2153 IC5

Review mechanisms for regulation of vascular tone

GPCRs: beta- adrenergic receptors coupled with adenylyl cyclase that converts ATP to cAMP (adenosine monophosphate) once activated by a ligand. INCREASE in cAMP > activates PKA (protein kinase A) > activates calcium channel that enhances release of calcium > calcium + calmodulin complex formation

CARDIAC MYOCYTES, beta-1 receptors

calcium + calmodulin > phosphorylates MLC

with phospate = inactive = vasodilation

without phosphate = active = contraction

SMOOTH MUSCLES, beta-2 receptors

Calcium + calmodulin activates MLC-kinase (enzyme) to add phosphate so results in contraction of smooth muscles.

MLC with phosphate = active = SM contraction

MLC without phosphate = inactive/less myosin cross-bridges = vasodilation

• caused by INCREASE IN cAMP > activated PKA leads to inhibitition of MLCK > no phosphorylation > vasodilation

• target for beta blockers —> want to increase cAMP

nitric oxide:

• activates guanylyl cyclase > deactivate myosin

Explain Mechanism of action of ACE inhibitors (-prils)

• ACE-i targets at: RAAS, specifically the inhibiting the ACE enzyme from converting angiotensin 1 to angiotensin 2 (the active form)

  • effects ACE-i: decrease in vasoconstriction, decrease in aldosterone secretion = less water and sodium retention

  • also inhibits the degradation of BRADYKININ > activates the prostaglandins and nitric oxide > vasodilation

• ARBs target at:

clinical uses of ACE-i

1. hypertension

2. cardiac failure

3. following myocardial infarction - reduces its workload

4. renal insufficiency - reduces the aldoesterone and retention, helps the kidney!

adverse effects of ACE-i

1. severe hypotension

2. acute renal failure

3. hypokalemia

4. angioedema and dry cough (more of bradykinin and substance P will induce inflammation-like responses including vasodilation and plasma extravasation —> angioedema. also idiosyncratic action that contributes to dry cough)

5. contraindication: pregnancy

Explain MoA of beta blockers and the difference between specific and non-specific beta blockers

• targets at:

  • cardiac myocytes: inhibits the beta 1 receptors to reduce adenylyl cyclase action (reduces cAMP formation and ultimately reduces contractility = lower heart rate)

  • specific vs non specific: specific will only target the beta 1 receptors, will have less off-target effects but selectivity can be lost at higher doses

Explain MoA of calcium channel blockers

• targets at: the calcium channel, prevents binding of calcium to calmodulin

• prevents less calcium influx > prevention of calcium + calmodulin complex > inactivates MLCK > decrease contraction of smooth muscles > decrease BP > ANTI-HYPERTENSION

• less calcium influx > decrease in myocardial contractility > decrease in cardiac output and oxygen requirement > ANTI-ANGINA

• in the myocardial cell calcium is stored in the sarcoplasmic reticulum which plays a role in the actin myosin complex?

Explain MoA of thiazides

• inhibit the reabsorption of NaCl back into the body by blocking the NaCl transporter > HIGHER salt content in urine > LESS water reabsorption in the collecting duct and more water peed out > REDUCTION in blood volume

• also enhances calcium reabsorption in the DCT via apical calcium channel and basolateral Na/Ca exchanger

• can be dependent on renal PGs synthesis

can you explain the 3 types of diuretics and their targets for anti hypertension

1. loop diuretics (works at ascending limb e.g. furosemide, bumetanide)

   1. e.g. hydrochlorothiazide and indapamide

2. thiazides: works at the distal convoluted tubule, inhibit the transporter

3. potassium sparing diuretics: works at the end of the DCT and collecting duct, inhibits sodium reabsorption

factors influencing blood pressure

arterial blood pressure = cardiac output x peripheral resistance

• cardiac output affected by heart rate, contractility and filling pressure

  • filling pressure determined by blood volume (how much blood that goes into the ventricle also determines the force of contraction, ventricular muscles stretch out more) and venous tone (affects preload!!! higher venous tone = a lot of contraction to push blood back to the heart because blood goes from higher to lower pressure)

• peripheral resistance (associated with afterload which is the force against which that the heart has to pump to contract to eject blood. Arteriolar tone: high tone = low diameter, contraction)

rapid mechanism for controlling a decrease in BP

body senses a drop in BP therefore want to increase CO. increase in sympathetic activity mediated by adrenergic system - neurotransmitter noepinephrine/adrenaline.

in the heart: binds to beta 1 adrenergic receptors in cardiac myocytes = increase in cardiac output by increase in contraction

in the smooth muscles (want to increase peripheral resistance so that there would be more blood outflow to the critical organs): binding to ALPHA 1 adrenergic receptors = vasoconstriction = increase peripheral resistance

long term mechanism for controlling BP/ Review the renin-angiotensin aldosterone system (RAAS)

through the RAAS : one of the first organs to detect drop in BP is kidneys.

= decrease in GFR + kidneys secrete renin in response

1. increase in renin = converts the now activated angiotensinogen to angiotensinogen 1 which is then converted to angiotensinogen 2 = vasoconstriction and increase in aldosterone secreted by ADRENAL GLAND = increase in sodium retention = water retention = increase in blood volume = increase in BP

2. decrease in GFR = increase in sodium retention = water retention = increase in blood volume = increase in BP

mechanism of ARBs (-sartan)

• blocks the angiotensin 2 AT1 receptor itself, preventing angiotensin 2 from sending down signals to receptors and exerting its effect

• because of the MoA, there is less/no dry cough

• contraindication = pregnancy

give examples of beta blockers

specific: atenolol, bisoprolol, metoprolol (A-M except carvedilol and labetalol)

non-specific: propranalol, pindolol, carvedilol (N-Z)

mixed: nebivolol (includes vasodilation via higher NO release) - beta 1 selective in LOW doses

bolded ones can be used for heart failure

clinical uses of beta blockers

1. hypertension (heart can relax)

2. cardiac failure

3. following myocardial infarction

4. abnormal heart rhythm

5. anxiety disorders (blocks adrenaline from binding)

adverse effects of beta blockers

1. hypotension

2. bradycardia

3. AV nodal block (when anti-arrythmia works too well)

4. reduced exercise capacity

5. relative contraindication: bronchoconstriction (esp. asthmatics)

   1. for nonspecific blockers, might be blocking the beta 2 receptors at the lungs. since cAMP is blocked, MLCK not activated —> more likely to trigger bronchoconstriction , can’t be dilated so astha is more easily triggered

6. CNS: vivid dreams, clinical depression

clinical uses for calcium channel blockers

1. hypertension

2. stable angina (Amplodipine)

3. myocardial infarction and stroke prevention (amplodipine)

explain the two types of calcium channel blockers

1. Dihydropyridines (DHPs): act on peripheral blood vessels for vasodilation, less effect on the heart. Examples include amlodipine and nifedipine.

   1. good for anti-angina and anti-hypertention

2. Non-dihydropyridines (non-DHPs): more effective in heart function, . They slow down the heart rate and are used to treat arrhythmias. Examples include verapamil and diltiazem.

   1. reduce SA nodal conduction - good for atrial filibration

adverse effects of CCB

1. Hypotension

2. Heart failure

3. Myocardial infarction

adverse effects of thiazides

1. HYPOkalemic metabolic aklalosis

2. hyperuricemia

3. hyperglycemia (contraindicated with DIABETIC patinets?_

4. hyperlimidemia (???)

5. hypercalcemia (can be used to treat, but might also cause)

6. HYPOnatremia (because less sodium being absorbed)

clinical uses of thiazides

1. hypertension

2. congestive heart failure

3. nephrolithiasis due to idiopathic hypercalciuria (enhance the reabsorption of calcium to reduce formation of minerals and stones in kidney)

4. nephrogenic diabetes insipidus

what are some second line anti-hypertensives?

potassium sparing diuretics / mineralcorticoid receptor agonists, alpha-blockers and hydralazine