ACE Inhibitors & Hypertension

• The lecture covers antihypertensive agents acting on the renin-angiotensin-aldosterone system (RAAS)

Lecture Objectives

• Describe the mechanism of action, therapeutic effect, and adverse effects of antihypertensive agents acting on RAAS
• Distinguish antihypertensive drug classes based on pharmacophore or structure-activity relationships (SAR)
• Discuss the influence of structure on the mechanism of action (MOA)
• Recognize peptidomimetic features of ACE inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and the renin inhibitor aliskiren
• Identify prodrugs that need activation or hydrolysis for activity
• Describe physiochemical properties or chemical metabolism routes that affect efficacy, toxicity, or pharmacokinetics (PK)

Lecture Outline

• Review pharmacology's basic model, including hypertension and RAAS ("Normal, Wrong, Fixed")
• Discuss pharmacology and medicinal chemistry of agents targeting renin, ACE, and angiotensin II receptors, including:
  • Classes
  • Specific Drugs
  • Mechanism of Action
  • SAR/Pharmacophore
  • Physiochemical Properties/Metabolism
  • Adverse Effects/Toxicity

Basic Pharmacology Model: Hypertension

• Normal physiology involves normal blood pressure, regulated blood volume, and proper kidney function
• Pathophysiology of hypertension includes increased blood volume and systemic vascular resistance (SVR)
• Treatment strategies aim to correct the pathophysiology

Physiology of Kidney and RAAS

• The kidney maintains long-term blood pressure regulation by controlling blood volume
• Low renal pressure stimulates hormone production which increases salt and water reabsorption
• The renin-angiotensin-aldosterone system (RAAS) is a collection of hormones that help control blood pressure
• Decreased renal arteriole pressure and sympathetic activation lead to renin production, increasing Angiotensin II (Ang II)
• Ang II constricts resistance vessels and stimulates aldosterone synthesis in the adrenal cortex
• Aldosterone increases renal sodium/water absorption and intravascular blood volume

RAAS Activation

• RAAS activates with low blood pressure
• Angiotensinogen converts to Angiotensin I via renin due to low blood pressure/volume and low blood sodium
• Angiotensin I converts to Angiotensin II via Angiotensin Converting Enzyme(ACE)
• Angiotensin II leads to vasoconstriction and aldosterone release, increasing sodium/water retention

Pathophysiology: Hypertension Details

• Increased cardiac output (CO) is due to abnormal sympathetic activation
• Increased systemic vascular resistance (SVR) results from blood vessel vasoconstriction, increased blood volume, and failure of RAAS

Malfunctions with Hypertension

• Impaired regulatory mechanisms
• Abnormal neuronal mechanisms
• Failure of RAAS to control blood volume/pressure
• Defects in peripheral regulation
• Disturbances in calcium, sodium, or natriuretic hormones

Hypertension Therapeutic Approaches

• Decrease sympathetic outflow or induce vasodilation achieved using beta blockers or alpha-2 agonists)
• Prevent sodium reabsorption or promote sodium excretion via diuretics
• Inhibit the Renin-Angiotensin-Aldosterone System (RAAS) through ACE inhibitors, ARBs, or renin inhibitors
• Promote vasodilation via vasodilators or alpha-1 antagonists
• Block voltage gated calcium channels (CCBs) to reduce cardiac output or cause vasodilation

Classes of Antihypertensives Acting on RAAS

• Angiotensin Converting Enzyme Inhibitors (ACEIs)
• Angiotensin II Receptor Blockers (ARBs)
• Direct Renin Inhibitor (DRI) - Aliskiren

ACE Inhibitors (ACEIs)

• Mechanism of Action: ACEIs prevent angiotensin I’s conversion to angiotensin II, reducing vasoconstriction and aldosterone production
• ACEIs also raise bradykinin levels, which leads to vasodilation and amplified prostaglandin production
• Increased bradykinin is associated with the adverse effect of dry coughs
• Specific ACEI Drugs: Lisinopril, Benazepril, Quinapril, Enalapril, Fosinopril, and Ramipril
• ACEIs block ACE, which breaks down peptides that turn Angiotensin I into Angiotensin II, increased levels of bradykinin that inhibit ACE

ACE Catalytic Site Properties:

• Cationic Site; Lys or Arg
• Catalytic Zn²⁺ Atom
• Hydrophobic Pocket

ACEIs Mechanism of Action

• ACEIs block the conversion of angiotensin I to angiotensin II via 3 major interactions in ACE
• It mimics ACE's substrate, angiotensin I with 3 major sites:
• Cationic site: binds the anionic carboxylate on the peptide terminus
• Zinc atom: stabilizes the intermediate
• Hydrophobic pocket: lends specificity for C-terminal aromatic or nonpolar compounds

SAR Map of ACEIs

• ACEIs are peptidomimetics of Angiotensin I with pharmacophores of 3 groups
• Hydrophobic Group: Aids in van der Waals contacts with ACE, containing N-Ring which requires COO- for binding to the receptor
• Zinc Binding Group
• Acidic/Anionic Group
• They bond with basic amino acids Lysine and Arginine

Types of Sulfhydryls

• Ionized sulfhydryl (S⁻) interacts with Zn²⁺ in ACE, which is an ionic interaction
• The sulfur group acts as a chelating agent, contributing to captopril's potency, and causes side effects
• Captopril -Sulfhydryl associated with side effects like skin rashes and metallic taste dysfunctions

Types of Carboxylates

• Most prodrugs contain ester group
• An ester addition boosts the carboxylic group’s bioavailability leading to easier Zn²⁺ binding to the site

ACEIs: Physiochemical Properties and Pharmacokinetics

• All ACEIs are amphoteric, except acidic captopril and fosinopril
• The N-ring has a carboxylic acid with a pKa ~2.5-3.5 that becomes ionized at physiological pH
• Dicarboxylate series have an additional carboxylic acid that’s ionized in the active form, but un-ionized in form of ester prodrug
• All ACEIs are have good lipid solubility except captopril, enalaprilat, and lisinopril
• Lisinopril has a di-zwitterion structure in the duodenum due to their hydrophilic abilities

ACEIs: Common Adverse Effects, Toxicity, and Drug Interactions

• ACEIs are contraindicated in pregnancy
• Hyperkalemia may occur due to blocking the RAAS pathway which decreases aldosterone production
• Severe hypotension may occur in hypovolemic patients
• Minor effects are observed with captopril like altered skin rashes or altered taste
• NSAIDs may impair ACAI efficacy by blocking the vasodilatation effects

ACEIs: Lisinopril

• Lisinopril is a lysine analog of enalapril, producing a similar MOA as other ACE inhibitors
• It is considered a carboxylic acid ACE inhibitor
• Lisinopril is a non-prodrug which has similar effects as captopril
• ACE Inhibitor (ACEI) drugs are used to therapeutically treat hypertension and heart failure

ACEIs: Enalapril, Benazepril, & Quinapril

• Enalapril, benazepril, and quinapril are all pro drug ACEIs that are metabolized via ester hydrolysis to produce a carboxylic acid that releases a zinc binded group
• Enalaprilat, benazeprilat, and quinaprilat are types of their active metabolites within ester structures by activation of hepatic esterases

ACEIs: Fosinopril

• Fosinopril is a phosphodiester prodrug which are activated to produce an agent via phosphodiester hydrolysis to produce a phosphinate group

Physiochemical Propertties and Pharmacokinetics of ACEI drugs

• A majority of ACEIs have LogP values between 1-5 and decent oral bioavailability
• EXCEPT captopril and lisinopril

Bradykinin and Dry Cough / Angioedema

• ACE-I (ACE inhibitors) lead to an accumulation in bradykinin
• Increased levels of bradykinin are linked to increased adverse effects like dry cough/angioedema

Angiotensin II Receptor Blockers (ARBs)

• ARBs antagonize angiotensin II by selectively blocking the AT₁ receptor, more selective for the AT₁ subtype
• Leads to vasodilation, decreased aldosterone/vasopressin/catecholamine secretion, and elevated sodium excretion
• Specific Drugs: Valsartan, Losartan, Irbesartan, Candesartan, and Telmisartan

ARBs (Angiotensin II Receptor Blockers) Drug Design

• ARBs are designed with the following peptidomimetics:
  • Mimics Iles
  • Offers bulky changes
  • Mimics His6
  • Xan be acidic to mimic carbonyloxide of aspartic acid

ARBs SAR Map

• Tetrazole helps increases affinity of the drug by forming the group
• Bioisostere helps the ARBs retain and activate the selectivity of valsartan in the body
• Pharmacophore:
  • Benzyl
  • Acetyl Imidazole
• Mimic Tyr/Asp, Ile, His, Phe

ARBs Physiochemical Properties

• Acids due to the use of carboxylate groups and or tetrazole
• The tetrazole helps increase lipophilic effects therefore resulting in higher binding
• Irbsartan has a high bioavailability of 60-80% due to its physiochemical properties
• Losartan also produced an active metabolite through phase I oxidation, increasing overall bioactivity

ARBs (Angiotensin II Receptor Blockers): Losartan, Valsartan, & Irbesartan

• Losartan, valsartan, and irbesartan are non-prodrug ARBs
• Losartan acts as antagonist to thromboxane which also reduces platelet aggregation, it’s also used for COX-dependent prostaglandin synthesis
• Valsartan concentrations are significantly decreased if taken with food

Candesartan cilexetil and Angiotensin II Blockers

• Candesartan cilexetil has inactive ester prodrug, of candesartan
• This agent is completely hydrolyzed to the carboxylic acid by the form of esterases in the GI tract.

ARBs Physiochemical Properties and Pharmacokinetics

• All ARBs are acidic from tetrazole
• Tetrazoles and carboxylate groups are ionized at physiologic pH
• The ring containing ARBs had greater binding than those without, since they are more lipophilic
• Irbesartan has a bioavailability of ~60% to 80%
• Losartan has an active metabolite from phase I oxidation

ARBs Common Adverse Effects, Toxicity, and Drug Interactions

• Hyperkalemia: May occur due to the blocking of RAAS pathway, decreasing aldosterone production
• Hyperkalemia: Risk increases when taken with potassium supplements
• Angioedema : May occur with ARBs, but not to cause an extensive extent similar to compared to ACEls
• Dry Cough: ARBs do not induce synthesis from bradykinin, which means this side effect is not a direct effect
• Teratogenic: ARBs are possibly teratogenic, leading to pregnancy complications

Direct Renin Inhibitor (DRI): Aliskiren

• Developed as peptidomimetics to the sequence (Pro7-Phe8-His⁹-Leu10-Val11-Ile12-His13-Asn14) of angiotensinogen
• Aliskiren inhibits renin, also is a non-peptide template that is highly specific
• Causes a non compensatory increase of renin to plasma leading to decrease of renin

Renin Peptidomimetic Design

• Transition from bonds to P₁ site
• It’s also can be applied through hepatobiliary with high levels of efficiency as it can be absorbed at high levels
• The renin that produces is Aliskiren

Aliskiren Physiochemical Properties and Pharmacokinetics

• Basic compound; hemifumarate
• LogP = 4.32 with unique unionized form
• Oral bioavailability is ~2.5% can be absorbed high rates as the hepatobiliary has greater percentages like 90

Aliskiren: Adverse Effects, Toxicity, and Drug Interactions

• Hyperkalemia : Occurs through blocking of RAAS pathway and decreasing aldosterone production
• Mild Gl complications like diarrhea has observed when the person has high Gl symptoms like 600md
• Angioedema and cough are possible, but to lesser extent than ACEIs
• This may increase creatine when treating with Aliskiren
• Possibly teratogenic also, it occurs at higher rates

Pharmacology Practice Questions:

Which drug competitively blocks angiotensin II to inhibit AT1 receptors?

• Losartan: Ang Ⅱ Inhibitor

Which adverse effects are caused by angiotensin II related inhibitors/blockers?

• Lisinopril causes angioedema

What is the mechanism for the following drugs?

• Aliskiren works with direct renin inhibitors
• ACEPI works with ace inhibitors
• ARB works with AT1 receptors

These questions cover ACE inhibitors, hypertension, ARBs mechanism of action, common adverse effects , and drug interactions. This also includes the role of aldosterone and systemic vascular resistance.