Finals Notes - Drug Design & Pharmacology

Table of Contents {#table-of-contents.TOCHeading} ================= [Introduction to Drug Design 2](#introduction-to-drug-design) [Pharmacology and Medicinal Chemistry of Antihypertensive agents 6](#pharmacology-and-medicinal-chemistry-of-antihypertensive-agents) Introduction to Drug Design =====...

Table of Contents {#table-of-contents.TOCHeading} ================= [Introduction to Drug Design 2](#introduction-to-drug-design) [Pharmacology and Medicinal Chemistry of Antihypertensive agents 6](#pharmacology-and-medicinal-chemistry-of-antihypertensive-agents) Introduction to Drug Design =========================== Targets of a drug are biomolecular structures which are typically proteins and can be various types of cellular component such as receptors, transporters, enzymes and even nucleic acids. For a target to be considered as a good target, it has to be disease-modifying and/or has a proven function in the pathophysiology of a disease. The target expression should not be uniformly distributed within the body to reduce off-target side effects. There should be a target/disease-specific biomarker such as blood pressure to monitor therapeutic efficacy. Target should also have a favourable 'assayability' enabling high throughput screening. For a drug to be utilised as a therapeutic product, it has to undergo 3 drug activity phases: 1. The pharmacodynamic phase. This phase ensures that the drug possesses good properties to provide the best pharmacological activity. 2. The pharmacokinetic phase. This phase ensures that the drug substance have suitable ADME parameters for good bioavailability and acceptable metabolic stability and elimination profile. 3. The pharmaceutical phase. This phase ensures that the drug substance possess suitable physicochemical properties to enable them to be formulated into dosage forms. For a molecule to be considered a good drug, it would usually have to follow Lipinski Rule of 5 - 5 hydrogen bond donors - 10 (5 x 2) hydrogen bond acceptors - A molecular weight of less than 500 Da - A calculated LogP of less than 5 The hydrogen bonding allows the molecule to interact with the target while the molecular weight and LogP allows it to pass through biological membranes. This is based off the observation that orally administered drugs are relatively small and moderately lipophilic. To elicit drug action, the drug must interact with a receptor in order to form a complex. It is the complex that triggers pharmacological action. Some functional groups and their binding includes: - Alkyl, aryl and heterocyclic groups - Hydrophobic interactions - Dipole-dipole interactions - Hydroxyl, carbonyl, amino groups - Hydrogen bonding - Acidic group - Ionised into anions, giving rise to charge-charge interaction - Charge-induced dipole interaction - Basic group - Ionised into cations, giving rise to charge-charge interaction - Charge-induced dipole interaction After forming these interactions, drugs will be able to interfere with signal transduction, receptor signalling or biochemical equilibria. Various binding studies can be done to evaluate the effectiveness of interaction that led to functional activity or therapeutic efficacy. One method is the pharmacophore model. This is done by creating models of different drugs of the same class and overlapping them. The overlapping groups between the molecules are called a pharmacophore. A pharmacophore is defined as a group of steric and electronic features that is necessary to ensure the optimal supramolecular interaction with a specific biological target structure and to trigger (or block) its biological response. A pharmacophoric element is an atom or a group off atoms common to active compounds and essential for activity. 3 pharmacophoric elements are necessary for it to be a pharmacophore. A pharmacophore that has less than 3 pharmacophoric elements tend to have more off target effects by binding to other proteins. **Gibbs Free Energy** The Gibbs Free Energy tells us whether the reaction is favoured under specific conditions. It is independent on the path of reaction and provides no information on the rate of reaction. From the Gibbs Free Energy equation, the binding affinity can also be determined based on the processes involved during the binding of a drug onto the target.  For the drug to have good binding affinity to the target, it depends on the interplay between ΔH and ΔS. Net ΔS should be positive - contributed by interplay of desolvation and complexation. Trapped water will cause entropy penalty to the net effect. ΔH (binding) should be greater than ΔH (desolvation); the non-covalent bonds formed should be stronger than strength of solvation. Weak intermolecular forces or fewer interaction points between ligand and target will not favour ΔH. K~d~ can also be used to indicate the binding affinity of a drug to its target. \ [\$\$K\_{d} = \\frac{\\left\\lbrack \\text{receptor} \\right\\rbrack\\lbrack drug\\rbrack}{\\lbrack complex\\rbrack}\$\$]{.math.display}\ This means that for a drug with a small K~d~ value, there would be a higher concentration of drug-receptor complexes compared to free drug and free receptor concentrations. This means that the drug has a high affinity to the target. \ [*ΔG* = *RT*ln *K*~*d*~]{.math.display}\ This means that if K~d~ is a small value, lnK~d~ \< 0 and ΔG \< 0. This means that the lower the K~d~, the more spontaneous the formation of complexes will become. In both cases, a lower K~d~ would indicate that more receptor complexes will be present, indicating a higher binding affinity. Since the complexes are the ones responsible for the drug effects, the lower K~d~ also means that there will be a stronger drug effect. Most useful drugs usually have a K~d~ lower than 1µM. A variety of experiments can also be utilised to determine the biological effect of a drug on a target. The experiments can be done In vitro or In vivo. Selectivity experiments can also be done to evaluate differential activity between pathogen/host or diseased cells/healthy cells. One commonly used experiment is the determination of the IC~50~ value. It is the concentration of drug required to give 50% inhibition of the measured activity. It can be used for comparing between different drugs. The IC~10~ and IC~90~ value should cover 2 units of log concentration. After a lead compound is identified using the above strategy, a structure activity relationship (SAR) study can be conducted to optimise the properties of the lead compound to make it more drug like. This includes modifying the chemical structure of the lead compound and analysing the derivatives in order to determine the biological responses as well as how the structural features contribute to enhance PK and PD properties. Some reasons of using SAR studies include: - Optimising pharmacological activity to improve potency - Enhance selectivity between targets - Determine stereoselectivity - Optimise ADME profile to improve pharmacokinetic properties - Enhance oral bioavailability - Enhance membrane permeability - Enhance water solubility - Optimise therapeutic index by improving safety profile - Determine toxicophore A Quantitative Structure Activity Relationship (QSAR) attempts to quantify the relationship between physicochemical parameters and biological activity of a substance. Some physicochemical parameters that can be used includes π (hydrophobicity), Log P (partition coefficient), σ (Hammett constant), Es (Taft's steric factor), MR (molecular refractivity). One method of QSAR is by Hansch Analysis. Hansch analysis attempts to mathematically relate drug action to measurable physicochemical properties. For example: \ [\$\$\\log\\frac{1}{C} = 1.22\\pi - 1.59\\delta + 7.89\\ \\ \\lbrack n = 22,\\ r\^{2} = 0.918\\rbrack\$\$]{.math.display}\ C is the biological response used in the experiment such as IC50, MIC. When C is a small value, log(1/C) will be a large value indicating that the substance is more active. From the equation, it can be seen that a +π value (more hydrophobic) is more preferred to a -π value. A -σ value (e/d) is preferred to a +σ value as they both will lead to a larger Log(1/C) value. The Hansch equation is often accompanied by the sample size (n) and corelation coefficient (r^2^) data. A good equation should have a large sample size as well as a corelation coefficient as close to 1 as possible. Alongside the Hansch equation, the Craig plot can be used in QSAR. Substituents of particular π/σ properties can be selected for the synthesis of the next compound or to generate a library of compounds. The Craig plot can also be used to determine which substituent group can be used in order to synthesise the compound with the highest biological activity. Pharmacology and Medicinal Chemistry of Antihypertensive agents ===============================================================  Angiotensin II produced in the RAS is a potent vasoconstrictor and causes the retention of salt and water. This causes an increase in blood pressure. ACEi and ARBs work by blocking the activity of angiotensin II. **Angiotensin Converting Enzyme Inhibitors (ACEi)** Eg. Captopril, Enalapril, Lisinopril, Perindopril, Ramipril Some clinical uses of ACEi are hypertension, cardiac failure, following myocardial infarction and renal insufficiency. Some adverse effects of ACEi are hypotension, renal failure, hyperkalaemia, angioedema, dry cough. The dry cough is caused by an increase in bradykinin which is normally inactivated by ACE. Bradykinin is a vasoactive peptide and causes bronchoconstriction which initiates cough. ACEi are contraindicated in pregnancy. ACE is a zinc metalloprotease that exhibits enzymatic activity like that of carboxypeptidase A. ACEi interacts with the active site of ACE through an array of intermolecular interactions, thus inhibiting the enzyme. ACEi have several similar features in order to allow it to carry out its function. - The N ring must contain a COOH to mimic the C-terminal of ACE - N ring can be a large heterocycle which increases the potency of the drug - Some Zn binding groups commonly used includes sulfhydryl, carboxylic acid and phosphinic acid groups. Sulfhydryl groups are not as commonly used due to it causing skin rash, taste disturbances and disulfide bond formation. - Esterification of carboxylic acid and phosphinic acid produces prodrugs for better oral bioavailability. **Angiotensin II Receptor Blockers (ARB)** Eg. Candesartan, Valsartan, Irbesartan, Losartan ARBs are mainly used for the treatment of hypertension. ARBs have a better adverse effect profile compared to ACEi. There is less angioedema and less to no dry cough. ARBs are also contraindicated in pregnancy. ARBs also have similar features to angiotensin II in order for it to carry out its function.  - The acidic group mimics Phe 8 at the C-terminal of angiotensin II which can be carboxylic acid or tetrazole - In the biphenyl series, substituents must be in the ortho position. Tetrazole are also favoured due to better metabolic stability, lipophilicity and oral bioavailability - The n-butyl group mimics Ile 5 and provides hydrophobic interactions - Imidazole mimics His 6 **Calcium channel blockers (CCB)** Calcium is a key component of the excitation-contraction coupling process in the CVS. It acts as a cellular messenger to link internal or external excitation with cellular responses. Inhibition of Ca2+ flow through these channels result in both vasodilation and decrease cellular response to contractile stimuli. This leads to a decrease in blood pressure. CCBs can be classified into **dihydropyridine (DHP) CCB** or **non-dihydropyridine (non-DHP) CCB.**  Some examples of DHP CCB includes Amlodipine, Felodipine, Nicardipine, Nifedipine. They are indicated in hypertension with the exception of amlodipine which is also indicated in stable angina and myocardial infarction. Some adverse effects of DHP CCB includes dizziness and peripheral oedema. Some examples of non-DHP CCB includes Verapamil and Diltiazem. They are indicated in hypertension and arrhythmia. Some adverse effects of non-DHP CCB includes dizziness, peripheral oedema (less than DHP CCBs), constipation which is more so with verapamil and digoxin interaction. Except for nifedipine, all other CCB are marketed as racemic mixtures. **Direct Renin Inhibitor** One example of a direct renin inhibitor is Aliskiren. It lowers blood pressure by blocking the conversion of angiotensinogen into angiotensin I by inhibiting the activity of renin. It reduces blood pressure with efficacy similar to diuretic and other RAS blockers. However, it is associated with a higher incidence of angioedema and diarrhoea. **Hydralazine** It is a direct arteriole vasodilator that inhibits inositol triphosphate (IP3)-induced release of calcium from the smooth muscle cells sarcoplasmic reticulum. This reduces peripheral resistance and thus lowers blood pressure. It is indicated for heart failure with reduced ejection fraction (given orally in combination with isosorbic dinitrate). It is also indicated for essential hypertension when first-line medications are unsuitable or inadequate. Some adverse effects include flushing, tachycardia and hypotension. Drugs acting on the sympathetic nervous system can also be used as antihypertensive agents. One common target are adrenoceptors in the arterioles and heart. The adrenoceptor subtypes mainly involved are the α1 and α2 in the arterioles and the β1 in the heart. Agonists of α1 adrenoceptor in the vascular smooth muscles of the arterioles stimulates the G protein through IP~3~ signal transduction. This leads to smoot muscle contraction causes vasoconstriction which increases peripheral resistance and thus leads to increased blood pressure. Agonists of α2 adrenoceptor in the CNS causes the inhibition of sympathetic output that results in reduction in peripheral renovascular resistance which leads to decrease in blood pressure. Agonists of β1 adrenoceptor in the heart activates MLCK. This enhances cardiac contraction and thus heart rate. This increases cardiac output and thus increases blood pressure. Agonists of β2 adrenoceptor in smooth muscles around the body such as the lungs, uterus and blood vessels can inhibit MLCK, which causes muscle relaxation. Based on all of these, **α1 adrenoceptor antagonists**, **centrally acting α2 agonists** and **β1 antagonists** are used as antihypertensive agents. **α1 blockers**  They are effective in managing initial hypertension, advantageous for older men with benign prostatic hyperplasia. They block the effect of the sympathetic nerve on blood vessels by selectively and competitively binding to the α1 adrenoceptor located on vascular smooth muscle. **α2 agonists** stimulation of the α2 adrenoceptor in the medulla oblongata causes inhibition of sympathetic output. This results in reduction of peripheral and renovascular resistance, reducing blood pressure. Some examples of α2 agonists are methyldopa and clonidine. Methyldopa is metabolised (decarboxylation followed by hydroxylation) in the CNS to α-methylnorepinehrine, an α2-adrenergic agonist. SAR studies of clonidine revealed that the imidazoline ring is not necessary for activity, but the phenyl ring is required with at least one o-Cl or Me group, this gave rise to Guanabenz and Guanfacine. **β blockers** Most of the β blockers used today are aryloxypropanolamines and arylthanolamines. Aryloxypropanolamines are more potent than arylthanolamines, however, both have overlapping functional groups that facilitate their binding to the β-adrenoceptor. They have: - At least one aromatic carbocycle and/or heteroaromatic ring system - A side chain attached to the ring which has a chiral secondary OH group and an amine. The amine is either attached to an isopropyl or tert butyl. - Majority of the selective β blockers are phenyloxypropanolamine containing a para-substituent. - The S-stereoisomer of aryloxypropanolamine is the active ligand that binds to the β adrenoceptor. However, majority of β blockers are administered as a racemic mixture with the exception of S-Timolol. β blockers can also be classified as lipophilic or hydrophilic. The difference in lipophilicity affects the PK of the drug. Lipophilic β blockers can cross the blood brain barrier into the CNS and are also extensively metabolized leading to shorter half-lives. **Mixed α/β adrenoceptor blockers** Both labetalol and carvedilol are mixed α/β adrenoceptor blockers. They are both also administered as a racemate. **Diuretics** Medical conditions such as hypertension, congestive heart failure, endocrine disturbances, and kidney & liver diseases can cause retention of excess fluid. Thus, **diuretics** are used in order to increase the production of urine by the kidneys, thereby reducing the amount of fluid retained in the body. This can be done via the inhibition of ion reabsorption, which leads to less water being reabsorbed back into the body. There are several ways to classify a diuretic. - By chemical structure - Thiazides (eg chlorothiazide, hydrochlorothiazide) inhibit Na+: Cl- cotransporter in the distal tubule - By mechanism of action - Osmotics (eg mannitol) promote Na+ and water loss through the nephron by excretion of non-reabsorbable filtrate - Carbonic anhydrase inhibitors (eg acetazolamide) inhibit Na+ and HCO3- in the proximal tubule - mineralocorticoid receptor antagonist (eg spironolactone) - By site of action - Loop diuretics (eg frusemide, bumetamide, torsemide) inhibit Na+:K+:2Cl- cotransporter in thick ascending limb - By effect on urine content - Potassium-sparing diuretics (eg amiloride, triamterene) inhibit Na+ reabsorption in the collecting duct Clinical Diagnosis and Management of Hypertension ================================================= There are different definitions for hypertension depending on the country. This also leads to a difference in how and when hypertension is being treated in these different countries. One widely accepted definition in Singapore of hypertension is the constant, repeated systolic blood pressure (SBP) in the office of ≥140mmHg and or diastolic BP (DBP) ≥90mmHg". Before office determination patients should be seated quietly for 5min and have 2 consecutive readings showing increased blood pressure. The blood pressure category of the patient also determines whether to treat the patient and also the type of treatment that is most appropriate. Hypertension can also be classified by the type of hypertension. This can also determine the treatment of the patient. Essential hypertension is when high blood pressure as stated above is present that is not a result of another medical condition. Instead, there can be other causes such as family history, obesity, diet etc. It is difficult to convince patients with essential hypertension to start treatment as many of them do not have comorbidities what impact their quality of life. Thus, they may believe that it is possible to live normally with essential hypertension. For these cases, the Global Risk Assessment which takes into account many factors to determine the cardiovascular risk of their hypertension can be used to determine if the patient requires treatment. Hypertension can also present with comorbidities. Some examples are established atherosclerotic cardiovascular disease (ASCVD) and renal failure. In these cases, the compelling indications which include the comorbidities that the patient has determine the treatment plan and choice of antihypertensives that the patient should receive. The presence of hypertension mediated organ damage (HMOD) such as retinal damage, heart failure, renal impairment and pulmonary oedema are also indications that a patient should be receiving treatment for hypertension and also the type of antihypertensive that should be given.  The diagram shows the treatment plan that should be adopted by the patient based on the blood pressure category, cardiovascular risk based on Global Risk Assessment and the presence of other risk factors. Generally, for all patients, lifestyle interventions will be recommended. For patients with a smaller elevation of blood pressure, the need for pharmacotherapy depends on the ability of achieving BP control with lifestyle intervention alone. For patients with a very high blood pressure or patients with very high cardiovascular risks, it is recommended to immediately start pharmacotherapy alongside lifestyle interventions. In order to monitor the progress of hypertension in the patients, different blood pressure readings can be taken. Office BPM are the BP readings taken in a medical setting while ABPM are the BP readings taken at home. There should also be blood pressure targets set with the patient. These targets depend several factors such as age of patient, cardiovascular risk, presence of comorbidities and presence of HMODs. [Isolated systolic hypertension] is characterised by a wide pulse pressure (SBP -- DBP \> 80mmHg). This is usually caused by aging and arteriolar stiffness. When treating ISH, it is important to start low and go slow. This ensures that there is no drastic reduction in diastolic blood pressure. [Orthostatic hypertension] is characterised by a decrease in systolic blood pressure of 20mmHg or a decrease in diastolic blood pressure of 10mmHg within 3min of standing when compared to the blood pressure taken from sitting or supine position. Some common etiologies of OH is age, severe volume depletion, baroreflex dysfunction, autonomic insufficiency and certain antihypertensives. It is important to find out the root cause of OH before initiating treatment. It is also important to inform the patient to rise slowly. After treatment, if the blood pressure does not decrease to normal levels, it would then be called resistant hypertension. In these cases, there is likely an underlying reason for the hypertension that is not being addressed which leads to the blood pressure remaining high. Some medications can cause an increase in blood pressure. Some examples include: - Corticosteroids such as cortisone, dexamethasone, hydrocortisone, prednisolone. - Nonsteroidal anti-inflammatory drugs (NSAIDs) such as celecoxib, diclofenac, ibuprofen, naproxen - Nasal decongestants such as phenylephrine hydrochloride and naphazoline hydrochloride - Erythropoietin - Herbal remedies There are also some medical conditions that can lead to resistant hypertension such as Liddle syndrome, apparent mineralocorticoid excess and Gordon syndrome. **Tips for home BP monitoring** Inappropriate sized cuffs is the \#1 cause of inaccurate BP measurement. Undersized cuffs raises BP while oversized cuffs lowers BP. Special methods can be used for special populations such as wrist meters for obese and right arm BP for pediatrics. The cuff should be at the level of the heart. This can be done by resting the elbow on a table. If the cuff is above the heart level, the BP will be lower and if the cuff is below the heart level, the BP will be higher. Patients should be given the following information for home BP monitoring - Take BP twice a day, before breakfast and the administration of meds and then in the evening - Avoid food, caffeine, alcohol 30minutes prior - Sit with legs and ankles uncrossed and back supported against a chair - Stay calm and don't talk while taking blood pressure - Wait for at least 1minute before the second reading - Take readings for 7 consecutive days prior to the next appointment - Calibrate the BP meter against clinic BP meter Applied Pharmacotherapeutics of Hypertension ============================================  If based on the presenting symptoms, it is determined that the patient requires medication for hypertension, first line antihypertensives can be given. The number of antihypertensive drugs given is based on the current blood pressure of the patient and also the BP target of the patient. Each antihypertensive drug lowers blood pressure by approximately 10/5mmHg. First line antihypertensive agents include: - Angiotensin converting enzyme inhibitors (ACEi) - Angiotensin receptor blockers (ARB) - Calcium channel blockers (CCB) of the DHP class - Diuretics The choice of antihypertensive is indicated mainly by the comorbidities present in the patient and also the side effects that are tolerated.  **ACE inhibitors** They are commonly given to patients with hypertension and comorbidities such as diabetes mellitus, chronic kidney disease and proteinuria. They are contraindicated in pregnancy and should be avoided in women who are planning pregnancy or breastfeeding. Some common side effects of ACEi include persistent dry cough, angioedema, dizziness and increased serum potassium levels. Patients starting on ACEi or increasing the dose of ACEi should be monitored for kidney function via serum creatinine and also serum potassium levels. **ARBs** The indications as well as contraindications for ARBs are the same as that of ACEi. ARBs also have a similar side effect profile as ACEi. However, persistent dry cough is less likely when taking ARBs. Patients starting on ARBs or increasing the dose of ACEi should be monitored for kidney function via serum creatinine and also serum potassium levels. **CCBs** CCBs can be given to most patients regardless of comorbidities present. Non-DHP CCBs are contraindicated in patients with heart failure with reduced ejection fraction. Some common side effects of CCBs are peripheral oedema, flushing, headache and hypotension. Laboratory monitoring tests are usually not needed for CCBs. **Diuretics** Diuretics are preferred for patients with osteoporosis, oedema, calcium nephrolithiasis with hypercalciuria. They should be used in caution in patients with increased risk for diabetes mellitus and gout. Some common side effects of diuretics are dizziness, electrolyte imbalance, increased urination, increased uric acid and impaired glucose control. Patients starting on diuretics should be monitored for kidney function as well as electrolytes before starting treatment. For patients with severe hypertension, several of the first-line agents can be given in combination to cause a greater decrease in blood pressure. However, there are some agents that should not be given in combination. If the patient still presents with hypertension despite all of these pharmacological interventions, third-line agents can then be considered. Some third-line agents include: - Aldosterone antagonists - Alpha-blockers - Centrally acting agents It is also important to ensure that the patient is adherent to their medications. If so, the patient should also be referred to a specialist for treatment. Cardiac Output and Heart Failure ================================ **Cardiac output** is defined as the volume of blood pumped by the left ventricle into the aorta per minute. \ [*cardiac* *output* = *stroke* *volume* × *heart* *rate*]{.math.display}\ Cardiac output is important as it determines the rate of blood flow through capillaries. This affects the transport of materials to and from tissues around the body. Cardiac output is affected by the following: - Preload/Volume in the ventricle - Heart which is determined by both heart rate and contractility - Afterload/resistance in the blood vessels **Heart failure** is defined as the failure of the heart to pump at a sufficient rate to service the metabolic requirements of the tissues. Heart failure can also be defined as the ability to do so only at elevated filling pressures (after compensation). Some causes of heart failure are: - Haemorrhage which causes a decrease in the preload due to less blood volume present in the body - Myocardial infarction which reduces the contractility of the heart muscles - Brachycardia which causes a lower heart rate - Hypertension which increases the peripheral resistance outside of the heart The body uses several mechanisms to compensate for heart failure. In an acute setting, the body activates the sympathetic nervous system and suppresses the parasympathetic nervous system in order to increase cardiac output.  In this case, patients generally present with an increased heart rate, increased strength of cardiac contractions and sweating. In the longer term, the body makes use of the RAAS system and the natriuretic peptide system in order to increase cardiac output. In this case, patients generally present with oliguria (less urine), oedema and breathlessness as well as remodelling of the heart and blood vessels. Excessive fluid reabsorption cannot increase cardiac output beyond a certain limit. In patients with heart failure, there are insufficient cardiac reserves and the increase in pressure by increasing fluid reabsorption does not lead to an increase in cardiac output. Instead, there might be excessive venous pressure causing oedema or pulmonary oedema leading to breathlessness. Over a long period of time, these can cause inflammation, fibrosis and hypertrophy of the heart muscle which remodels the heart. There can also be a decrease in NO in the blood which is an important vasodilator. Heart failure can be classified into heart failure with reduced ejection fraction (HFrEF) when the ejection fraction falls below 40% and heart failure with preserved ejection fraction (HFpEV) when the ejection fraction remains above 40%.  Applied Pharmacotherapeutics of Heart Failure =============================================