Pathophysiology 2 Flashcards
HTN increases the risk of?
- stroke
- heart failure
- myocardial infarction
- renal failure
Essential HTN?
95%
- no underlying cause
- treated to lower and reduce risk of other diseases
- lifelong disorder requiring management
Secondary HTN?
- 5%
- diagnosable cause
- can be cured by treatment of underlying cause
Symptoms of HTN?
-none except when super high
Prehypertension?
systolic 120-139
diastolic 80-89
-progress to HTN at rate of >10% per year
-lifestyle can reverse it back to normal
Renin-Angiotension-Aldosterone-System in Essential Hypertension
Low: better BP response to diuretics and CCB’s
Normal
High: CV risk, better to ACE inhibitors
Causes of Secondary HTN?
- renal parenchymal disease (acute nephritis, chronic glomerulonephritis)
- renovascular disease (renal artery stenosis, arteriosclerosis, fibroplasia)
- endocrine causes
3 Endocrine Diseases that cause HTN?
-primary hyperaldosteronism
-pheochromocytoma
-Cushing’s syndrome
each less than 1%
Other endocrine conditions that cause HTN besides main 3?
- acromegaly
- diabetes mellitus
- obesity
- congenital adrenal hyperplasia
- estrogen-induced hypertension
- pregnancy-induced hypertension
- renin-secreting tumors
- hypothyroidism
- hyperthyroidism
- Liddle syndrome
Pheochromocytoma: Sympathochromaffin
1) sympathetic nervous system including postganglionic neurons, the vast majority of which release norepinephrine among other neurotransmitters
2) chromaffin tissues including particularly the adrenal medullae which are the major source of circulating epinephrine among other hormones
Norepinephrine & Epinephrine
- catecholamines
- dihydroxyphenly nucleus and amine side chain
What comprises the autonomic nervous system?
- sympathochromaffin system
- parasympathetic nervous system
Hemodynamic response to epinephrine?
-increased systolic, but not diastolic, BP and increased heat rate
Hemodynamic response to norepinephrine?
-increased systolic and diastolic BP with reflex restraint of the increased heart rate
Pheochromocytoma
-catecholamine producing tumors, composed of chromaffin cells, that typically produce labile hypertension and paroxysmal symptoms
Rare
1) HTN is curable
2) untreated risk for lethal THN paroxysm
3) some are malignant
4) clue to presence of familial AD syndrome
Pheochromocytoma Diagnosis
-clinical suspicion & biochemical confirmation and then anatomical localization
Pheochromocytoma Symptoms
-paroxysmal symptoms
-headache, diaphoresis, palpitations
-labile HTN
-family history
Precipitated by: positional changes, emotional stress, abdominal pressure, direct pressure on tumor, medications
Pheochromocytoma Metabolic Features
- hypercatabolism
- increased metabolic rate, profuse sweating, hyperglycemia, weight loss
Pheochromocytoma Hematological Manifestations
- orthostatic hypotension
- elevated hemocrit
- erythrocytosis INCREASED ERYTHROPOIETIN
Pheochromocytoma Biochemical
-measure metanephrines and and VMA
(metabolites)
-NE and E
-all measured in urine
Pheochromocytoma Location
- in adrenal medulla 90%
- 99% in abdomen
- rest in mediastinum
Pheochromocytoma Treatment
surgical excision
Mineralocorticoid Excess
excess aldosterone
Mineralocorticoids
- stimulate the distal renal tubules to reabsorb sodium from tubular fluid
- excrete more potassium and hydrogen ions (acid)
- increase open sodium and K+ channels in the luminal membrane of tubular cells and increase synthesis of basolateral membrane Na+/K+ ATPase, which generates the gradients that drive ion movement
- expand extracellular fluid volume
- increase blood pressure
- lower plasma K+ levels, increase plasma pH 1
What activates the Mineralocorticoid Receptor?
- cortisol
- aldosterone
Primary Mineralocorticoid?
- aldosterone b/c an enzyme (11-beta hydroxysteroid dehydrogenase) coexists with this receptor in the renal tubule and converts cortisol to inactive cortisone
- *Licorice make metabolite that inhibits 11-beta…**
Mineralocorticoid Excess causes?
- HTN
- Hypokalemic alkalosis
What regulates Aldosterone secretion?
-volume of extracellular fluid
Dehydration Cascase
-Dehydration stimulates renin
-Renin causes release of angiotensin I, converted to angiotensin II by (ACE)
-ANG II stimulates aldosterone secretion
Negative Feedback Loop
Angiotensin II
potent vasoconstrictor
Renin secretion is stimulated by?
sympathetic nervous system (via beta-adrenergic receptors)
Is ACTH part of the physiologic control of aldosterone?
no
Mineralocorticoid Excess from?
1) autonomous aldosterone secretion
ex: adrenal adenoma (primary hyperaldosteronism)
2) increased renin secretion
(secondary hyperaldosteronism)
What is used to diagnose primary hyperaldosteronism?
-ration of plasma aldosterone to plasma renin activity
Primary Hyperaldosteronism
-excessive production of aldosterone due to adrenal disorder, NOT due to excess renin secretion
Secondary Hyperaldosteronism
-increased secretion of both renin and aldosterone
Etiology of Primary Hyperaldosteronism
- 2/3 are do to aldosterone-secreting adrenal adenoma
- small <2cm diameter
- remaining of cases due to bilateral adrenal hyperplasia (idopathic)
Clinical Findings of Primary Hyperaldosteronism
- hypertension: increased Na+
- hypokalemia: may cause muscle weakness, cramps, polyuria
Diagnosis of Primary Hyperaldosteronism
-suspected with hypertension & spontaneous hypokalemia
-excess aldosterone secretion is not under normal control by renin
ration of aldosterone/renin >50
Glucocorticoids
-catabolic effects on protein metabolism
-suppress immunity & inflammation
-necessary for normal CV function
primary is cortisol
most commonly used drug: predisone
potent for negative feedback: dexamethasone
Glucocorticoids Excess
Cushing’s Syndrome
- obesity from appetite stimulation
- catabolic effects cause weakness of skeletal muscle & connective tissue of skin
- bone mass decreases & fractures common
- 80% HTN by 1)angiotension 2)mineralocorticoid
3) vascular reactivity
Cortisol Angiotension in Cushings Syndrome
- stimulate hepatic synthesis of angiotensinogen, acted upon by renin & angiotensin converting enzyme to the potent vasoconstrictor angiotension II
- in some patients with Cushing’s
Mineralocorticoid in Cushing’s Syndrome
-high conc. cortisol bind/activate mineralocorticoid receptors causing HTN and hypokalemia
-suppress plasma renin
cushings only with paraneoplastic production of ACTH
Vascular reactivity in Cushing’s Syndrome
-give cortisol in normal subjects enhances vascular reactivity to pressors (causing vasocontriction), increased peripheral resistance and elevated BP
What triggers realease of natriuretic peptides?
-increased wall stretch due to volume & pressure overload in patient with heart failure by atrial & ventricular myocytes
Normal BNP
100 indicates heart failure also urine uroguanylin levels
BMI
Weight (Kg)/ [Height (m)]^2
- can overestimate degree of obesity in shorter muscular person
- normal is 30 obese
Total Energy Expenditure (TEE)
basal/resting energy expenditure (REE)*main
-decreases with age
thermic effect of food (TEF)
mandatory physical activities of daily living (ADL)
volitional physical activity or exercise
non-exercise activity thermogenesis (NEAT)
non-exercise activity thermogenesis (NEAT)
- activities of daily living
- yard work, walking to work, fidgeting
What is the afferent limb of the energy homeostasis loop?
food consumption
hunger is?
physiological response to appetite
Arcuate Nucleus (ARC)
- base of hypothalamus
- express hormone/neuropeptides that regulate feeding
After eating, satiety signals are provided by?
- vagal afferent projections to the brainstem
- GLP-1 and serotoninergic neurons
Neuropeptide Y
-hypothalamic orexigenic signals
-rapidly stimulates food intake in rodents
hyperphagia and weight gain
Agouti-related protein (AgRP)
- hypothalamic orexigenic signals
- expressed exclusively in arcuate nucleus of hypothalamus
- increase food intake in rodents for several days (longer lived)
- antagonism of melanocortin receptors MC3 & MC4
Hypocretins/Orexins
- hypothalamic orexigenic signals
- stimulate food intake
- hypo increase in response to exercise, neuroglycopenia & enforced wakefulness
- hypo hormones localize to lateral hypothalamus
Endocannabinoid System
-endogenous signaling system receptors CB1 & CB2, endogenous anandamide -activated to: reduce pain/anxiety modulate body temp. hormone release/smooth muscle tone inhibit motor behavior extinguish aversive memories INDUCE APPETITE
Overactivation of CB1
- increase appetite by hypothalamus effect
- increase motivation to eat effect nucleus accumbens
- increase fat accumulation effect peripheral adipocytes
Anorexigenic Neuropeptides
- from hypothalamus inhibit food intake or induce satiety
- melanocortins
- cocain&hetamine regulated transcript (CART)
- serotonin
Melanocortins
- come from POMC
- precurser that gives rise to ACTH, alphaMSH (act on MC receptors and decreases appetite)
- weight loss = inhibition of POMC
Leptin
-secreted by fat cells
-absence leads to overfeeding, massive obesity, delayed sexual maturation, immune defects in ob mice
Increased by feeding
Decreased during fasting, or after weight loss
POMC/CART
-downstream effector neurons of leptin
Serotonin
- anorexigenic
- over ridden by SSRI’s
Adiponectin
- secreted in abundance by fat cells from insulin sensitive persons
- deficient in persons with obesity/insulin resistance
Insuline
- regulate food intake through interaction with central hypothalamic neurons
- secreted in direct proportion to fat mass
- postprandial insulin secretion is potent signal for leptin secretion
Pancreatic Polypeptide (PP)
- secreted by specialized endocrine cells within islets of Langerhans
- plasma levels increase after meal
Ghrelin
-endogenous ligand for growth hormone secretagogue receptor
-synthesized/secreted by oxynic cells of stomach
(goes to anterior pituitary)
-stimulates growth hormone secretion by somatotrophs
-stimulates food intake
-peripheral signal for hunger & meal initiation
Peptide YY
- synthesized by mucosal endocrine L cells located in intestine and large bowel
- released during feeding, serves as anorectic/satiety signal from intestinal cells
Glucagon-like-peptide-1
-derived from precursor molecule preproglucagon
“incretins” - effect in boosting postprandial insulin secretion
-inhibition of feeding in rodents
Cholecystokinin
- best known for role in food digestion, stimulation of pancreatic enzyme secretion and gallbladder conc.
- potent satiety factor
Anorexigenic Signal of Leptin Targets?
Hypothalamus
Anorexigenic Signal of Peptide YY Targets?
Hypothalamus
Anorexigenic Signal of Pancreatic Polypeptide Targets?
Hypothalamus
Anorexigenic Signal of Insulin Targets?
Hypothalamus
Anorexigenic Signal of Cholecystokinin Targets?
Brain stem/ Vagus
Anorexigenic Signal of GLP-1 Targets?
Local GI/diverse
Orexigenic Signal of ghrelin Targets?
Hypothalamus
What is the only food signal activated preprandially?
Ghrelin, the rest are activated by food ingestion and attenuated by fasting or starvation
Causes of hypoglycemia?
1) iatrogenic
2) spontaneous
Spontaneous Hypoglycemia?
1) fasting
2) postprandial
- nondiabetic populace
Iatrogenic Hypoglycemia
- hypoglycemia in the setting of diabetes
- complicates therapy with insulin or sulfonylureas
- limiting factor to aggressive efforts to achieve optimal glycemic control in patients with DM
- Hypo is big problem with DM Type I
Risk factors of Iatrogenic Hypoglycemia
- skipped/insufficient meals
- unaccustomed physical exertion
- misguided therapy
- alcohol
- drug overdose
- recurrent episodes of hypoglycemia
Symptoms of Iatrogenic Hypoglycemia
- Autonomic(neurogenic): tremulousness, sweating, palpitations, hunger b/c of increasing counterregulatory hormones - 1st
- Neuroglycopenic: as glucose decreases further, impaired concentration, irritability, blurred vision, lethargy & development of seizure or coma - 2nd
- Hypoglycemia unawareness: defective counterregulation, blunting of autonomic systems, seizures, coma without warning symptoms
Isolated episodes of mild Iatrogenic hypoglycemia?
-may not require specific intervention
Recurrent episodes of Iatrogenic hypoglycemia?
- review lifestyle factors
- content, timing, distribution of meals, meds dose and timing
1) give readily absorbable carbs (sugar)
2) IV dextrose for severe
3) Glucagon if can’t maintain oral intake or no IV is avaliable
4) Education
5) Patients with hypoglycemia unawareness should monitor a lot
Spontaneous Hypoglycemia
1) fasting
2) postprandial hypoglycemia
Fasting Hypoglycemia
- can be caused by inappropriate insulin secretion, alcohol, several hepatic/renal insufficiency, hypopituitarism, glucocorticoid deficiency
- surreptitous insulin injection
- ingestion of sulfonylurea
Postprandial hypoglycemia
-suspect if vague symptoms hours after meal
Alimentarly Hypoglycemia
-occur in patients with a history of partial gastrectomy or intestinal resection with symptoms 1-2 hrs after eating
Functional Hypoglcemia
-symptoms of hypoglycemia (may or not confirmed by glucose measurement) occur in patients who have not undergone gastrointestinal surgery
Diagnosis of Spontaneous Hypoglycemia
1) episodic autonomic symptoms
2) recurrent seizures, dementia, and bizarre behavior
3) definitive diagnosis
4) patients who develop hypoglycemia
