Cv Pharm Peripheral Resistance I-Iii

Front 1

What are the functions of the peripheral vasculature?

Back 1

1. To supply local metabolic needs of the organs they perfuse
2. To regulate certain body functions such as body temperature (cutaneous vessels) and filtration of waste (renal vessels)
3. To regulate arterial blood pressure and to maintain circulating blood volume appropriate to the available blood volume (homeostasis)

Front 2

Describe neural (sympathetic) vs. local control of various vascular beds

Back 2

a. Sympathetic activation causes prompt vasoconstriction in some vascular beds (e.g., cutaneous, splanchnic) but has very little effect on some other beds (e.g., cerebral, coronary). Blood flow of the latter are predominantly controlled by "local" factors
b. Examples of some of the local factors
i. Cerebral- CO2 tension
ii. Coronary- hypoxia
iii. Skeletal muscle- lactate and other metabolites

Front 3

Describe the vascular tone of various vascular beds

Back 3

a. Neurogenic (sympathetic) tone
Vascular beds actively controlled by the sympathetic nervous system have "high" neurogenic tone. Sympathectomy will result in pronounced vasodilation.
b. Myogenic (basal) tone
This refers to an inherent myogenic activity of the vascular smooth muscle and can be represented by the residual degree of contraction of the resistance vessels in a denervated bed. Vascular beds which are predominantly under local control have "high" basal tone. Removal of sympathetic innervation has very little effect on blood flow.
c. Role of shear stress and autoregulation

Front 4

Describe active vascular beds

Back 4

Active vascular beds have high basal tone, low sympathetic tone and are autoregulated, i.e., local mechanisms are present to maintain a constant blood flow when the perfusion pressure (arterial blood pressure) changes

Front 5

Describe passive vascular beds

Back 5

Passive vascular beds have low basal tone and high sympathetic tone. They are not autoregulated.
Examples: cutaneous, splenic, pulmonary

Front 6

Describe how the functions of various vascular segments differ

Back 6

a. Arterial - Control of resistance and blood flow distribution
b. Capillary - Interchange of water, electrolytes, and dissolved substanced between blood and tissues, via filtration and diffusion
c. Venous - Control of capacitance and circulating volume

Front 7

What is the result in vasculature of sympathetic activation?

Back 7

The sympathetic system innervates both arterial and venous beds. Sympathetic activation results in arteriolar constriction (increase in pressure) and ventricular constriction (increase in venous return to the heart)

Front 8

Describe how drugs affect vasculature

Back 8

May affect primarily the arterial vessels, or both arteries and veins, or both groups and the capillaries as well (to increase permeability). Drug effects on veins have been less well studied than those of arteries

Front 9

Describe the pulmonary circulation

Back 9

-A low pressure circuit
-Usually considered as being comprised of capacitance vessels.
-Pulmonary beds often react very differently fromt the systemic vascular beds
a. Physiological stimuli such as hypoxia (alveolar), CO2 and acidosis, all of which dilate systemic vessels, cause pulmonary vasoconstriction
b. Most peripheral vasodilators (5-HT, histamine, ACh, and ATP) cause pulmonary vasoconstriction. 5-HT and histamine are the most potent pulmonary vasoconstrictors

Front 10

Describe how drugs directly act on vasculature

Back 10

-Through a direct action on the vascular smooth muscle. Relaxation of vascular smooth muscle often results from an increase in cystolic cyclic AMP or cyclic GMP concentration
-Through an action on the vascular smooth muscle via specific receptors (e.g. alpha- or beta-adrenergic, muscarinic, histaminergic, etc.)

Front 11

Describe how drugs indirectly act on vasculature

Back 11

a. They can modify sympathetic nervous system function
b. They may affect the baroreceptor reflexes which bring about changes in autonomic nervous activity to the heart and blood vessels
c. They may modify cardiac function (changes in heart rate and/or contractile force). Most "vasoactive" drugs also have direct actions on the heart
d. Vasodilation by some drugs is achieved through liberation of an endothelium derived relaxing factor (EDRF), e.g., acetylcholine, bradykinin.
e. May affect NO levels. NO is a reactive free radical that acts as an IC or EC regulatory substance

Front 12

What are the uses of drugs that affect peripheral resistance?

Back 12

-Congestive heart failure
-Hypertension
-Anti-ischemic vasodilators

Front 13

For what do you use drugs that are decrease peripheral resistance?

Back 13

They are used to treat elevated BP and heart failure

Front 14

What types of drugs decrease peripheral resistance?

Back 14

-Sympatholytics: Drugs which modify the efferent sympathetic nervous system. The site of action can be at the CNS, the baroreceptor, the sympathetic ganglia, the adrenergic terminals or the adrenergic receptors (alpha and beta)

-Vasodilators: Drugs which act directly to relax vascular smooth muscle

-Saluretics: Drugs which lower the body's store of sodium

-Angiotensine converting enzyme inhibitors (ACE inhibitors): Drugs which lower the plasma renin activity (PRA) or angiotensin activity

-Angiotensin II (AII) receptor blockers

Front 15

What classes of drugs have been used as sympatholytics?

Back 15

-Drugs that act on the CNS to decrease sympathetic outflow (alpha methyldopa, clonidine)
-Drugs that sensitize baroreceptors (veriloid)
-Drugs that block autonomic ganglia (trimethaphan)
-Drugs that block NE release from adrenergic terminals

Front 16

What are the common side effects of sympatholytics?

Back 16

a. Those due to decreased sympathetic function:
Postural hypotension, exercise hypotension, failure of ejaculation, nasal congestion

b. Those due to increased parasympathetic effects in dually innervated organs:
Bradycardia, abdominal cramps, diarrhea, exacerbation of peptic ulcer

Front 17

Describe Alpha-methyldopa

Back 17

-Drugs acting in the CNS to decrease sympathetic outflow
-Pharmacologic activity of the drug attributed to its metabolic product, alpha-methylnorepinephrine
-The only centrally acting drug still used today as an antihypertensive drug
-Drug of choice to treat hypertension in pregnant women where there is a record of safety

Front 18

Describe the mechanism of action of Alpha-methyldopa

Back 18

i. The primary antihypertensive action of alpha-methyl-NE is considered to be on the CNS, from activation of central alpha2 receptors
ii. Alpha-methylnorepinephrine as a false transmitter of peripheral adrenergic neurons may contribute to the hypotensive action, but the signficance of this effect has been questioned
iii. Methyldopa inhibits dopa decarboxylase and tryptophan hydroxylase. These properties probably do not contribute to the drug's hypotensive action, but may very well be related to its CNS side effects.

Front 19

Describe the untoward effects of Alpha-methyldopa

Back 19

i. Sedation and drowsiness often appear but tend to decrease with time
ii. Other CNS effects (decreased mental acuity, vertigo, lactation, extrapyramidal signs and psychic depression) may occur, but are less common than with reserpine
iii. Dry mouth and nasal congestion (of central origin) are commonly seen
iv. Less orthostatic hypotension and less disturbance of male sex function when compared with those produced by guanethidine for any given reduction in BP.
v. "Allergic" reactions (e.g. drug fever).
vi. Positive Coombs' test is seen in over 20% of patients with chronic use and is dose-related. True hemolytic anemia is rare.

Front 20

Describe the effectiveness of Alpha-methyldopa

Back 20

i. Alpha-methyldopa is moderately potent and could be used in combination with other drugs, to treat patients with moderately severe hypertension
ii. Antihypertensive effect of the drug is erratic; both effectiveness and dosage vary greatly from patient to patient. This may be related to absorption of the drug. GI absorption is incomplete (~50%) and varies not only in different individuals, but in the same person from day to day
iii. Alpha-methyldopa has been shown to cause selective renal vasodilation. This is a desirable feature for patients with compromised renal function. However, in patients with severely impaired renal function, excretion can be retarded and drug may accumulate with chronic use

Front 21

Describe Prazosin

Back 21

Alpha-adrenergic antagonists

Front 22

Describe the mechanism of action for Prazosin

Back 22

a. Prazosin is a quinazoline derivative, unrelated chemically to any of the existing antihypertensive drugs
b. The principal mechanism of action has been attributed to selective blockade of alpha1-adrenergic receptors
c. The drug may have a direct vasodilator property. It is a potent phosphodiesterase inhibitor
d. The drug does not cause tachycardia, increase in CO, or increase in PRA. This is because alpha2-receptors are not affected, and thus there is no accelerated release of NE

Front 23

Describe the untoward effects of Prazosin

Back 23

a. Orthostatic hypertension, which is usually most pronounced within 90 mins of initial drug therapy, and has been referred to as "first dose" effect
b. Nasal congestion, dry mouth, etc.; secondary to alpha-blockade
c. Fluid retention in some patients

Front 24

Describe the effectiveness of Prazosin

Back 24

-Not a potent drug
-Used widely for treatment of mild hypertension because it does not greatly affect lipid metabolism
-Phentolamine competitive alpha receptor antagonist, nonselective, used for hypertensive crisis from phechromacytoma

Front 25

Describe propranolol

Back 25

-Beta-adrenergic blocking drugs
-First drug was propranolol
-Blocks both beta1 and beta2 receptors (nonselective)
-Very short plasma half-life

Front 26

What beta-adrenergic blocking drugs are approved in the USA?

Back 26

a. Propranolol - Nonselective, short duration of action
b. Timolol
c. Metoprolol-More selective in blocking beta1-receptors in low doses
d. Nadolol- Nonselective, but longer acting
e. Atenolol- Relative beta1-receptor selective, longer acting
f. Pindolol - Partial agonist
g. Acebutalol - Relative beta1-selective, partial agonist, long-acting active metabolite
h. Esmalol- used clinically for hypertensive emergencies, beta1-selective, short duration of action

Front 27

What are the cardiovascular effects of beta-receptor blockade?

Back 27

-Competitive
a) Slows sinus rate and AV condunction
b) Decreases force of contraction (negative inotropy)
c) Increases peripheral resistance (reflex)
d) Decreases BP in about 50% of hypertensives
e) Cardiac effects are more apparent under condition of increased sympathetic tone

Front 28

What are the bronchial and bronchiolar effects of beta-receptor blockade?

Back 28

-Blocks the bronchodilation mediated by beta-receptor activation
-This is most apparent in asthmatics
-The beta1-selective blockers also can precipitate asthmatic attacks at higher doses

Front 29

Describe the untoward effects of beta blockers

Back 29

a. Depressed myocardial function or even heart failure may occur in patients with compromised cardiac function who depend on sympathetic tone for maintenance of CO, esp when high doses of the drug are used
b. "Propanolol withdrawal rebound" (severe myocardial ischemia or myocardial infarction) has been reported after abrupt cessation of therapy with propanolol
c. Increase in airway resistance can occur in asthmatics, esp with nonselective members
d. Augmentation of the hypoglycemic action of insulin in diabetic
e. Fatigue, depression

Front 30

Describe the therapeutic uses of beta blockers

Back 30

a. Cardiac arrhythmias
b. Angina pectoris
c. Essential hypertension
d. Prophylaxis of migraine headache
e. Thyrotoxicosis
f. CHF - potential use

Front 31

Describe the mechanism by which beta blockers treat essential hypertension

Back 31

-Decreased plasma renin activity (PRA). However, not all "responding" patients have high PRA before therapy
-Adaptation of vascular resistance to chronic depression of CO. All patients receiving propranolol have reduced CO but only the "responders" have decreased total peripheral resistance
-Reduction of sympathetic activity, through blockade of presynaptic beta1 receptors. NE released at nerve terminals in addition to acting on postjunctional alpha1 and beta1 receptors also stimulates these presynaptic receptors to cause an increase in NE release from the terminals (positive feedback as compared to negative feedback from presynaptic alpha2 receptors. Therefore, blocking presynaptic beta receptors decreases NE release from nerve terminals.

Front 32

Describe the effectiveness of beta blockers in treating essential hypertension

Back 32

-Many now use beta blockers as the initial drug, alont, to treat mild hypertensives. Also used as an adjunct to alleviate the cardiac stimulating effects of vasodilators
-When used alone, 50% of patients experience a lowering of BP. Most of the responders have high or normal PRA before therapy. Reduction of BP is gradual (it may take weeks) and mild, but sustained. Dose requirement varies between patients
-The choice of beta blocker for monotherapy is proimarily because it produces relatively few side effects
-When beta blocker is not effective, addition of a 2nd drug (a diuretic or vasodilator) can increase success rate to about 80%
-Newer agents such as nadolol and atenolol are gaining popularity because of their longer duration of action (one dose daily)
-Selectivity for beta1 receptors of agents such as metoprolol is only significant when low doses are used

Front 33

What are the third generation beta blockers

Back 33

-Beta antagonists with additional CV effects
-Labetalol
-Carvedilol

Front 34

Describe Labetalol

Back 34

-Has both alpha- and beta-adrenergic blocking activities. Also inhibits the reuptake of NE into nerve terminals
-Blockade is alpha1-selective and beta-nonselective with bet-blocking potency 3-7 times that of its alpha-blocking potency. The drug also has intrinsic sympathomimetic activity (primarily beta2)
-Well absorbed, extensive first-pass hepatic metabolism, plasma t1/2 3-5 hrs, but the duration of action is longer
d. The drug has the combined advantages of alpha and beta blocking drugs (rapid onset of action, vasodilating properties, blunting of the rise in HR and BP in response to exertion or stress).

Front 35

Describe Carvedilol

Back 35

-Blocks beta1, beta2, alpha1 receptors; several cardiac ion channels including HERG K channels
-Inverse agonist of beta2 receptor
-Does not upregulate downregulated beta1 receptors
-Has antioxidant, and antiproliferative properties
-Used in combination but should not be considered for sole treatment of severe refractory in HF
-Longer lasting than labetalol
-Used in conditions associated with catecholamine excess such as "clonidine withdrawal", cocaine crises and patients with systolic HF