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PHRM 844 Module #2 > ANS Control of Blood Pressure > Flashcards

ANS Control of Blood Pressure Flashcards

1
Q

Define hypertension and distinguish primary from secondary HTN

A

systolic BP: pressure inside arteries when the heart pumps
diastolic BP: pressure when the heart relaxes between beats
HTN: diastolic pressure > 80 mmHg and systolic pressure > 130 mmHg; resting pulse pressure (SBP-DBP) > 65 mmHg - pulse pressure > 40 us unhealthy, pulse pressure > 60 is a risk factor for heart disease
HTN often asymptomatic
primary (essential) HTN has no definitive cause (85-80% of all cases), secondary HTN has a known cause

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2
Q

Causes of secondary HTN

A

kidney disease, renal artery constriction - stenosis, cysts, glomerulunephritis
tumors - pheochromocytoma
endocrine disease - cushing’s syndrome (excessive secretion of glucocorticoids), conn’s syndrome (excessive production of aldosterone/hyperaldosteronism)
coarctation of the aorta
pregnancy –> preeclampsia
medication adverse effects: high estrogen oral contraceptives, antidepressants, rebound HTN
A: aldosteronism; B: bad kidneys; C: cushing;s/coarctation; D: drugs; E: endocrine disorders

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3
Q

Classifying hypertension

A

normal: s - less than 120, d - less than 80
elevated: s - 120-129, d - less than 80
stage 1: s - 130-139, d - 80-90
stage 2: s - 140 or higher, d - 90 or higher
hypertensive crisis: s - higher than 180, d - higher than 120

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4
Q

Type of HTN

A

systolic and diastolic HTN
isolated diastolic HTN
isolated systolic HTN

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5
Q

Identify risk factors for HTN and diseases linked with HTN

A

risk factors: diet (high salt intake and low potassium intake), race, advancing age, obesity, excess alcohol consumption, physical inactivity, family h/o HTN, DM, stress, reduced # of nephrons; hyperlipidemia, diabetic nephropathy
diseases: pheochromocytoma, chronic renal disease, primary aldosteronism, renovascular, coarctation of the aorta, cushing syndrome

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6
Q

Age

A

increases with age, > 50yo and SBP > 140 mmHg = high risk for CV disease

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7
Q

Sex

A

<55yr more common in men
>55yr more common in women

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8
Q

Genetic factors

A

have a family history of HTN

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9
Q

Race

A

more common in african americans

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10
Q

Strategies for reducing risk of HTN

A

lifestyle: diet + exercise - weight loss, salt reduction, exercise, reduct alcohol consumption, cease cigarette smoking
pharmacotherapy strategies: reduce systolic BP, reduce cardiac output, reduce vascular resistance
typically initiate lifestyle changes before pharmacological interventions

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11
Q

Lifestyle modifications to reduce BP

A

lose weight if overweight and adopt DASH diet - both are comparable to pharmacologic treatment
increased physical activity, dietary sodium reduction, moderate alcohol consumption
effect of single drug therapy on SBP: 8-14 mmHg

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12
Q

End mechanism of HTN

A

increase TPR; vascular disease

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13
Q

HTN treatment challenges

A

non-compliance - requires continual, daily drug tx; many anti-hypertensive drugs have undesirable side effects including ED in men, general sexual dysfunction and serious CNS effects

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14
Q

Predict a baroreceptor reflex when presented with an event that changes BP or CO

A

BP = cardiac output x total peripheral vascular resistance
CO = cardiac stroke volume x heart rate
SV is determined by cardiac contractility, venous return to the heart (preload), resistance the left ventricle must overcome to eject blood into aorta (afterload)

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15
Q

Baroreceptor reflex

A

decrease in BP: activated sympathetic fibers that feed back and innervate the heart (beta1), increase heart rate - reflex tachycardia; innervate blood vessels (alpha1) - vasoconstriction; inhibits vagus (PSNS) –> net result: increase BP
increase in BP: inhibits sympathetic fibers; activates vagus (PSNS), decrease HR - reflex bradycardia, no direct effects on blood vessels –> net result: decrease BP

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16
Q

Identify organs that are sites of action for antihypertensive agents, and which organs are at risk for damage due to HTN

A

sites of action: heart, kidney
at risk for damage: eyes (vision loss); brain (stroke); kidney (kidney disease/failure); heart (heart failure, coronary artery disease, angina/ischemia, MI)

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17
Q

Link receptors that are part of the sympathetic nervous system with their locations and mechanisms of action for controlling BP

A

dopamine at dopamine receptors cause vasodilation
phenylephrine at alpha receptors cause vasoconstriction, decrease HR
epinephrine at alpha receptor causes vasoconstriction, at beta2 receptor causes vasodilation
isoproterenol at beta receptors cause vasodilation

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18
Q

Neuron types in the ANS

A

parasympathetic: acetylcholine (endogenous), muscarin and nicotine (exogenous) - cholinergic
sympathetic: main focus for BP; norepinephrine and epinephrine (endogenous) - adrenergic

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19
Q

Adrenoceptors

A

norepinephrine and epinephrine receptors - alpha, alpa1 and alpha2, and beta, beta1, beta2, and beta3
main focus for BP control

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20
Q

Adrenergic receptors

A

alpha 1: Gq-coupled
alpha 2: Gi-coupled
beta: Gs-coupled

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21
Q

epinephrine affects

A

beta1, beta2 > alpha1, alpha2
beta 1: cardiac stimulation (innervated)
beta 2: cardiac stimulation, vasodilation (uninnervated)
alpha 1: vasoconstriction (innervated)
alpha 2: vasoconstriction (uninnervated)

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22
Q

norepinephrine affects

A

alpha1, alpha2, beta1
alpha 1: vasoconstriction (innervated)
alpha 2: vasoconstriction (uninnervated)
beta 1: cardiac stimulation (innervated)

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23
Q

vascular smooth muscle adrenergic receptor distribution

A

alpha1: +++
alpha2: none
beta1: none
beta2: ++

24
Q

Targets for antihypertensive drugs

A

heart –> reduce CO, both sympathetic and parasympathetic nervous systems
resistance of arterioles
resistance of veins
kidney: reduce fluids, reduce blood volume

25
Q

Adrenergic receptor subtypes - alpha1

A

signal via Gq pathway: mobilize Ca2+ from intracellular stores
found on: vascular smooth, genitourinary smooth muscle, intestinal smooth muscle, heart, liver
mediates vasoconstriction

26
Q

alpha1 antagonist

A

undergo extensive metabolism, excreted mainly in bile
vasodilators
relaxation of smooth muscle in enlarged prostate and in bladder base
ex. prazosin, terazosin, doxazosin
contain quinazoline ring and piperazine ring
quinazolines produce peripheral vasodilation w/o causing reflex tachycardia or increased cardiac output
SE: first-dose phenomenon, postural hypotension and syncope

27
Q

Prazosin + terazosin

A

Action: a1 antagonism in arterioles and venules
* Effect: decrease total peripheral resistance with less reflex tachycardia than
nonselective antagonist (phentolamine)
* Compensatory Effects: reflex tachycardia, renin release (co-administer diuretic to
decrease retention of salt and water)
Clinical Use:
Benign prostatic hyperplasia (BPH), HTN (not first-line)
Reynaud’s disease (numbness due to cold or stress producing vasoconstriction in hands/feet)
Problems:
Minor
“First dose phenomenon” – orthostatic hypotension and syncope particularly with first dose (most common with the prazosin but can also occur with other alpha1 adrenergic antagonists).

28
Q

Comparing alpha1 vs. non-selective alpha blockers

A

alpha1: no tachycardia
non-selective: reflex tachycardia

29
Q

Adrenergic receptor subtypes-alpha2

A

Signals through Gi
Inhibit adenylyl cyclase Activate certain K+ channels Inhibit neuronal Ca++ channels
Found pre-synaptically and function as autoreceptors to inhibit sympathetic output
Results in decreased transmitter release
Clinically manipulated for
Agonist
Hypertension Pain Glaucoma

30
Q

Direct acting adrenergic receptor agonists: alpha2 receptors

A

inhibit sympathetic signal
reduce BP by reducing sympathetic output from the brain
inhibition of NE release; decreased sympathetic tone in CNS: decreases HR, contractility, renin release, and vasoconstriction
clonidine, methyldopa, guanabenz, guanfacine, brimonidine, apraclonidine, tizanidine

31
Q

Clonidine

A

(Phenylimino)imidazolidine - direct centrally-acting imidazolidines; Selective a2 receptor agonist (also
imidazoline receptor) - inhibit NE release, decrease sympathetic outflow and lower BP
activation of a2 receptors in CNS (decrease SNS activity) and presynapes
The basicity of the guanidine group pKa = 13.6 is decreased to pKa = 8.0 because the dichlorophenyl ring (now can get into CNS)
t1⁄2 8-12 hr
pKa ~8.0 *
Good lipophilicity;
Administration: Oral, parenteral, transdermal
* Uses: Hypertension, opiate withdrawal , ADHD
* Side effects: hypotension, sedation, dry mouth

32
Q

Guanabenz and Guanfacine

A

Open-ring” imidazolidines
Two atom bridge to the guanidine group decreases the pKa so that the drug is mostly non-ionized at physiological pH
Guanabenz has the shortest t-1/2 at ~ 6 hours. Half-life of clonidine and guanfacine is 12-16 hours
Administration: oral
Uses: Hypertension, ADHD (guanfacine)

33
Q

Methyldopa

A

Methyldopa (Aldomet): A prodrug metabolized to active a2 receptor agonist, (1R, 2S)-a- methylnorepinephrine
Act at CNS a2 receptors to decrease sympathetic outflow
Water soluble, ester hydrochloride salt Methyldopate is used for parenteral solutions
Administration: Methyldopa, oral; Methyldopate; parenteral
Uses: Hypertension (especially during pregnancy)
methyldopate –> (esterases) to methyldopa –> (L-aromatic amino acid decarboxylase) to alpha-methyldopamine –> (dopamine beta-hydroxylase) to (1R,2S alpha methylnorepinephrine

34
Q

Clonidine, methyldopa

A

Action: central a2 agonist reducing sympathetic outflow from vasomotor centers of brainstem
* Clonidine: a2 agonism reducing sympathetic outflow from vasomotor
centers of brainstem
* Methyldopa: “false” transmitter: displaces NE from vesicle, converted
to a-methylNE which is a2 agonist
* Effect: decrease total peripheral resistance, decrease heart rate
(more consistent with clonidine), reduce renin activity

35
Q

Adrenergic receptor subtypes: beta1, beta2, beta3

A

signal through Gs
activate adenylyl cyclase
increase cAMP leading to protein kinase activation
results in phosphorylation of ion channels and other proteins

36
Q

Beta blockers (beta-adrenergic receptor antagonists) cardiovascular indications

A

ANGINA
Reduction in myocardial oxygen demand due to decreased heart rate and contractility
CARDIAC ARRHYTHMIA
Slow AV nodal conduction
POST-MYOCARDIAL INFARCTION
Reduction in myocardial oxygen demand Slow AV nodal conduction
HYPERTENSION
Decrease cardiac output Inhibition of renin secretion
CONGESTIVE HEART FAILURE
Decreases chronic overstimulation/toxicity of compensatory catecholamines

37
Q

Beta-adrenergic receptor antagonists structure

A

aryloxypropanolamines
aromatic ring structure and a bulkly alkyl group

38
Q

Non-selective beta-adrenergic receptor antagonists properties

A

Non-selective (at beta1 and beta2)
Lipophilic
Extensive hepatic metabolism, “first-pass”
Local anesthetic properties
Blockade is activity- dependent
ex. propranolol

39
Q

Beta-adrenergic receptor antagonists pharmacological effects

A

Decreased cardiac output and heart rate
 Reduced renin release
 Increase VLDL, Decrease HDL
 Inhibit lipolysis
 Inhibit compensatory glycogenolysis and glucose release in response to hypoglycemia
 Increase bronchial airway resistance
therapeutic uses for beta-adrenergic receptor antagonists: Hypertension, angina, cardiac arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, congestive heart failure (types II and III)

40
Q

Non-selective beta-adrenergic receptor antagonist: Nadolol

A

Less lipophilic than propranolol
 Long half-life: ~20 hours
 Mostly excreted unchanged in urine
 Administered: Oral
 Uses: Hypertension, angina,
migraine

41
Q

Non-selective beta-adrenergic receptor antagonist: timolol

A

Thiadiazole nucleus with morpholine ring
 Administered: Oral, Ophthalmic
 Uses: glaucoma, hypertension,
angina, migraine

42
Q

Non-selective beta-adrenergic receptor antagonist: pindolol

A

Possesses “Intrinsic sympathomimetic activity (ISA)
 Partial agonist
 Less likely to cause bradycardia
and lipid abnormalities
 Good for patients who have severe bradycardia or little cardiac reserve
 Administered: Oral
 Uses: Hypertension, angina, migraine

43
Q

Non-selective beta-adrenergic receptor antagonist: carteolol

A

 Possesses “Intrinsic sympathomimetic activity (ISA)
 Partial agonist
 Less likely to cause bradycardia
and lipid abnormalities
 Administered: Oral, Opththalmic
 Uses: Hypertension, glaucoma

44
Q

Selective beta1-adrenergic receptor antagonists structure

A

main diff b/w selective and nonselective: aromatic ring, para substituted
para-substituted phenyl derivatives
 “Cardioselective”
 Less bronchconstriction
 Moderate lipophilicity
 Half-life: 3-4 hours
 Significant first-pass metabolism  Administered: Oral, parenteral
 Uses: Hypertension, angina, antiarrhythmic, congestive heart failure

45
Q

Beta1 selective antagonist: metoprolol

A

selective antagonist at beta1 receptor
problems: minor but rebound HTN if discontinued abruptly

46
Q

Selective beta1-adrenergic receptor antagonists:

A

“Cardioselective”
 Less bronchconstriction
 Low lipophilicity, “Water-soluble Metoprolol”
 Half-life: 6-9 hours; has more hydrophilicity, metabolism slower, half-life longer
Administered: Oral, parenteral
 Uses: Hypertension, angina

47
Q

Selective beta1-adrenergic receptor antagonists: esmolol

A

Very short acting; ester easily hydrolyzed by esterases
 Half-life: 9 minutes
 Rapid hydrolysis by esterases found in red blood cells
 Administered: Parenteral
Note: incompatible with sodium bicarbonate
 Uses: Supraventricular tachycardia, atrial fibrillation/flutter, perioperative hypertension

48
Q

3rd generation beta1-adrenergic receptor antagonists: properties

A

ex. nebivolol
beta 1 selective
low lipid solubility
vasodilation due to NO production
HTN

49
Q

SEs & contraindications of beta-blockers

A

SEs: Bradycardia, AV block, sedation, mask symptoms
of hypoglycemia, withdrawal syndrome
Contraindications: Asthma, COPD, congestive heart failure (Type IV)

50
Q

Mixed adrenergic receptor antagonists: labetalol

A

Non-selective beta receptor antagonist
alpha1 receptor antagonist
Two asymmetric carbons (1 and 1’)
(1R, 1’R)-isomer possesses beta-blocking activity
(1S, 1’R)-isomer possesses greatest alpha1 receptor blocking activity
beta-blocking activity prevents reflex tachycardia normally associated with alpha1receptor antagonists
Administered: Oral, parenteral
Uses: Hypertension, hypertensive crisis

51
Q

Mixed adrenergic receptor antagonists: carvedilol

A

Non-selective b receptor antagonist
 a1 receptor antagonist
 Both enantiomers antagonize a1 receptors
 Only (S)-enantiomer possesses b- blocking activity
b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists
 Administered: Oral
 Uses: Hypertension, congestive heart failure

52
Q

Effects of carvedilol and labetolol

A

decrease total peripheral resistance via decreasing a-mediated
vasoconstriction resulting in lower blood pressure; prevent reflex tachycardia

53
Q

Dopamine receptor agonist: fenoldopam

A

Action: agonist at dopamine-1 receptor– does not activate alpha1 or beta receptors Clinical Use:
* Severe hypertension
Problems: should not be used in patients with glaucoma due to increases in intraocular pressure
Of Note: maintains or increases renal perfusion while lowering blood pressure; particularly useful in patients with renal impairment

54
Q

Indirect acting sympatholytics

A
  • Metyrosine: inhibits synthesis of catecholamines
  • Reserpine: depletes monoamines
  • (Guanethedine: chemical sympathectomy)
55
Q

Catecholamine synthetic pathway: inhibiting with metyrosine

A

action: inhibits tyrosine hydroxylase, depletes catecholamines everywhere
use: perioperative mangement of pheochromocytoma
problems: depletes catecholamines everywhere

56
Q

VMAT inhibitor reserpine

A

Action:
* Nonselective, irreversible inhibitor of Vesicular Monoamine Transporter (VMAT)
* Depletes stored NE
* Slow onset of action
* Sustained effect (weeks)
Clinical Use:
* Hypertension but rarely used because of adverse
effects
Problems:
* Peripheral adverse effects (orthostatic hypotension, increased GI activity)
* CNS effects such as sedation, severe depression and suicide in susceptible individuals

PHRM 844 Module #2 (23 decks)

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