Antihypertensives
Pharmacology of Antihypertensive Agents: Classes
1. Agents which interfere with the Renin-Angiotensin System 2. Drugs acting on the Sympathetic Nervous System 3. Vasodilators
Clonidine Experiment
❖ Remove α₂ receptors from mice → Clonidine can't lower BP ❖ People thought this meant that I₁Rc doesn't help lower BP ❖ It actually means that the I₁Rc is involved in a signaling cascaded that also involved α₂ ➢ Binds to I₁Rc first, then binds to α₂ later
β-blockers - Possible Mechanism of antihypertensive action: Conventional Wisdom Rank
1. *They inhibit the release of renin* 2. They interrupt a positive feedback loop between vascular contraction and cardiac contractility 3. They inhibit sympathetic nerve activity (both centrally and in periphery) 4. They decrease CO ❖ Could also possibly up-regulate vascular β₂-adrenoceptors to decrease TPR
Physiologically CO and PVR are maintained minute to minute by?
1. Arterioles 2. Postcapillary venules 3. Heart 4. Kidney - volume of intravascular fluid
The 4 sites of CO/PVR maintenance are controlled by what?
1. Sympathetic innervation 2. Renin-angiotensin-aldosterone system 3. "Metabolic" factors (i.e., Ca²⁺)
Drugs Acting on the Sympathetic Nervous System
1. β-adrenoceptor (β-AR) antagonists 2. α₁-adrenoceptor (α₁-AR) antagonists 3. α₂-adrenoceptor(α₂-AR) agonists
Major Factors Controlling Blood Pressure
Almost all anti-HTN drugs lower BP by *reducing TPR* regardless of MOA. *Pick reduce TPR, that's probably the answer on the exam.*
In hypertension therapy, which makes the best sense pharmacologically as additional therapy to further reduce BP in a patient on captopril? A. Nifedipine XL B. Aliskiren C. Losartan D. Enalapril
Answer A: Nifedipine XL ❖ All other 3 affect the RAS → Don't combine drugs that affect the RAS
In hypertension therapy, which of the following is nonsense? A. Pindolol, a "β-blocker with ISA", can produce reflex tachycardia B. Clonidine may lower BP via a central effect mediated by imidazoline I1-Rc C. Propranolol may lower BP by blocking β₂ adrenoceptors on sympathetic nerve endings that increase NE release
Answer A: Pindolol, a "β-blocker with ISA", can produce reflex tachycardia ❖ Reflex tachycardia is mediated through the β receptors but you are blocking those receptors
Advantages of chronic use of an ARB instead of ACE-I for hypertension include all of the following EXCEPT: A. Side effects due to bradykinin are avoided B. Angiotensin II levels are decreased C. Angiotensin II, type 2 receptors (AT₂) are still available D. Angiotensin II production by peptidases other than ACE, is avoided.
Answer B: Angiotensin II levels are decreased
Pindolol treatment: A. Produces greater bradycardia than propranolol B. Decreases heart rate in hypertension C. Produces reflex tachycardia similar to prazosin D. Is preferential for β₁-adrenoceptors
Answer B: Decreases heart rate in hypertension
Reasons for switching a hypertensive patient from captopril to losartan include: A. To decrease levels of circulating angiotensin-II (A-II) B. To decrease side effects produced by bradykinin C. To increase the vasodilatory effect of bradykinin through the release of NO D. To downregulate the angiotensin AT1-receptors E. To prevent A-II signaling via AT₂-receptors
Answer B: To decrease side effects produced by bradykinin
In the treatment of hypertension, which of the following is least likely to cause an up-regulation of the receptors involved in its own mechanism of action: A. Reserpine B. Captopril C. Clonidine D. Aliskiren
Answer C: Clonidine ❖ Reserpine depletes catecholamines. ❖ Captopril is an ACE inhibitor → prevents formation of NT ❖ Aliskiren - direct renin inhibitor → prevents formation of NT ❖ All of these remove the agonist → Upregulation of receptors ❖ Only one that doesn't do that is Clonidine, which is an agonist → it regulates receptor downregulation. ➢ Agonists would lead to tolerance → rc downregulation ➢ Antagonists would lead to receptor desensitization → rc upregulation
The mechanism of propranolol's antihypertensive effect may include all of the below, EXCEPT: A. Inhibiting the + feedback loop where increased peripheral vasoconstriction results in increased cardiac contractility B. Antagonism of pre-junctional fascilatory ß2-adrenoceptors C. A decrease in sympathetically stimulated renin release from the kidney D. Downregulation of vascular β₂-adrenoceptors
Answer D: Downregulation of vascular β₂-adrenoceptors ❖ Blockers will never downregulate receptors ❖ Only agonists will lead to downregulation/tolerance of receptor
ACE inhibitors, lower blood pressure, and do all of the following EXCEPT: A. Block cardiac remodeling B. Enhance effects of diuretics in the proximal tubule C. Decrease aldosterone release D. Increase preload
Answer D: Increase preload
Calcium Channel Blockers
❖ Three chemically diverse classes ➢ Dihydropyridines ➢ Diphenylalkylamines ➢ Benzothiazines ❖ MOA: All these agents lower BP primarily by blocking *L-type calcium channels* (red box) and reducing arterial resistance
Vasodilators: Only _____ are 1st line
Ca²⁺ channel blockers
Other agents interfering with sympathetic neurotransmission: Guanadrel
Does not enter the central nervous system. Enters sympathetic nerves via neuronal uptake and depletes NE from nerve terminals. Results in decreased CO and TPR (important pharmacological tool but *seldom used clinically*).
Cardiovascular Response to Vasodilators
Lowers TPR but leads to increase in reflex SNS and RAS
NO Mechanism of Action
NO → inc cGMP → PKG is activated → MLC Kinase is phosphorylated and becomes inactive → no contraction → Relaxation
Other agents interfering with sympathetic neurotransmission: Guanethidine
Pharmacology similar to guanadrel.
Renin release pathway
Renin release → increases Ang I → Ang 2 → Ang 2 facilitates more NE release
The majority of drugs used in HTN therapy produce their effects by targeting the _____ and/or the _____
SNS, Renin Angiotensin System ➢ This is one of the few *positive* feedback loops in biology.
α₂ receptor agonists have a net _____ effect.
Sympatholytic (decrease in sympathetic activity)
Non-Dihydropyridine Calcium Channel Blockers: Why are these agents less likely to worsen cardiac ischemia (compared to dihydropyridines)?
They directly and indirectly reduce cardiac oxygen demand (instead of making it go up)
How do positive feedback loops tend to stop?
They simply exhaust themselves
What is the basic problem with hypertension?
The body is now convinced the elevated blood pressure is "correct." Therefore homeostatic mechanisms will attempt to reset any therapy-induced alterations in BP.
Some β-Blockers Used in Hypertension
❖ Propranolol is the prototype (1st discovered) ❖ Timolol used for glaucoma ❖ Carvedilol also used as an α₁ blocking agent but that does not affect its MOA ➢ FDA approved for CHF (Metoprolol is too) ❖ Bisoprolol: Most potent β₁ preferential ➢ EMEA (Europe) approved for CHF
Vasodilators: Calcium Channel Blockers
❖ Prototypes ❖ Metabolic interference of vascular smooth muscle contraction in the arteries ❖ Primarily inhibit calcium entry
In hypertensives, baroreflex and renal blood-volume control system are set at a _____ level.
higher
β₁ receptor activation ____ renin release.
stimulates
β-blockers - Possible Mechanism of antihypertensive action: All of these mechanisms are supposed to occur at steady state, (3-7 days) but sometimes blood pressure falls after several _____ so this goes against some of the MOAs.
weeks
Why would you use a β-blocker to decrease BP?
β blockers are used to decrease HR via decreasing AV node conduction
The pathways through which direct renin inhibitors, ACE inhibitors, ARBs, and aldosterone-receptor antagonists inhibit the renin-angiotensin-aldosterone system
❖ *Aliskerin (direct renin inhibitor)*: Inhibits renin directly (which converts angiotensinogen to A-I) ❖ *ACEI* - inhibits ACE (which converts A-I to A-II and degrades bradykinin) ❖ *ARB* - inhibits the AT1R ❖ *Aldosterone receptor antagonist*: (inhibits the aldosterone receptor) ❖ Not suggested to combine agents inhibiting RAS
Toxicity of ACE-I
❖ *Cough - due to BradyKinin accumulation in lung (5-20%)* ❖ Hyperkalemia - with other drugs ❖ Fetus - discontinue during 1st trimester, affects growth, teratogenic ➢ Angiotensin is important in matrix formation so ACE inhibitors affect fetal growth. ❖ Angioneurotic Edema - nose, throat, mouth, larynx, tongue, can be severe and life threatening, due to bradykinin probably.
Vasodilators: Sodium Nitroprusside
❖ *Nitric oxide (NO) donor*, not NO releaser from endogenous stores. ❖ Produces arteriolar and venous dilation. ❖ Used to treat hypertensive emergencies - Very effective vasodilator ➢ Need to put foil around tube because it's light sensitive ❖ Toxicity with long-term administration can lead to cyanide toxicity. This can be prevented by concomitant *thiosulfate* administration as this is the rate limiting factor in cyanide metabolism to thiocynate
Angiotensin Converting Enzyme Inhibitors (ACE inhibitors): Table 1
❖ A lot of "me-too drugs ❖ *-pril* ❖ Enalapril is a prodrug ➢ Experiment: Won't work isolated in blood vessel, the liver is not there to convert it to an active drug ❖ Captopril is *not* a prodrug ➢ Experiment: Will work isolated in blood vessel, as it is not a prodrug ➢ 1st ACEI discovered: Isolated from snake venom that caused hypotension as an *irreversible ACE antagonist*, modified to be a competitive inhibitor
Vasodilators: Minoxidil
❖ Activates K-ATP channels in vascular smooth muscle which leads to hyperpolarization and impairs Ca²⁺ influx ❖ Used best reserved for severe hypertension, never used alone. ❖ *General responses to vasodilators* ❖ Use usually limited by significant fluid retention, aggravation of ischemia, hypertrichosis (hair growth). ❖ *Primary use is topically to promote hair growth*
Aldosterone Antagonists
❖ Aldactone and Eplerenone ❖ Has important use in CHF ❖ Will lower BP ❖ Aldactone was the first aldosterone antagonist ➢ Men get breasts and other unfavorable side effects ❖ Eplerenone (Inspra®) has fewer steroid related side effects (gynecomastia in males, menstrual irregularities and post-menopausal bleeding in females). ➢ *Also decreases mortality in heart failure post-MI*
Normal Blood Pressure Regulation: The "Plumbing Problem"
❖ All the HTN drugs just treat BP like a "plumbing problem" ➢ All antihypertensives act via interfering with normal mechanisms ❖ Just treat the symptoms (symptomatic treatment), not the underlying cause
Angiotensin Converting Enzyme Inhibitors (ACEI): MOA
❖ Although several mechanisms can contribute, the main mechanism by which ACE-I lower blood pressure is *decreasing Angiotensin II (A-II) production*. ❖ Decreasing A-II reduces arteriolar resistance, increases Na and water excretion and reduces sympathetic outflow. ❖ Also decreases aldosterone release. Aldosterone opposes BP effects of diuretics, therefore, ACE-I can significantly improve response to even a low dose of diuretic. ➢ ACEI is usually coupled with thiazide diuretic ❖ May increase AT-receptor levels (agonists receptors) ➢ Anytime you decrease the NT, the body wants to restore the amount of receptor activation, so it will increase the number of receptors
Sympathetic Neuron
❖ Angiotensin II is the most vasoactive hormone that binds to the AT1Rc (angiotensin 1 receptor) ❖ AT1Rc - modulates *vasoconstriction* and other undesirable things in regards to lowering BP; some AT1Rc are on the sympathetic neuron that facilitates more NE release; When you release NE → β₁ stimulation releases renin → SNS facilitates more renin which produces more A-II, that facilitates NE, etc. → This is the positive feedback loop! ❖ AT2Rc: Didn't talk about this, just know there are other types
Angiotensin Receptor Antagonists (ARBs): MOA
❖ Antagonists of Angiotensin II (A-II) at AT₁-angiotensin receptors. ❖ Two receptors for A-II: AT₁ and AT₂ ❖ All major CV effects are through AT₁. AT₁-receptors couple to Gq and Gi, (and ß-arrestin). ➢ The ligand tells the receptor which pathway to take ➢ Effects are detrimental ➢ This is the *target of ARBs* ❖ AT₂-receptors couple to Gi? (not certain) ➢ Most effects are beneficial ➢ No reason to block this one ❖ Can increase A-II levels because AT1-receptors involved in feedback inhibition of renin release ❖ AT₂ receptors mediate NO production (vasodilator and has anti-proliferative effects)
JNC-8
❖ Appeared 11 years ago, approved in 2014 ❖ Considered a step backwards ➢ Over 60 → Treat when BP is over 150/90 ➢ Under 60 → Treat when BP is over 140/90 ❖ The target of many studies was 140/90 so we didn't know the benefit of going below that number
BP Equation
❖ BP = CO X PVR ➢ Blood Pressure = Cardiac Output X Resistance of blood through arterioles
Specific Vasodilator Agents Used in Hypertension: Hydralazine
❖ Basic Mechanism of Antihypertensive Action: ➢ Acts directly on vascular smooth muscle to reduce sarcoplasmic reticulum Ca²⁺ release ➢ Also causes release of Nitric Oxide (NO) from endothelial cells (needs endothelial cells for this to be a MOA)
β-blockers - Possible Mechanism of antihypertensive action: CNS effects
❖ Blocking β-receptors in the CNS decreases sympathetic nerve activity ❖ Arguing against the above theory is that we have made hydrophilic blocker, they have less sedation (can't get into the CNS) and are equally effective at lowering blood pressure as compared to the beta blockers that can cross the BBB. ➢ Thus, the β-blockers could work by getting through the CNS, or it can work even without working in the CNS.
Classifications and Recommendations from the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure
❖ Blue box = Normal BP ❖ We used to treat starting when BP reaches 140/90 ❖ Now we start treatment at BP 120-139 (Red box) → More aggressive ➢ We want to lower BP in people that have compelling indications like other disease states
Mixed α₁/α₂-adrenoceptor antagonist used in hypertension: Phentolamine
❖ Can block both α₁ and α₂ ❖ Primary mechanism of action for decreasing BP is same as for α₁-AR preferential antagonists. ❖ There is α₂ mediated vasoconstriction but this is offset by the MOA of α₂ agonists
Theoretical advantages of AT1-receptor antagonism over inhibition of A-II synthesis
❖ Can block specific receptor subtypes (decrease side effects, leave "beneficial" effects of AT2-receptors) ❖ Can block the action of A-II irrespective of source (i.e., other peptidases besides ACE can produce A-II). ❖ Eliminate bradykinin side effects ❖ Can block effects of A-I at AT1-receptors ➢ A-1 can also activate AT1R, but if we just block the receptor we don't have to worry about it
Non-Dihydropyridine Calcium Channel Blockers: Diltiazem
❖ Cardiac depression vs. vascular effects intermediate between verapamil and DHP. ❖ Some use in hypertension
Possible Mechanisms of β-AR Antagonist Antihypertensive Action: Chronic Effects
❖ Chronically HR stays down, but stroke volume goes up to compensate for it ➢ CO doesn't change ➢ This is why we have tremors, slowing of HR is why β-blockers are contraindicated in olympic shooting events (β agonists are contraindicated because the build muscles) ❖ Takes 3-6 weeks for β-blockers to lower BP to its maximum, so it's not the change in CO that lowers BP
Blood Pressure Effects of α₂-AR Agonists
❖ Decrease BP inhibiting sympathetic activity and reduce both CO and *arterial resistance* (large CNS component especially for imidazolines and phenylethylamines). ❖ Less interference with exercise induced hemodynamic changes (compared to β-blockers and α₁-AR antagonists) ❖ *Imidazolines tend to produce sedation to some degree. Sudden discontinuation leads to rebound with BP rising above pretreatment levels. DO NOT STOP THIS MED SUDDENLY* ➢ *This is a test question*
Non-Dihydropyridine Calcium Channel Blockers: Verapamil
❖ Decreases cardiac force and rate as well as arterial resistance (More than DHP) ➢ There is no PDE inhibition ❖ Also used for angina and arrhythmias.
Other agents interfering with sympathetic neurotransmission: Reserpine
❖ Depletes monoamines by inhibiting Vascular Monoamine Transporter (VMAT). Primarily NE and 5-HT, but also depletes Dopamine and EPI from nerve terminals and CNS. (vesicle protects neurotransmitter from degradation by MAO) ❖ Still used due to low cost [used in VA because of low cost], despite CNS side effects of sedation and depression ❖ Remains an important pharmacological tool in research to rule out neuronal involvement.
Calcium Channel Blockers: Dihydropyridines (DHP)
❖ Dihydropyridines (i.e., nifedipine) in general are more "vascular selective" and are more prone to produce reflex tachycardia and increase cardiac O₂ demand ❖ Sustained Release DHP and other classes of Ca channel blockers used first-line in HTN ❖ Dihydropyridines with short half-life are no longer used in HTN (they produced great reflex tachycardia and could precipitate angina due to increased oxygen demand by heart) ❖ Inhibit PDE which break down cAMP ➢ In the heart when you stimulate β receptor → ↑cAMP → contraction ❖ So you block calcium entry while also blocking PDE → more increase in cAMP ➢ Two apposing effects (increase contraction due to cAMP but decrease contactility because of the blocked Ca²⁺ channels → Cancel each other out ❖ In blood vessels: ➢ Block Ca²⁺ channels → vasodilation ➢ ↑cAMP → vasodilation ➢ Additive effects
Aliskiren
❖ Direct renin inhibitor ❖ Binds to the active site of renin and prevents the conversion of angiotensinogen into angiotensin I ❖ Not a β-blocker, which prevents renin release
Endothelin receptor antagonists
❖ Endothelin (ET) is similar to angiotensin II in that it is a peptide that is formed by peptidases (in this case Endothelin Converting Enzyme), and it has 2 receptors, ET-A (bad) and ET-B (good). ➢ It is almost an irreversible vasoconstrictor ❖ ET-A receptor mediates potent vasoconstriction by ET ❖ Primary use of endothelin antagonists is in *pulmonary hypertension.* ➢ Primarily affects women in their 30s and has a 90% 8 year mortality ➢ Prolongs life and improves quality of life for pulmonary htn patients ❖ Also being tried for treatment of resistant hypertension.
Angiotensin II actions
❖ Everything it does seems bad ➢ Helpful if you get cut or attacked by a lion and won't stop bleeding though ❖ All are mediated by the *AT1Rc* subtype
ISA Drugs
❖ ISA: Intrinsic sympathomimetic activity ❖ This is really a bad term ❖ Will be more extensively discussed in CHF, but basically means they are very weak agonists when compared to epinephrine or norepinephrine. ❖ If there is circulating NE/EPI these drugs act as blockers ❖ If the receptor were empty they would act as weak agonists ❖ Designed to minimize the bradycardia and bronchoconstriction in people seen with COPD
Possible Mechanisms of β-AR Antagonist Antihypertensive Action: Acute Effects
❖ If you give somebody a beta blocker their heart rate will fall acutely. ❖ CO goes down ➢ Remember: one of the determinants of BP → *CO* X TPR = BP
Some α₂-adrenoceptor agonists used in hypertension
❖ Imidazolines ➢ Clonidine ➢ Guanfacine ❖ Phenylethylamines ➢ α-methyldopa (acts purely through α receptor)
2 chemical classes of α₂-AR agonists: Imidazolines vs Phenylethylamines
❖ Imidazolines may also activate I₁ receptors to lower BP. ❖ I₁Rc = Imidazoline receptor ➢ There are receptors like 2 and 3 but those aren't really receptors but are basically binding sites ➢ Does binding contribute to the MOA
Other agents interfering with sympathetic neurotransmission: Metyrosine
❖ Inhibits tyrosine hydroxylase (the rate limiting enzyme in the formation of catecholamines) ❖ Use reserved for pheochromocytomas (tumors that produce too much adrenaline)
Angiotensin Receptor Antagonists (ARBs): Drugs
❖ Losartan ❖ Valsartan ❖ Eprosartan ❖ Irbesartan ❖ Candesartan ❖ Telmisartan ❖ Tasosartan
Compensatory Physiologic Response to Vasodilator Therapy
❖ Lowers systemic vascular resistance and arterial pressure but increases SNS outflow and renin release ❖ If you use β-blocker you can block reflex increase in renin release and block increase in systemic vascular resistance, cardiac contractility, HR ❖ If you use diuretics, can block the decrease of renal sodium excretion and effects of aldosterone ❖ You can use 2 types of drugs but at lower doses instead of maxing out 1 drug
How do you you choose a BP medication?
❖ Money ➢ All the -prils (ACEIs) have generics ➢ Not all the -sartans (ARBs) have generics ❖ ARB is preferred over ACEI due to side effects such as cough and edema
Metformin and ACE inhibitors
❖ No overwhelming data to prove that this combination causes lactic acidosis ❖ Ethanol and metformin cause lactic acidosis
Preferential α₁-adrenoceptor antagonists used in hypertension
❖ Prazosin (prototype) ❖ Doxazosin ❖ Terazosin
α₂ receptors: synapse
❖ Presynaptic α₂ receptor is the major reason for ↓BP ❖ Review: Postsynaptic ➢ AT₁R - Vasoconstriction ➢ α₁ receptor: Vasoconstriction ➢ β₁ receptor: Plays a large role in coronary, in blood vessels they vasodilate ➢ α₂ receptor can contract or release NO
Review of the Renin-Angiotensin System and Control of BP
❖ Renin turns angiotensinogen → ang 1. ➢ Renin is under control of beta-1 receptors ❖ Ang-I is mild vasoactive peptide ❖ Ang-II causes 95% of CV effects, including the detrimental effects ❖ ACE converts ang 1 → ang 2 ➢ ACE inhibitors: Main MOA → ↓ANG-II ➢ ACE : Also degrades bradykinin so it is possible that this is another MOA. Inhibit ACE → ↑bradykinin → ↑NO/Prostacycline/EDHF (vasodilators)
α₁-adrenoceptor (α₁-AR) antagonists: α₁ receptors
❖ Richest target ❖ Most classic target for reducing BP ❖ Most important subtype of receptors to maintain contractile vascular tone ❖ If you block these → will cause vasodilation → so much that it can cause trouble/problems ❖ If you give EPI/NE to blood vessel → will constrict blood vessels via α₁ rc; blocking this will cause vasodilation ❖ α₁ receptor blockers → BP drops very quickly
Site of Blood Pressure Control: The Blood Vessels
❖ Seldom changes CO, changes *BP* ❖ Targets: ➢ Ang II/RAS ➢ Sympathetics ➢ "Other mechanisms" like CCBs (more intracellular Ca = more likely for contraction)
Combined α₁-and-β₁/β₂-Adrenoceptor Antagonists: Labetalol
❖ Seldom used ❖ Equimolar mixture of 4 stereoisomers ❖ 2 are inactive, 1 is α1-AR antagonist, other is non-selective β-blocker with ISA. (Same blocking power) ❖ Lowers BP by reducing arterial resistance, CO unchanged at rest.
Imidazolines vs Phenylethylamines: I₁Rc Controversy
❖ Some α₂-adrenoceptor antagonists [ex phentolamine] do not completely block the BP effect of clonidine, but do for the phenylethylamine, alpha-methyl dopa ➢ suggests that Clonidine is working at a site that the α₂ blocker doesn't block and that there is another site (imidazoline site) ❖ *Rilmenidine* is preferential for I1 versus α₂-AR and lowers BP with less side effects than most in class ❖ Evidence suggest the primary site of action in the CNS is different. (Imidazolines bind to receptors in the ventromedullary region, the rostroventrolateral medulla (RVLM), and phenylethylamines act on the nucleus tractus solitarius (NTS). ➢ Two chemical classes appear to go to different parts of the brain to lower BP ❖ Clinical uses indicate differences. *Clonidine and Imidazolines* can be used in treatment of opiate withdrawal and as an adjunct pre-op to *increase sedation*, but phenylethylamines cannot ➢ Shows that imidazoline binding site is a mechanism for lowering BP
β₂ receptor activation on the heart
❖ Stimulates heart contractility ➢ In the lungs and vessels it relaxes ➢ Both couple with Gs and stimulate cyclic AMP → PKA → whatever PKA phosphorylates determine whether you get inotropy (increase heart contractility), chronotropy (HR increases), or vasodilation ➢ So you can't classify a receptor based of its response, β₂ can be inhibitory or facilitative
Clinical trail and guideline basis for compelling indications for individual drug classes
❖ Table showing the compelling indications and the drugs classes that might be used ❖ ex. heart failure, MI, diabetes
A Randomized Trial of Intensive versus Standard Blood-Pressure Control (The SPRINT Research Group)
❖ Targeted getting people to BP of 120 ❖ Result → Less CV events ➢ Showed 2014 guidelines won't last long ❖ Only adverse fix of 2014 guidelines is dizziness ❖ Went back to the theory: "lower the better" ❖ Conclusion: Lower BP without symptoms is better ➢ No such thing as too low BP as long as you are asymptomatic (no dizziness)
Physiological Response to Hydralazine
❖ The general responses to vasodilators ❖ Can cause headaches in doses required as single agents ❖ Causes drug induced lupus-like syndrome, especially with large doses (>200 mg/d), therefore, very seldom used by itself but sometimes used in combination with other agents (HCTZ and reserpine) ❖ Overall still seldom used
Integrative regulation of blood pressure by activation of different α₂-adrenergic receptor subtypes.
❖ The non-selective α₂-agonist main effects are decreases sympathetic outflow (inhibitory effect on CNS) and decreased NE from SNS nerve terminals ❖ You see some vasoconstriction but net effect is vasodilation and decrease of total peripheral resistance ❖ *α₂-A*: Leads to decrease in BP by inhibiting central sympathetic outflow as well as NE release from sympathetic nerves ❖ *α₂-B*: May counteract the effects subtype A by causing direct vasoconstriction and salt-induced hypertension ❖ *α₂-C*: Participate in α₂-mediated vasoconstriction after exposure to cold temperature
Cardiovascular Response to α₁-AR Antagonists
❖ They are effective vasodilators → MAP & TPR fall quickly and then you get a massive sympathetic compensatory response ❖ BP lowering effect can be reduced long-term by Na and H₂O retention which can be reduced by diuretics ❖ Postural hypotension can be marked, especially with initial dose. Usually tolerance develops to this ❖ α₁-AR antagonists are also used to decrease intra-urethral pressure (mediated through α₁A) in BPH. Claim that some (ie tamsulosin) are useful in BPH with little effect on BP ❖ Allhat study terminated the doxazosin branch early due to lack of protective effects at developing CHF ➢ Therefore not 1st line agents ➢ Still used for malignant or resistant hypertension
β-blockers - Possible Mechanism of antihypertensive action: Blocking renin release because they are a β₁ blocker
❖ This one sounds reasonable ➢ Only argument against these is that β -blockers also lower blood pressure in patients with low renin levels. ❖ Recall: β₂-AR at sympathetic nerves facilitate NE release ➢ Block these = decrease NE release ❖ So this could be true, but we made β₁ preferential blockers that aren't really good at reducing β₂ but they still reduce pressure equally well ❖ MOA could be blocking β₂-receptor to decrease NE release, however, that can't be the only reason because the selective β₁ blockers can decrease pressure too.
β-blockers - Possible Mechanism of antihypertensive action: A positive feedback loop
❖ Thought that with age, whatever triggers hypertension, there's a stiffening of the arterial resistance so the peripheral vascular resistance goes up ❖ Heart contracts a bit harder to get more blood through it and blood vessels constrict a little more. it's like a tug-of-war between the two. ➢ Administering a β-blocker may break this cycle. The β-blocker stops the ability of the heart to increase its rate and contractility. → heart gives up so the vessels will give up on the tug-of-war ➢ Once the heart rate goes down, the peripheral vessels will relax more too
Original vs. Current Classifications of Adrenergic Receptors
❖ Top: Original ➢ Sympathetic had both excitatory and inhibitory properties ➢ Stimulated heart, but relaxed lungs, conclusion was there were different types of receptors ❖ Bottom: Current ➢ We don't see α₁-C because it is the same as α₁-A ➢ Activation of α₂ receptors results in a *net decrease* in sympathetic activity ➢ The β receptors don't have subtypes for each type
Should you give give and ACEI with an ARB?
❖ We used to do this until 3 years ago, but there is an increased risk of heart failure ❖ Guideline now says do not use more than 1 agent that interferes with RAS ❖ You could give a β-blocker and RAS-1 agent though
Angiotensin I Receptor
❖ You can tell that is is the AT1R because you see Gq ❖ Mediates Ca entry and this causes blood vessels to contract ❖ Primary Neuropeptide that activates it is Ang-II
Sympathetic Neuron: Receptor Actions
❖ β receptors on the postsynaptic membrane vasodilate ❖ α₁ receptors on the postsynaptic membrane vasoconstrict ❖ α₂ receptors act as sensors on presynaptic site and decrease NE release
Combined α₁-and-β₁/β₂-Adrenoceptor Antagonists: Carvedilol
❖ β₁/β₂ AR antagonist, also α₁-AR antagonist but with lower affinity than its affinity for β₁ and β₂. ❖ MOA is same as for other β-blockers: little or no contribution from α₁-AR blockade. (10 fold less) ❖ First β-blocker approved by FDA for the treatment of congestive heart failure (CHF).
Mirabegron
❖ β₃ agonist ❖ Used for overactive bladder ❖ β₃ relaxes bladder
Vasodilators: Arterial Vasodilators
❖ ↓BP by lowering arterial resistance ❖ Result in reflex activation of the SNS → ↑HR/force, increased plasma renin activity (PRA) and fluid retention by kidney ➢ *True of all vasodilators*
Vasodilators: Arterial and Venous Vasodilators
❖ ↓BP by lowering arterial resistance and also by increasing venous pooling and reducing venous return (due to venous dilation). ❖ Reduce venous return and ↓CO because of the blood pooling
Acute Cardiovascular Response to α₂-AR Agonists
❖ ↓CO ❖ ↓TPR ❖ Chronic: ➢ ←→ CO ➢ ↓TPR
