- Losartan (Cozaar): The overall cardiovascular effects seen with losartan are due to the combined actions of the parent drug and the 14% of it oxidized to active metabolites that are 10-40x more potent

o Metabolism: CYP2C9/3A4 oxidizes the imidazole-methanol to carboxylic acid à more potent.

o Structure: This is a biphenyl series –sartan that has a tetrazole in the ortho-position as its ‘acidic group’ and a chlorine+methanol to hydrogen bond with the active site Phe8

- Candesartan Cilexetil (Atacand) and Olmesartan medoxomil (Benicar) are prodrugs, as conferred by their flamboyant Oxygen groups. These are highly reactive and are cleaved off quickly by esterases. They are completely metabolized to their active metaoblites in the intestinal walls.

- Azilisartan medoxomil (Edarbi): With similar prodrug behavior as to Candesartan, Azilisartan is completely metabolized to the active metabolite in the intestinal wall. In this compound, the tetrazole ring is replaced by an oxo-oxadiazole ring which is less acidic. Surprisingly, this binds more tightly to AT1 than other ARBs and dissociates more slowly.

o Shows better control of 24h systolic BP than the other ARBs. Renin Inhibitors: As discussed at the beginning of the lecture, Renin catalyzes the RLE of the RAAS system followed by secretion from the juxtaglomerular kidney cells. It is a proteolytic enzyme, converting Ang à AngI. Classic drug design would select Renin as the ideal target, however all efforts have failed.

- Enzyme Activity: Renin cleaves between Leu10 and Val11, two hydrophobic AA. - Aliskiren (Tekturna): Orally available selective inhibitor of renin, the first and only approved. It is contraX with

ARBs/ACE-I in patients with diabetes. It has a stacking group (NCCO) to bind in the active site. Thus far, the drug is not really working too well.

(2/5) Orjala Lecture: Chemistry of Antihypertensives II Calcium Channel Blockers (CCB): CCBs, or calcium antagonists, act by decreasing Ca2+ ion entry into excitable nerve and muscle cells through the Voltage-dependent and Time-dependent slow L-type Calcium Channels. As such, they affect muscular contraction, smooth muscle vasculature, and cardiac muscle contractility. Currently, there are 10 CCB available in the US for therapeutic use. They are grouped into 4 classes:

- 1,4-dihydro-pyridines (1,4-DHPs): Nifedipine + 7 others! Largest class of CCB - Phenylalkylamines (PAA): Verapamil only. Better affinity for the heart Ca2+ channels - Benzothiazepines (BTZ): Diltiazem only. Better affinity for the heart Ca2+ channels - Diaminopropranol ethers (DAPE): Bepridil only. AE. No longer marketed.

CCB Selectivity and MoA - CCB are selective for the L-type high-voltage-activated calcium channels (except Bepridil). Calcium influx is

influenced through binding to specific sites located within the channels. - What’s the deal? It’s just Ca2+!? Intracellular [Ca2+] is in the nanomolar range, whereas extracellular it is

millimolar. As such, Ca2+ is a significant second messenger. - General MoA: Ca2+ channels can exists in 3 different conformations: (1) Open, (2) Inactive, (3) Resting

Resting: Following a recovery period, the channel waits in the closed conformation for arrival of the next action potential (AP). à Arrival and propagation of an AP is modulated by Na2+, significantly changing the resting membrane potential and activating the voltage-dependent L-type Ca2+ channel Open: Ca2+ influx occurs only for a short duration before rapidly becoming inactivated Inactivated: The L-type Ca2+ channel will need to recover before being activated again Use-Dependency: CCB are more effective when the Ca2+ are used more frequently. Meaning, longer, more intense, and more frequent membrane depolarizations will make

them more effective. CCB preferentially interact with their receptors in the open or inactive state. - Sites of Drug-Action: On the a-1 subunit of the Ca2+ channel, there are 3 different binding sites

o These sites are allosterically-interacting, meaning activity at one site affects the others. § Negative Allosterism: If bound, Verapamil will prevent BTZ and 1,4DHP binding, +vice versa

• ContraX: \ these cannot be used together § Positive Allosterism: If bound, BTZ and 1,4DHP will enhance the binding of each other.

• This can be used together, however stringent therapeutic windows prevent safe use.

o 1,4-DHP: Bind on the extracellular side, freezing them in their inactivated state. o PAA: Verapamil diffuses across the membrane, then binds within the channel from the intracellular side o BTZ: Diltazem binds to the extracellular side, blocking the open channel.

Verapamil (Calan, Isoptin): Verapamil is the phenylalkylamine (PAA) compound used for heart rhythm stuff, not BP - Metabolism: Highly absorbed and very lipophilic, Verapamil (T1/2= 7h) peaks at 1-2h but has low bioavailability

o CYP3A4: Sold as a racemate, the more active (S,-) isomer is rapidly N-demethylated by hepatic and intestinal CYP to the less active metabolite: Norverapamil, Only 20% as potent, norverapamil undergoes further CYP3A4 demethylations until subsequent elimination as a glucuronide in the urine.

o PGP Efflux Transporter: Verapamil is a substrate for PGP, drastically increasing intestinal absorption of other PGP substrates, such as digoxin in a dose-dependent manner. Verapamil can cause lethal [Digoxin]

Diltiazem (Cardizem): Diltiazem is the benzothiazepine (BZT) compound, has a 7-membered thiazine ring - Metabolism: Highly lipophilic, Diltiazem has a very fast onset but faces an extensive metabolic repertoire

o Esterase: Hydrolysis of Diltiazem’s ester forms the active metabolite Deacetyldiltiazem. The effects of diltiazem therapy is a combination of itself and its active metabolite (50% potency)

o CYP3A4: Sold only as the single (+) enantiomer, CYP goes to town on Diltiazem during phase 1 metabolism, conferring O- and N-demethylation, aromatic hydroxylation, and further ester hydrolysis

o Sulfation/Glucuronidation: Excretion in the urine is aided by sulfate or glucuronide conjugation 1,4-DHPs: The DHP structure has a few notable peculiarities

(1). Non-Aromatic Ring: The ‘dihydro’ refers to the reduced 1,4-rig members. The 1,4-DHP ring is essential for CCB activity. (2). ‘X’-o/m- EWG: Benzene ring has an ortho/meta EWG helping to install a 90º bend between rings. Thus its size is important for ‘locking’ the conformation. (3). R3 and R5 must be: Carboxylic acid esters. They pull across

the pyridine ring, influencing the pKa of N (ß) so as to make it neutral - Amlodipine (Novasc): The only 1,4-DHP with a different R6. It alters

binding and lengthens the T1/2 to 30-50h. This is nice for once-daily dosing, however it is troublesome in cases of overdose.

- Clevidipine (Cleviprex): Short-acting 1,4-DHP CCB, T1/2 is only 1-2 minutes following IV admin, so it is given as a o/w emulsion. Used in clinical settings when HT is becoming a critical threat.

- Metabolism: Once the 1,4-DHPs are oxidatively metabolized by hepatic CYP3A4 to pyridine, activity is gone o To be excreted, it needs to be made more water soluble, either by ester cleavage or oxidation by CYP

§ The more extender/further ou the R3 and R5 esters are, the more quickly they are metabolized o Grapefruit Juice: The flavonoids and furanocoumarines found in grapefruit juice inhibit intestinal 3A4

isozymes. Co-administration with 1,4-DHP will cause increased systemic [1,4-DHP] – ContraX - Newer 1,4-DHPs: By adjusting the R3 or R5 groups, optical activity and a pair of stereoisomers may be generated.

In the case of Isradipine, swapping R3 for a Nitro (NO2) group produces opposing products: R: Block, S: Activate o Due to the opposing effects, they are termed Calcium Channel Modulators, used in CHF

b-Adrenergic Antagonists for treating HT - Non-Selective/1st-Gen: Using the Oxymethylene bridge: Propranolol, Nadolol, Timolol, Pindolol

o More lipophilic, cross BBB and induce AE like dizziness, confusion, depression - Selective/2nd-Gen: Addition of Hydrophilic groups: Acebutolol, Atenolol, Bisoprolol, Metoprolol

o More Hydrophilic, less crossing the BBB, limiting the CNS AE. - Intrinsic Sympathomimetic Activity (ISA): Acebutolol, Carteolol, Pindolol, and Penbutolol each

have a –meta/-para hydrogen bonding substituent on the phenyl ring capable of partially stimulating b receptors. Penbutolol’s is added via metabolic biotransformation.

- Mixed a/b Adrenergic Antagonists/3rd-Gen: Most popular are Labetalol and Carvedilol. Each are marketed as racemates, Labetolol even has 4 stereoisomers. Labetalol and Carvedilol both have a1-antagonism producing vasodilation, and nonselective b-antagonism, causing bronchoconstriction (beware asthmatics!)

Centrally Acting a2-Agonists - L-Methyldopa: Pro-drug capable of crossing the BBB via L-Aryl-AA-Transporter. Converted by

L-Aryl-AA-decarboxylase and DA-b-hydroxylase to a-methyl-NE. à Binds to a2 receptors in the brain non-specifically, slowing down the sympathetic tone. The AA moiety is critical for its BBB penetration

- Clonidine: Hydroxylated at the 4-position (N is para-oriented), subsequent glucuronidation/sulfate conjugation - Guanfacine: More selective for a2 than clonidine of guanabenz. Metabolized at 3 position

Arterial Vasodilators - Hydralazine is a 2nd/3rd line agent, typically used to treat hypertensive crises. It is also used as first-line therapy

along with Labetalol to treat Preeclampsia (pregnant lady severe HT) o Hydralazine Metabolism: Well absorbed in the GI tract, extensively metabolized in GI mucosa + Liver o Genetic Variation: Acetylation shows distinct genetic contribution. Slow acetylaters may require lower

doses, and fast acetylaters may need higher doses. - Minoxidil is a 3rd/4th line prodrug. It must be activated by hepatic sulfotransferase to

minoxidil N-O-sulfate. Side effect is Hirsutism – so used to treat male pattern baldness o Glucuronidation (Minoxidil N-O-Glucuronide) for excretion

(2/6-8) Schlemmer Recitation: Pharmacology of Antihypertensives How does all this work? Recall, Blood Pressure (BP) = Cardiac Output (CO) • Peripheral Vascular Resistance (PVR)

- CO = Heart Rate (HR) • Stroke Volume (SV) - If you’re going to change BP, you much change one of these other dependent variables.

Diuretic [Sodium Water Balance]: Typically the first pharmacological treatment given for treating Hypertension - Short-term MoA: Decrease blood volume and CO, while decrease Na+ stores. This levels off in 6-8 weeks. - Long-term MoA: Sodium within muscles causes stiffness, rigidity. Long-term Na+ depletion leaves to decreased

PVR and CO normalizes. - Classes: While there are multiple classes of diuretics, only Thiazides and potassium-sparing diuretics are

clinically relevant. Loop, for example, are not as effective in treating HT. - Thiazides

o Most frequently prescribed, effective at treating mild to moderate essential HT. They are less effective in individuals with cardiac or renal comorbidities

o Dosing: Lower doses produce similar antihypertensive action as the higher doses. Use the lower dose!

o MoA: Inhibit NaCl reabsorption in the distal convoluted tubule on the luminal (urine) side. § Blocking Na+/Cl- transporter enhances downstream Ca2+ reabsorption! § Acute effect: COß, PVR~Ý - Reduction in blood volume § Chronic effect (>6-8w): CO Normalizes, PVRß

o AE: Hypokalemia (Kß), Hyperuricemia (Gout!), Hyperglycemia (only worry if you’re diabetic), HLÝ § The major AE to be concerned with is hypokalemia. In cardiac patients, this can be a big deal.

- Potassium-Sparing Diuretics o Avoids K depletion and enhances the natriuretic effect of other diuretics o Aldosterone Antagonists: Block aldosterone receptors in the late distal and

cortical collecting tubules. Normally, aldosterone functions to increase BP. o AE: Hyperkalemia (KÝ), Gynecomastia, Hypochloremic metabolic acidosis

CNS-Acting Sympathoplegic [DSympathetic] Indication: Used to treat moderate HT - MoA: Reduce sympathetic nervous system outflow from the brain. - Class Advantage: These drugs maintain the baroreceptor reflex, meaning, orthostatic

hypotension is low. Falls in the elderly lead to broken hips. The mortality rate of broken hips is 20% - blood clots during recovery.

- Indication: Used to treat moderate HT - Methyldopa: Methyldopa will be converted to a-methyl-NE by endogenous enzymes, a false transmitter

o CNS Activity: BPß. Action related to CO and HR is controversial, though minimally will decrease both. § The Schlemm says: a-methyl-NE stimulates post-synaptic a-adrenoceptors to reduce PVR § But I believe: I propose a-methyl-NE stimulatess pre-synaptic a2 autoreceptors and blocks post-

synaptic a receptors, leading to ßsympathetic outflow and BPß. Schlemmer rejected my thought o Peripheral Activity: While replacing NE as a false transmitter, it does not produce antihypertensive action

- Clonidine: o CNS Activity: BPß, HRß, Parasympathetic ToneÝ, ßSympathetic outflow. Functions as a direct agonist

of a-adrenoceptors in the medulla of the brain o Peripheral Activity: Clonidine is associated with an initial BPÝ, due to the peripheral a-receptors on

arterioles. When administered IV, patient will experience transient vasoconstriction. However, this peripheral action is very brief as they are only partial agonists at peripheral adrenoceptors

o AE: Dry mouth (a-mediated response), Sedation, Sudden withdrawal after chronic use – rebound § It is recommended to taper off the drug when d/c

Thiazides Non-Thiazides

Chlorthiazide HCTZ

Chlorthalidone

Aldosterone Antagonists

Inhibitors of Na+ Influx

Spironolactone Eplerenone

Triamterene Amiloride

CNS-Acting Sympathoplegics Methyldopa Clonidine Guanabenz Guanfacine

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your hair