic effects on target tissue, including Serotoli cells
  3. negative feedback loop: testosterone inhibits LH secretion through direct action on pituitary, as well as inhibits secretion of GnRH from hypothalamus
  4. separate negative feedback loop exists between FSH and Serotoli cells secreting inhibin B (TGF-β-like hormone)
227
Q

What are the adverse effects of anabolic steroids? (5)

A
  • decrease spermatogenesis and testicular atrophy
  • gynecomastia
  • liver and kidney damage
  • cardiac hypertrophy, decreases HDL, increases LDL
  • psychological changes

PHRM 100 – APPP (23 decks)

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