Exam #5: Review Material Flashcards
How does smooth muscle differ from skeletal muscle?
- Smooth muscle is non-striated vs. striated skeletal muscle
- Different types of smooth muscle exist (multi-unit vs. unitary) in different organs
What contractile component is missing from smooth muscle that is present in skeletal muscle?
Troponin Complex
- Indicative of a different role of Ca++ in smooth muscle
Smooth muscle does contain actin, myosin, and tropomyosin
How are myosin heads arranged in smooth muscle? How is this different from skeletal muscle?
Mysoin heads in smooth muscle are NOT all arranged in the same direction
What takes the place of z-discs in smooth muscle?
Dense bodies
What is the function of dense bodies?
- Transmission of force from once cell to another
- Anchor for thin filaments
How does the point of regulation differ from skeletal muscle to smooth muscle?
Remember, smooth muscle DOES NOT contain TnC; thus:
Skeletal=
1) Ca++ from SR binds TnC
2) Ca++/TnC= tropomyosin moves to expose myosin binding sites on actin
Smooth
1) Ca++ binds Calmodulin
2) Ca++/Calmodulin increase MLCK
3) MLCK increases Myosin ATPase
4) Phosphorylated myosin binds actin
What is different between contraction of skeletal muscle & smooth muscle?
1) In smooth muscle ECF Ca++ is the PRIMARY source of Ca++, NOT SR Ca++ as in skeletal muscle
2) MLCK is only present in smooth muscle
3) Myosin ATPase is constitutively active in skeletal muscle; smooth muscle, this is regulated
What are the signs and symptoms of Type II DM?
1) Asymptomatic initially
2) Infections become more frequent b/c of the energy (glucose) source for microorganisms
3) Neuropathy
4) Classic severe insulin deficiency signs occurs late in the progression of symptoms
5) Obesity & metabolic syndrome
*****#4, note that type II DM becomes apparent when the Beta-cells are no longer able to compensate for increased resistance to insulin
What are the distinguishing features between Type I and Type II DM related to B-cell function?
Type I= absolute beta cell destruction leading to beta cell destruction
- Decrease in beta-cell mass
Type II= insulin resistance followed by an insulin secretory defect
- Increase in beta-cell mass
*Note that there are 2x subtypes of DM-I, a & b. A= autoimmune, B= idiopathic–diagnosis is based on NOT finding autoantibodies
What are the distinguishing features between Type I and Type II DM related to insulin sensitivity?
- In type-II DM the body is NOT responding to insulin i.e. a decrease in insulin sensitivity, which initially results in an INCREASE in insulin secretion–a compensatory mechanism
- Type I, the body simply is NOT producing insulin
What are the therapeutic strategies employed & rationale for these strategies in treating Type I DM?
1) Diet i.e. balanced carbs, fat, and protein
2) Patient education on:
- Carb counting
- Insulin action
- Blood glucose targets
3) Insulin ABSOLUTELY required it must be non-PO route b/c insulin is a peptide that will be degraded in the GI tract
What are the therapeutic strategies employed & rationale for these strategies in treating Type II DM?
First, remember that potential therapies for the DM may have a negative impact on the overall Metabolic Syndrome in DM-II, which presents a challenge to treating DM-II
1) Diet
2) Patient education
3) Pharmacologic strategies
*Insulin is used ONLY when other agents DO NOT allow for achievement of therapeutic goals
What are the acute complications potentially experienced by DM patients? How are these addressed?
Hypoglycemia (e.g. insulin overdose)
- Glucose
- Glucagon
DKA
- Restore plasma volume
- Reduce blood glucose
- Correct acidosis
- Replenish electrolytes
Outline the different pharmacological strategies that are used to treat DM-II.
1) Increase insulin secretion
2) Increase insulin action
3) Inhibit gluconeogenesis
4) Inhibit glucose digestion & absorption from the GI tract
5) Suppress glucagon secretion
How can you pharmacologically increase insulin secretion in DM-II?
- GLP1 analogs are used to activate GLP1 receptors to promote insulin secretion
- DPP4 (enzymes that breaks down GLP1) inhibitors, which indirectly promote insulin secretion
- Inhibition of ATP-sensitive K+ channels on B-cells to eventually cause insulin release
What is the relationship between flow, velocity or flow, and cross-sectional area in the vascular system?
v= Q/A
v= velocity of flow (cm/sec) Q= flow (mL/sec) A= cross-sectional area (cm2)
*Velocity is slower in larger vessels
What is Ohm’s law as it relates to the vascular system?
Q=dP/R
Q= flow (mL/min) dP= pressure difference mmHg R= resistance
*Thus, flow increases with pressure & decrease with increasing resistance–main source of resistance is arterioles.
What is Poiseuille’s Law?
R= 8nl/pir4
R= resistance n= viscosity of blood l= length of BV r4= radius raised to 4th power
What is TPR? How does TPR systemic compare to TPR pulmonic?
TPR= dP/CO
TPR-systemic= Psystemic-RAP/CO TPR-pulmonic= Ppulmonic-LAP/CO
*****Note, CO= HR x SV
Also, TPR ~MAP/CO
TEMPERATURE INCREASE–Explain temperature-induced changes in skin blood flow, sweating, shivering, thermogenesis, & piloerection.
Generally, remember that the temperature regulating center is located in the anterior hypothalamus. In response to temperature increase, mechanisms are activated to increase heat-loss:
1) Vasodilation= warm blood from core at surface–>heat loss to environment
- Alpha-1 adrenergic inhibition
2) Sweating leads to evaporation & heat loss
- SNS CHOLINERGIC stim.
3) Shivering, thermogenesis, piloerection are INHIBITED
TEMPERATURE DECREASE–Explain temperature-induced changes in skin blood flow, sweating, shivering, thermogenesis, piloerection.
Generally, remember that the temperature regulating center is located in the anterior hypothalamus. In response to temperature increase, mechanisms are activated to increase heat-loss:
SNS:
1) Vasoconstriction= decreased thermal conductivity
- Alpha-1 mediated/ NOREPINEPHRINE
2) Thermogenesis= metabolic generation of heat
- Beta-adrenergic mediated/ EPINEPHRINE
- PNS–>TRH–>TSH–Thyroxine
Posterior Hypothalamus
3) Shivering= skeletal muscle heat generation
Sweating is inhibited
What are the differences between myelinated & unmyelinated nerves? Specifically, where are the voltage-gated Na+ channels? Which conducts more rapidly? Which conducts more efficiently?
Myelinated nerves are myelinated & non-myelinated ones are not.
- Nodes of Ranvier
- Myelinated neurons BOTH conduct more rapidly & are more efficient
How does myasthenia gravis affect synaptic transmission? is the problem pre-synaptic or post-synaptic? Is this an autoimmune disease?
- Autoimmune
- Post-synaptic
- Antibodies against NAChR, an important mediator of EPPs
How does Eaton-Lambert Syndrome affect synaptic transmission? is the problem pre-synaptic or post-synaptic? Is this an autoimmune disease?
- Often occurs in patients with small-cell carcinoma of the lung (& breast cancer)
- Patients have antibodies to voltage gated Ca++ channels
- Autoimmune & pre-synaptic
- Less Ca++ enters pre-synaptic terminals; thus, less ACh is released, which results in muscle weakness
How does botulinum toxin affect synaptic transmission? is the problem pre-synaptic or post-synaptic? Is this an autoimmune disease?
- Botulinum toxins cleave SNARE proteins*
- Vesicles will not properly dock to pre-synaptic membrane
- ACh will not be released
- Symptoms:
1) NMJ paralysis
2) Muscle weakness
*As does tetanus toxin, but tetanus causes tetanic contraction.
How does a-bugarotoxin affect synaptic transmission? is the problem pre-synaptic or post-synaptic? Is this an autoimmune disease?
- A peptide from the venom of a banded krait (snake)
- Irreversibly blocks NAChR
- Post-synaptic
What is the difference between GPIba, GPVI, GPIIb/IIIa
- GPIba binds vFW to mediate platelet tethering
- GPVI binds collagen for strong platelet adhesion & activation
- GPIIb/IIIa binds fibrinogen, forming the platelet plug
What is the P2Y12 receptor? What drug antagonises this receptor?
Is the receptor for ADP on platelets, which leads to platelet activation
*Plavix is a P2Y12 antagonist
What are PARs? Why are PARs important?
PAR stands for “Protease activated receptors,” which are GPCRs on the surface of platelets that are activated by thrombin
*Activation of PARs leads to further platelet activation & is important because this links the platelet & coagulation systems
What is the Thromboxane A2 receptor?
A platelet receptor
Thromboxane A2 works in an autocrine fashion, increasing platelet activation; it also is a vasoconstrictor
What are Collagen, vWF, and fibrinogen ligands for?
Collagen= GPVI vFW= GPIba Fibrinogen= GPIIb/IIIa
What are Thromboxane A2, ADP, & thrombin ligands for?
TXA2R
P2Y12R (plavix antagonist)
PARs
Outline the vascular response to tissue damage. Specifically address the functions of ADP, 5-HT, and Thromboxane A2.
1) Damaged tissue secretes factors that cause vasoconstriction
2) Platelets become activated
3) Activated platelets secrete Thromboxane A2 & Serotonin, leading to further vasoconstriction
Vasoconstriction prevents blood loss & slows flow to give platelets a better chance of adhering.
Describe the effects of constricting either the afferent or the efferent arteriole on renal blood flow (RBF).
Afferent= decrease RBF Efferent= decrease RBF
Describe the effects of constricting either the afferent or the efferent arteriole on GFR.
Afferent= decreased GFR Efferent= increased GFR
How could you increase the glomerular hydrostatic pressure by constricting the efferent or afferent arterioles?
Constricting the efferent arteriole
What is the source of fibroblast growth factor 23 (FGF 23).
Osteoblasts and osteocytes in bone
What is FGF23?
“fibroblast growth factor 23”
What are the effects of FGF23 on the kidney?
1) Decreased reabsorption of phosphate
2) Decreases the production of calcitriol
What stimulates the secretion of FGF23?
1) Elevated phosphate levels
2) Calcitriol i.e. active Vitamin D
What are the relationships between FGF23 and parathyroid hormone and calcitriol and their actions?
Vitamin D= increased reabsorption of Ca++ & phosphate
FGF23= decreased reabsorption of Ca++ & phosphate
PTH= increased absorption of Ca++. decreased absorption of phosphate
How does the autonomic nervous system differ from the somatic nervous system in terms of neruons?
- In the somatic nervous system, there is one large neuron that synapses directly on the effect cell
- In the ANS, there are two neurons (preganglionic & post ganglionic, with an intervening ganglia)
How do the sympathetic & parasympathetic nervous systems differ organization of the neurons?
- Sympathetic= Short pre-ganglionic & long post-ganlgionic fiber
- Parasympathetic= Long pre-ganglion & short post-ganglionic
*Note that the the ganglia of the PNS are clustered within the walls of visceral organs
What is the alternate name for the sympathetic nervous system?
Thoraco-lumbar division
What is the intermediolateral cell column?
- Lateral horn of the spinal cord
- Location of the cell bodies of autonomic ganglia
Describe the path of sympathetic outflow.
1) Cell body in the intermediolateral column
2) Preganglionic axon exits the spinal cord via the ventral root w/ somatic motor neurons
3) Diverge from somatic & enter the white rami communicantes
Describe cranial outflow.
- Preganglionic fibers follow certain cranial nerves
- Ganglia lie very close to target organs
Specific cranial nerves= oculumotor, fascial, glossopharyngeal, & vagus
Describe sacral outflow.
- Parasymathetic fibers emerge from the spinal cord in a bundle known as the nervi erigentes
- Synapse with pelvic ganglia
- Short postganglionic fibers to target organs
What is the enteric nervous system?
Two ganglia sandwhiched between the layers of the gut:
- Myenteric (Auerbach’s)
- Submucosal (Meissner’s)
Specifically, where is the myenteric plexus located? What does the myenteric plexus control?
- Between the external longitudinal & deep circular smooth muscle layers
- Motility
Specifically, where is the submucosal plexus located? What does the submocosal plexus control?
- Between the circular muscularis mucosae
- Ion & fluid transport
What NT is released from all of the preganglionic fibers?
ACh
*Regardless of system, all preganglionic fibers release ACh
What do the postganglionic fibers of the PNS release?
ACh
What do the postganglionic fibers of the SNS release?
NE/Epi or DA
What is the exception to postganglionic fibers of the SNS releasing NE/Epi or DA?
Thermoregulatory sweat glands, which posses muscarinic receptors & respond to ACh
What neurotransmitter do postganglionic fibers to the renal vascular smooth muscle release?
DA
What NTs are released by the adrenal medulla?
Epi & NE
What receptors are present in the target organs of the PNS?
Muscarinic ACh
What receptors are present in the thermoregulatory sweat glands?
Muscarinic ACh
What receptors are present in the target organs of the SNS? What are the two exceptions to this?
- Alpha & Beta Adrenergic
- Exceptions:
1) thermoregulatory sweat
2) renal vasculature
What receptors are present in the renal vasculature?
DA-1
What receptors are present in skeletal muscle?
Nicotinic ACh
How is ACh synthesized?
1) Uptake of choline from the ECF via the Na+ dependent choline transporter (CHT)
2) Conjugation by ChAT (AcetylCoA + Choline)
3) Final product: ACh
Note that acetylcholine is synthesized in BOTH the cytoplasm & in the mitochondria. ChAT= choline acteyltransferase
What drug can block the choline transporter (CHT)?
Hemicholiniums
*Note that these are not used clinically.
How is ACh stored?
Once ACh is synthesized, it is transported into the storage vesicle via the “vesicle assocaited transporter” (VAT)
What drug blocks VAT?
Vescamicol
How is ACh released?
1) Depolarization of nerve
2) Voltage-dependent Ca++ entry
3) Ca++ binds Calmodulin, activating “vesicle associated membrane proteins,” VAMPs & “synaptosome-assocaited proteins,” (SNAPs)
4) Exocytosis
What is the function of the VAMPs & SNAPs?
- Docking storage vesicles on the inner surface of the nerve terminal facing the synapse
- Fusion of the synaptic vesicle with the neural membrane
What does botulinum toxin block?
VAMPs & SNAPs
*Botulinum toxin enzymatically removes two amino acids from one or more of these fusion peptides
How is ACh action terminated?
1) Rapid hydrolysis of ACh via acetylcholine esterase (AChE)
2) Choline re-uptake into terminals
3) ACh interaction with ACh autoreceptors
What does acetylcholine esterase break ACh into?
Choline & Acetate
What drug blocks Acetylcholine esterase? What happens at the synapse in response to these drugs? Give an example of an AChE inhibitor.
- AChE inhibitors
- Increase ACh concentrations & over-stimulation of receptors
*Neostigmine is an AChE inhibitor
How are catecholamines synthesized?
1) Tyrosine is converted to DOPA via Tyrosine Hydroxylase*
2) DOPA is converted to Dopamine
3) Dopamine is converted to Norepinephrine
Note that this is the rate-limiting step
What drug blocks tyrosine hydroxylase? What step of the catecholamine synthesis process does this drug block?
- Metyrosine
- Conversion of Tyrosine to DOPA
What part of catecholamine synthesis only occurs in the adrenal medulla?
Norepinephrine is converted to Epinephrine
What is tyramine?
Tyramine is a naturally occurring monoamine compound, and a trace amine derived from the metabolism of tyrosine (alternative to DOPA)
What causes an increase in Tyramine?
Ingested of naturally occurring fermented cheese
What is Tyramine a precursor of?
Norephinephrine
How are catecholamines stored?
Synthesized catecholamines are transported into vesicles for storage via the “Vesicular Monoamine Transporter (VMAT)”
*Note that the conversion of norephinephrine to epinephrine occurs in the vesicle, if the converting enzyme is available.
What blocks VMAT? What is the mechanism of action?
Reserprine, blocks VMAT & causes a depletion of catecholamine stores
Still used today for “resistant hypertension
How are the catecholamines released?
Similar exocytosis mechanism as ACh
What drug blocks VAMP?
Bretylium
How is catecholamine transmission terminated?
1) Diffusion into the circulation & metabolized by liver COMT (catechol-O-methyl transferase)
2) Binding to an autoreceptor on the pre-synaptic nerve terminal
3) Neuronal Re-uptake via NET1 (NE transporter on the presynaptic nerve terminal), where:
- Repackaged in vesicles
- Metabolized by mitochondiral monoamine oxidase (MAO)
4) Extraneuronal uptake via extraneuronal transporters (ENT or NET2)
What is the mechanism of action of cocaine & tricyclic antidepressants?
NET1 antagnoists that leads to an increase in NE in the synaptic cleft
What is the effect of MAO antagonists? How are they related to Tyramine?
MAO is a mitochondrial enzyme that metabolizes catecholamines
- Irreversible MAO antagonists enhance the availability of Tyramine
- Can lead to hypertensive crisis
What is the rate-limiting step in catecholamine synthesis?
Conversion of Tyrosine to DOPA via Tyrosine Hydroxylase
What are the muscles of inspiration?
Diaphragm
External intercostals
Scaleni
SCM
What are the muscles of expiration?
Abdominal wall muscles
What is FVC?
Forced vital capacity= total amount of air that can be forcibly expired after maximal inspiration
What is FEV1?
The volume of air that can be forcibly expired in the first second
*Speed
Why is the FEV1/FVC ratio important?
It is a reflection of RESISTANCE to airflow
- Big ratio= small resistance
- Small ratio= big resistance (obstructive)
.75- 0.8= normal
What is FEF 25, 50, & 75?
Forced expiratory flow rate at varying volumes of air out
How does the FEV1/FVC ratio change in obstructive lung disease? Why?
Less than 0.7
- FCV & FEV1 decreased, but FEV1 is decreased more than FVC
How does the FEV1/FVC ratio change in restrictive lung disease? Why?
Greater than 0.8
FVC & FEV1 are decreased, but FEV1 is decreased less than FVC
Draw the flow volume curve curve in obstructive lung disease.
N/A
Draw the flow volume curve curve in restrictive lung disease.
N/A
Draw the flow volume curve curve in upper airway obstruction.
N/A
How does restrictive lung disease effect FEV1, FVC & FEV1/FVC ratio?
asdf
How does obstructive lung disease effect FEV1, FVC & FEV1/FVC ratio?
asdf
What are the three most prevalent obstructive lung disorders?
Asthma
Chronic Bronchitis
Emphysema
What are the main differences between asthma, chronic bronchitis, and emphysema?
- Asthma is the most reversible of obstructive lung diseases
- Chronic bronchitis is hallmarked by increased sputum production
- Emphysema involves the most damage to the alveolar wall
Outline the pathophysiology of allergic asthma.
In response to an allergen, a myraid of inflammatory cells release inflammatory mediators that result in:
1) Bronchoconstriction
2) Plasma exudation
3) Edema
4) Vasodilation
5) Mucus hypersecretion
6) Activation of sensory nerves
Chronic inflammation leads to structural changes including:
1) Thickening of the basement membrane
2) Smooth muscle hypertrophy & hyperplasia
3) Angiogenesis
4) Hyperplasia of mucus-secreting cells
What are the therapeutic options in asthma?
Acute reliever
Controller
What are the receptors for rescue treatments?
- B-2 adrenergic (bronchodilation)
- Anticholinergics (M3)
List the controller treatments used for asthma.
Inhaled corticosteroids Antileukotrienes Long-acting B-agonists Theophylline Systemic corticosteroids Anti-IgE
How is asthma manifested on PFT?
Decreased airflow rates throughout the vital capacity
- Decreased PEFR
- Decreased FEV1
- Decreased MMEFR
