ANS Control of Blood Pressure Flashcards
Define hypertension and distinguish primary from secondary HTN
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
Causes of secondary HTN
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
Classifying hypertension
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
Type of HTN
systolic and diastolic HTN
isolated diastolic HTN
isolated systolic HTN
Identify risk factors for HTN and diseases linked with HTN
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
Age
increases with age, > 50yo and SBP > 140 mmHg = high risk for CV disease
Sex
<55yr more common in men
>55yr more common in women
Genetic factors
have a family history of HTN
Race
more common in african americans
Strategies for reducing risk of HTN
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
Lifestyle modifications to reduce BP
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
End mechanism of HTN
increase TPR; vascular disease
HTN treatment challenges
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
Predict a baroreceptor reflex when presented with an event that changes BP or CO
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)
Baroreceptor reflex
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
Identify organs that are sites of action for antihypertensive agents, and which organs are at risk for damage due to HTN
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)
Link receptors that are part of the sympathetic nervous system with their locations and mechanisms of action for controlling BP
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
Neuron types in the ANS
parasympathetic: acetylcholine (endogenous), muscarin and nicotine (exogenous) - cholinergic
sympathetic: main focus for BP; norepinephrine and epinephrine (endogenous) - adrenergic
Adrenoceptors
norepinephrine and epinephrine receptors - alpha, alpa1 and alpha2, and beta, beta1, beta2, and beta3
main focus for BP control
Adrenergic receptors
alpha 1: Gq-coupled
alpha 2: Gi-coupled
beta: Gs-coupled
epinephrine affects
beta1, beta2 > alpha1, alpha2
beta 1: cardiac stimulation (innervated)
beta 2: cardiac stimulation, vasodilation (uninnervated)
alpha 1: vasoconstriction (innervated)
alpha 2: vasoconstriction (uninnervated)
norepinephrine affects
alpha1, alpha2, beta1
alpha 1: vasoconstriction (innervated)
alpha 2: vasoconstriction (uninnervated)
beta 1: cardiac stimulation (innervated)
vascular smooth muscle adrenergic receptor distribution
alpha1: +++
alpha2: none
beta1: none
beta2: ++
Targets for antihypertensive drugs
heart –> reduce CO, both sympathetic and parasympathetic nervous systems
resistance of arterioles
resistance of veins
kidney: reduce fluids, reduce blood volume
Adrenergic receptor subtypes - alpha1
signal via Gq pathway: mobilize Ca2+ from intracellular stores
found on: vascular smooth, genitourinary smooth muscle, intestinal smooth muscle, heart, liver
mediates vasoconstriction
alpha1 antagonist
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
Prazosin + terazosin
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).
Comparing alpha1 vs. non-selective alpha blockers
alpha1: no tachycardia
non-selective: reflex tachycardia
Adrenergic receptor subtypes-alpha2
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
Direct acting adrenergic receptor agonists: alpha2 receptors
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
Clonidine
(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
Guanabenz and Guanfacine
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)
Methyldopa
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
Clonidine, methyldopa
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
Adrenergic receptor subtypes: beta1, beta2, beta3
signal through Gs
activate adenylyl cyclase
increase cAMP leading to protein kinase activation
results in phosphorylation of ion channels and other proteins
Beta blockers (beta-adrenergic receptor antagonists) cardiovascular indications
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
Beta-adrenergic receptor antagonists structure
aryloxypropanolamines
aromatic ring structure and a bulkly alkyl group
Non-selective beta-adrenergic receptor antagonists properties
Non-selective (at beta1 and beta2)
Lipophilic
Extensive hepatic metabolism, “first-pass”
Local anesthetic properties
Blockade is activity- dependent
ex. propranolol
Beta-adrenergic receptor antagonists pharmacological effects
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)
Non-selective beta-adrenergic receptor antagonist: Nadolol
Less lipophilic than propranolol
Long half-life: ~20 hours
Mostly excreted unchanged in urine
Administered: Oral
Uses: Hypertension, angina,
migraine
Non-selective beta-adrenergic receptor antagonist: timolol
Thiadiazole nucleus with morpholine ring
Administered: Oral, Ophthalmic
Uses: glaucoma, hypertension,
angina, migraine
Non-selective beta-adrenergic receptor antagonist: pindolol
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
Non-selective beta-adrenergic receptor antagonist: carteolol
Possesses “Intrinsic sympathomimetic activity (ISA)
Partial agonist
Less likely to cause bradycardia
and lipid abnormalities
Administered: Oral, Opththalmic
Uses: Hypertension, glaucoma
Selective beta1-adrenergic receptor antagonists structure
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
Beta1 selective antagonist: metoprolol
selective antagonist at beta1 receptor
problems: minor but rebound HTN if discontinued abruptly
Selective beta1-adrenergic receptor antagonists:
“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
Selective beta1-adrenergic receptor antagonists: esmolol
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
3rd generation beta1-adrenergic receptor antagonists: properties
ex. nebivolol
beta 1 selective
low lipid solubility
vasodilation due to NO production
HTN
SEs & contraindications of beta-blockers
SEs: Bradycardia, AV block, sedation, mask symptoms
of hypoglycemia, withdrawal syndrome
Contraindications: Asthma, COPD, congestive heart failure (Type IV)
Mixed adrenergic receptor antagonists: labetalol
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
Mixed adrenergic receptor antagonists: carvedilol
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
Effects of carvedilol and labetolol
decrease total peripheral resistance via decreasing a-mediated
vasoconstriction resulting in lower blood pressure; prevent reflex tachycardia
Dopamine receptor agonist: fenoldopam
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
Indirect acting sympatholytics
- Metyrosine: inhibits synthesis of catecholamines
- Reserpine: depletes monoamines
- (Guanethedine: chemical sympathectomy)
Catecholamine synthetic pathway: inhibiting with metyrosine
action: inhibits tyrosine hydroxylase, depletes catecholamines everywhere
use: perioperative mangement of pheochromocytoma
problems: depletes catecholamines everywhere
VMAT inhibitor reserpine
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
