Introd CV Pharmacol Flashcards
what are drugs and endogenous mediators - key ones to consider?
a) Neuro-Sympathetic: Methoxamine > Norepinephrine > Epinephrine> Isoproterenol
a1 Activation > a1, a2, b1 > a1, a2, b1, b2 > b1, b2, b3
b) Endocrine : Renin - Angiotensin II –Aldosterone (RAS), Vasopressin (ADH), ANP
c) Paracrine: Endothelial Mediators - Nitric Oxide (NO), Endothelin-1 (ET-1)
d) Local Control: Besides Autacoids Myogenic tone, metabolic factors- Lactic acid, pH.
what is the importance of control (regulatory) systems?
First column is norepinephrine. It is a vasoconstrictor and so there is increase in blood pressure, there is then a decrease in heart rate. Profound effect on blood vessel.
Second column – epinephrine will increase blood pressure and increase heart rate. Beta receptors in blood vessels will not be effected as much. Diastolic decreases. Systolic increases.
Diastolic decreases in the third one. Increase in heart rate, slight fall in blood pressure but profound decrease in peripheral resistance.
Fig. #1. Effect of methoxamine on a patient
with a supraventricular tachycardia.
Note that methoxamine converts the
tachycardia to normal sinus rhythm.
Fig. #2. Effect of an intravenous infusion of Norepinephrine,
Epinephrine and Isoprenaline in man. Note that while
noradrenaline activates ß1-adrenergic receptors in the heart directly, the overall effect of norepinephrine is a decrease in HR via baroreceptor relex following increase in BP due its predominant vascular a adrenergic Receptor activation
(from the Pharmacological Basis of Therapeutics,
ed. by Goodman and Gilman).
what is a good conclusion from the graph slide?
Conclusion from the last slide
√ The regulatory systems of the circulation modify the direct effects of drugs.
√ The net effect of a drug will be the summation of its direct effect and the secondary compensatory adjustments by the systems that regulate the circulation.
√ Agents that increase BP usually cause a baro-reflexively mediated decrease in heart rate [HR] (eg. methoxamine, phenylephrine, noradrenaline).
what is the relationship between blood pressure (BP), cardiac output (CO), and total peripher resistance (TPR) ?
α1 selective agonists - Methoxamine or Phenylephrine
Causes Vasoconstriction - increase TPR, BP & increase Afterload,
Venoconstriction – increase Venous Return & increase Preload while
Nitroglycerin, Vaso/Venodilator: decrease Afterload decrease Prelaod
Everytime the heart contracts is stroke volume. Cardiac output = heart rate x stroke volume. TPR is mainly in the resistance arterioles, like the smaller blood vessels in the periphery, if there is difficulty contracting the heart because of the right side, increase in sympathetic resistance this will icnrease blood pressure.
what are the determinants of blood pressure?
Pressure anywhere in the circulation is a function of the properties (capacity, compliance, elasticity) of the compartment and the volume of blood contained within it.
The volume of blood contained within a compartment depends on the rate of flow into it to the rate at which blood flows out of it.
Consider Fig. #3 and the blood pressure in the major arteries.
The rate of flow into the major arteries is the Cardiac Output (CO) – (the total flow pumped by the heart/min = SV x HR) and the rate at which blood leaves the major arteries is determined by the Total Peripheral Resistance (TPR) which is the summation of all the resistances in the circulation. i.e. BP = CO x TPR Thus, a drug may increase blood pressure (BP) either by increasing CO (SV x HR) or by causing vasoconstriction (Increase TPR) at the level of resistant arterioles. The normal BP (120/80 mmHg) is maintained by Neural (sympathetic tone), Endocrine (RAS, Vasopressin, ANP), Paracrine and Autocrine factors.
what are determinates of total peripheral resistance?
Flow through a vascular bed is equal to the pressure difference across the bed (Pa - Pv) divided by the Resistance (R) to flow or
F = (Pa – Pv)/R “Blood FLOW is INVERSELY Related to R or the TPR”
Resistance to flow is determined by the lumen of the vessel, as resistance is inversely related and Total peripheral resistance (TPR) is the summation of all the resistances in the circulation.
Consider the effect of a vasoconstrictor drug (eg Phenylephrine). What effect will it have on blood flow and blood pressure? decrease BF, increase TPR and increase BP - Use Fig. #3 to visualize the changes.
Consider the effect of a arteriolar vasodilator drug (eg. Hydralazine). What effect will it have on blood flow and blood pressure? Hydralazine Increase BF, Decrease TPR and decrease BP. Use Fig. #3 to visualize.
√ Because BP is controlled over a narrow range, a change in blood flow by a drug is largely due to a change in the resistance of the vasculature or due to changes in lumen size of the arterioles. Resistance in the arterioles determines the effect on overall TPR & BP.
√ A arteriolar constrictor drug will decrease blood flow and increase TPR and BP while an arteriolar dilator drug will increase blood flow and decrease TPR and decrease BP .
√ Nitroglycerin Relieves acute angina by acting as a Venodilator - Reducing the Venous Return to the heart – decreasing the extra load/demand on the heart and it relieves cardiac ischemia (angina).
what is a good conclusion slide to total peripheral resistance?
Conclusion
√ In the healthy patient under resting conditions or under mild exercise, the cardiac output is largely determined by the venous return, not by changes in heart rate or cardiac contractility.
√ venous return is a determined in part by the total peripheral resistance. Thus, an arteriolar constrictor will decrease venous return and therefore cardiac output, while an arteriolar dilator drug will increase venous return and therefore cardiac output (CO).
Role of cardiac function CO = HR * SV (stroke Volume)
Thus, in a healthy individual CO is largely determined by the Venous Return.
what are the effects of isoproterenol and adrenaline on BP, TPR, and CO?
Fig. #4a.
Effect of Isoproterenol on contractile force, BP, aortic flow (CO) and HR before and after Propranolol. (Lab. evaluation of antianginal agents- MM. Winbury).
b-blocker, Propranolol, blocks all the actions of non-selective b agonist – Isoprenaline.
Fig #4b.
Effect of Adrenaline (Epinephrine) on contractile force, BP, Aortic flow CO and HR before and after Propranolol. Note: BP greatly increases after propranolol Admin. due to a-R mediated vasoconstriction that is not blocked by Propranolol. decrease CO is due to normalization of HR & Cardiac contractility by Propranolol.
Because of the alpha 1 effect you see the increase in arterial pressure for adrenaline.
what is the nervous sytems control mechanism of the circulatoin?
A. Remote (Extrinsic) Control Systems
These systems regulate BP and Blood Volume.
Nervous systems
The heart is innervated by both Sympathetic (SNS) and Parasympathetic (PNS), the limbs of the autonomic nervous system (ANS), while all the blood vessels are innervated primarily by the SNS.
Review the baroreceptor reflex using Fig. # 5 shown in the next slide.
what is the baroreceptor reflex?
Fig. #5. Proposed Pathway of the Baroreceptor Reflex Arc. Primary afferent fibers from the carotid sinus/body and cardiac receptors travel on the IXth and Xth cranial nerves terminating in the nucleus of the tractus solitarius (NTS).
When BP falls, afferent impulse to the CNS increase sympathetic drive to enhance HR and cardiac performance to compensate. Similarly, when the BP increases, sympathetic drive is reduced resulting in immediate fall in HR. (from The Brain and Hypertension; Reflections on 35 Years of Inquiry into the Neurobiology of the Circulation, Donald J. Reis, Circulation 70 (Suppl III), 31-45, 1984, with permission.)
Activation of the SNS induces the following responses…
Release of Norepinephrine from Sympathetic Nerve Ending leads to:
1. Vasoconstriction of resistance type arterioles – Direct Effect
(a-1 R mediated increase in TPR, increase BP and increase After Load on Heart)
2. Reabsorption of tissue fluid as a result of a
decrease in capillary pressure
3. increase Venoconstriction- Cap. Vessels (increase Ven.Return, increase Preload)
4. Release of Renin and Increase in Renin- Angiotensin II-
Aldosterone activity (Indirect -increase blood volume, increase plasma Na+)
5. Increase in HR and Cardiac Contractility (b adrenergic effect).
Note: Increased Sympathetic Drive leads to increased activation of
b1 receptor mediated Renin Release from the Renal Juxta Glomerular Cells that promotes Angiotensin II (Ang II) generation (another potent endogenous vasoconstrictor). Ang II also stimulates Aldosterone Release from the Adrenal Cortex to promote increased blood volume and elevated plasma Na+. increase Vasoconstriction, increase Blood Volume, increase Plasma Na+ leads to elevated BP – cause for Hypertension.
what does angiotensin II do?
increases vasoconstriction and vascular remodeling
for humoral systems what is the RAAS ?
a) Renin-Angiotensin-Aldosterone System (RAAS)
Fig. #6 shows Factors regulating the Release of Renin.
In Physiological Condition, when BP, Blood Volume, plasma Na+ FALL, there is increase Renal
Sympathetic Drive that leads to b1-R mediated RENIN Release increase Ang II-ALDO to increase BP.
In pathological state, there is
chronic increase Sympathetic Drive,
increase Renin, increase Ang II leading to
Elevated BP – Essential HT.
where is ACE found and what does it do/?
Angiotensin-converting enzyme, converts angiotensin I to angiotensin II.
Angiotensin II stimulates the adrenal cortex to produce aldosterone which stimulates the kidney to retain sodium and water and to increase the extracellular fluid which leads to increased blood pressure.
Angiotensin II can also directly effect arterioles
aldosterone can also lead to hypokalemia angiotensin II can lead to release of vasopressin which causes water to be reabsorbed. vasopressin can also lead to vasoconstriction.
what are the major effects of the ACE inhibitors?
Fig #7. Major actions of the RAAS system (Pharmacology: Lippincott’s Illustrated Review) XX
Ang II Converting Enzyme (ACE) Inhibitors decrease Renin-induced Ang II formation. This leads to decreased Aldosterone Release from the Adrenal Cortex leading to reduced blood volume and plasma Na+. Ang II-evoked sympathetic activation, Ang II-induced vasoconstriction are reduced. The metabolism (breakdown) of Bradykinin, a vasodilator, is reduced. Bradykinin levels increase. ACE Inhibitors : decrease Ang II decrease aldosterone, increased BK Levels, all these ensure fall in TPR and great decrease in BP–classical effects of ACE Inhibitor therapy.
