Drugs: From Molecules to Man

Lecture 1: Introduction Lecture

Lectures 2+3: Types of Protein TargetTransporter – where a protein binds to a specific binding site and is carried either actively or passively across a membrane. This is good for transporting nutrients or setting up a concentration gradient. The main transporters involved are symporters and antiporters. Symporters use the electrochemical gradient of one ion (typically Na+) to carry another ion or molecule across a cell membrane. Antiporters use the electrochemical gradient to drive another in the opposite direction. The Na+/K+ ATP pump uses ATP in order to exchange 2K+ for 3Na+ and an Na+/H+ exchanger uses the Na+ gradient established to pump H+ ions in the opposite direction.

Ion channels are hydrophilic pathways that allow ions to move through a hydrophobic environment and are important where the gradient across a membrane must be quickly adjusted, such as in neurons. Selectivity filters on ion channels ensure that only ions of the correct size and charge are able to pass through. Channel proteins can be both charge and ligand gated.

Nuclear Hormone Receptors are intracellular receptors which bind to lipid soluble ligands and are responses for many important signalling molecules and metabolites. These include sex hormone receptors such as testosterone, retinoic acid receptors (vitamin C), corticosteroid receptors, thyroid hormone receptors and vitamin D receptors. The receptors are mostly found in the cytoplasm. Nuclear Hormone Receptors can control expression and repression of certain genes, the changes in gene expression brought about by NHRs culminate in changes in protein expression and thus cell behaviour, these changes occur slowly compared to other types of signalling, hours or days.

G-Protein Coupled Receptors are the most diverse and medically important receptor class. All GPCRs have the same 7 transmembrane domain structure with the NH3 terminals outside the cell. This structure is shared with bacteriorhodopsin

cAMP is produced from ATP by adenylate cyclase. Its main effect is to switch protein kinases from the inactive to the active conformation. Protein kinases phosphorylate proteins at specific sites to regulate their activity. Kinases can be either very specific, such as myosin light chain kinase, or promiscuous, such as PKA. Often the cAMP production is regulated by GPCRs. A particular type of G-protein, the Gs (stimulatory) protein enhances adenylate cyclase activity. Signalling pathways coupled to GPCRs involving cAMP include adrenaline, noradrenaline, glucagon, dopamine, somatostatin, parathyroid hormone and many others. Proteins regulated by cAMP dependent protein kinases include myosin light chain kinase and PKA (protein kinase A). Another protein, G i, woks in the same way as Gs, but instead acts to inhibit cAMP production. Different neurotransmitters and hormones can increase or decrease the adenylate cyclase activity depending on whether their GPCRs prefer to interact with Gs or Gi, and their relative intrecellular concentrations; it also depends on what targets are present for PKA to act on.

The function of phospholipase C is to split the complex PIP2 into diacyl glycerol (DAG) and the head group inosital triphosphate (IP3). DAG remains in the membrane and activates phospholipase C, while IP3 is released into the cytoplasm where it binds to the ER and causes the release of Ca 2+ from intracellular stores, to enhance the activity of protein kinase C. Phospholipase C is activated by G q. Signals coupled to IP3/ phospholipase C include Ach, NA, vasopressin, serotonin and many others. Proteins regulated by Ca2+ include adenyl cyclase, myosin light chain kinases, cAMP and phosphodiesterases. Proteins regulated by protein kinase C include glycogen synthase.

Lecture 4: Drug-Receptor BondsLipids and DNA have little specifity as drug targets as they act as binding sites rather than receptors. The drug makes specific bonds with the binding protein domain and this has a conformational effect on the protein, either altering or stabilising its structure. The chemical nature of the drug pocket depends on which amino acids bind to it. Drug-receptor bonds include strong electrostatic bonds (ionic, ion-dipole and dipole-dipole), and significantly weaker hydrogen bonds. Other drug-receptor bonds include hydrophobic and covalent bonds as well as van der Waals forces. Re-arrangement of water molecules around a molecule forces it to become less ordered and leads to a gain in entropy. Van der Waals forces consist of local dipoles and are very weak at 2kJ/mol, covalent bonds are very strong at >100kJ/mol and connect irreversible enzyme inhibitors. Organophosphates can covalently modify acetylcholinesterase, paralysing individuals.

Stereoisomers are non-super-imposable mirror images, but have identical physical properties. Dextro (D/+) enantiomers rotate plane polarised light clockwise, and Laevo (L/-) counter clockwise. Mirror-image drugs will not bind to specific binding sites and receptors with a larger degree of attachment are said to have a greater affinity. A pharmacore is the 3D arrangement of functional groups necessary for biological activity to result. Another way of classifying enantiomers is with the Rectus (Right) and Sinister (Left) system. The atoms are labelled 1-4 from highest to lowest priority (the higher the atomic number of the atom, the higher the priority), with the lowest priority atom facing towards you, look at the direction in which the priority ascends.

Lecture 5: Drug-Receptor InteractionsReceptors recognise extracellular substances and transduce their information. Agonists bind to receptors and transduction occurs, where the signal is converted into a different type. Antagonists bind to the receptors and block transduction. AJ Clark isolated frog muscle and added Ach, he found that it caused relaxation of the heart muscle but contraction of the rectus abdominus muscles. Through experimentation he concluded that there was no relationship between the amount of drug present in the cell and the resulting response.

Kd, the dissociation constant is the concentration at which the drug gives half-maximal binding. As the Kd increases the drug binds with less affinity for the receptor. If drug X has a K d of 5nM, and drug Y has a Kd of 50nM, drug X is has a 10x higher affinity than Y. It is much easier to identify K d on a log graph. A concentration: response graph produces a rectangular hyperbola, a log concentration: response graph produces a sigmoid shape. Radioligand binding involves incubating a sample of receptors with a radioactive form of a complementary drug. The receptors are then separated to get rid of excess unbound radioactivity by centrifugation or filtration.

EC50 is the concentration that gives 50% of the maximum response, sometimes receptors are left unoccupied because they are not always needed for a maximum response to be achieved. One receptor may activate four enzymes, for example. Function is not always related to affinity, but it is often used to measure potency; the higher the EC50, the lower the potency since more drug is required to achieve a response. IC50 is the concentration of an antagonist that gives 50% of the control response. Affinity is not the same as potency: Kd is not always the same as EC50.

pD2 (pEC 50)=−log10EC 50

Selectivity is the relative potency for a drug eliciting one effect compared with another effect.

Lecture 6: Competitive AntagonistsProfessor Langley experimented with the effects of the drugs pilocarpine and atropine on salivary secretion of sedated cats. Pilocarpine caused the cat to salivate much more than in the control sample, and atropine caused it to salivate much less. When atropine was added followed by pilocarpine, only a little more saliva than usual was produced and Langley concluded that atropine prevents the binding of pilocarpine to a specific site on a cell. We now know that atropine is a competitive antagonist at muscarinic acetylcholine receptors. If a receptor requires 50% occupancy by an agonist, it will produce a full response when these requirements are met, and it will produce half the response at 25% occupancy. By convention an agonist is assigned the symbol “A”, and an antagonist “B”. KB is the dissociation constant of an antagonist and is equal to the concentration required to occupy 50% of the receptor, where Kb is the rate of the backwards reaction, and Kf the forwards reaction.

K B=Kb

K f=

[B ]+[R−RA−RB ][RB ]

pA2 is ameasure of potency , calculated by−log10 KB

The Gaddum equation calculates the concentration required in order to occupy the same number of receptors in the presence or absence of an antagonist.

[A '}with anta gonist[A ]without antagonist=

[B ]Ka

+1

Lecture 7: Agonists to AntagonistsClark hypothesised that amplification is an enzyme cascade caused by drug occupancy of a binding site. Adrenaline binds to receptors in the liver, activates adenylate cyclase, which in turn activates cAMP. Many steps then follow, eventually leading to glycogen release, which is converted to glucose. Clark based his prediction of this theory on two assumptions; that the agonist occupancy is proportional to fractional occupancy (Fractional occupancy is the fraction of all receptors that are bound to ligand) – true, and that a maximum response exists when all receptor sites are occupied – not true. Often Kd (binding affinity) is not equal to EC50 (potency required for a response). Partial agonists give a response whose maximum is less than that of a full agonist; it can therefore antagonise an agonist to ensure a smaller response is produced. Affinity is the capacity of the ligand to bind; efficacy is its capacity to excite. A response requires both factors to be present, competitive antagonists have no efficacy and partial agonists only have some. Tissue-spare receptors, or receptor coupling, means a maximum effect can be produced by an agonist when only a small percentage of the receptors are occupied. The proportion of spare receptors varies between tissues.

Functional antagonists can have different effects on the same or different cell types in a system. Salbutamol causes bronchodilation, methacholine causes bronchoconstriction and when both drugs are added they effectively cancel each other out, producing no effect. An indirect agonist releases a chemical from one cell type, which then acts on another cell type, whilst an indirect antagonist prevents the reaction of the released chemical on the second cell type. An indirect agonist has no specific activity on the neurotransmitter receptor itself, they can work through transporter blockade, induction of transmitter release and inhibition of transmitter breakdown. Nicotine acts by promoting NA release, which increases the heart rate. Competitive antagonists do not have an intrinsic efficacy, antagonists antagonise endogenous mediators responsible for tone (basal activity), for example atropine decreases salivary secretion.

Lecture 8: Physiology of the Cardiovascular and Respiratory SystemsThe nervous system is divided into the Central and Peripheral Nervous Systems.The PNS is divided into the Afferent (sensory) and Efferent (motor) Nervous Systems.The Efferent Nervous System is divided into the Autonomic and Somatic Nervous Systems.The Autonomic Nervous System is divided into the Sympathetic and Parasympathetic divisions.

Acetylcholine acts on nicotinic acetylcholine receptors at the synapse between pre- and post-ganglionic neurons in both the sympathetic and parasympathetic systems. The sympathetic system has short pre-ganglionic fibres, and the parasympathetic has long pre-ganglionic fibres. The sympathetic nervous system has adrenergic receptors on which agonists such as adrenaline and noradrenaline can act. Stimulation of the SNS leads to the “flight or fight” response, with such results as an increased heart rate and blood flow to muscles. It also inhibits GI peristalsis and leads to bronchial and pupil dilation. The parasympathetic nervous system has muscarinic acetylcholine receptors at the effectors and stimulation of the PNS leads to “rest and digest” responses, including a decreased heart rate, increased GI motility and gastric acid secretion, and also bronchial and pupil contraction.

The control of vascular smooth muscle tone is largely sympathetic and involves α and β2 receptors. At the α adrenoreceptors when [NA]={A], vasoconstriction occurs, at the β adrenoreceptors, when

[NA]≤[A], vasodilation occurs. Sympathetic activation of vascular smooth muscle in the skin and kidney leads to vasoconstriction, sympathetic activation of that in the muscle and liver leads to vasodilation. Emotion or exercise triggers the sympathetic neuron to release Ach, triggering NO release from the endothelium of the blood vessels, causing vasodilation. At rest, smooth muscle in the respiratory tract is fully dilated, irritation causes parasympathetic activation and constriction.

Lecture 9: Hypertensive Drugs - Antagonists at AdrenoreceptorsPrimary/ Essential/ Idiopathic hypertension results from an unknown cause, secondary hypertension has a known cause, such as polycystic renal disease, renal artery stenosis and phaeochromocytoma, a neuroendochrine tumour of the adrenal medulla. Hypertension diagnosis is most commonly based on diastolic blood pressure.

Mild Hypertension 90 – 105 mm HgModerate Hypertension 105 – 120 mm Hg

Severe Hypertension 120 + mm Hg

Hypertension can result in an increased mortality from coronary disease ad myocardial infarction, or a stroke (from cerebral haemorrhage or thromboembolism). Antihypertensive drugs include α and β adrenoreceptor antagonists, ACE inhibitors, thiazide diuretics and calcium channel blockers. Treatment involves a reduction in the risk factors for cardiovascular disease, such as smoking, obesity and hypercholesterolaemia.

Mean Arterial Blood Pressure=CardiacOutput ×Per ipheral Resistance

CardiacOutput=Heart Rate×StrokeVolume

Reducing the peripheral resistance initially lowers the blood pressure, but baroreceptor activation produces a reflex activation in cardiac output. This reduces the fall in blood pressure.

α adrenoreceptors are useful in phaeochromocytoma treatment. An increased adrenaline secretion causes episodes of severe hypertension, phentolamine is a non-selective α antagonist and so causes vasodilation and stops adrenaline release. It is not, however, suitable for treatment of hypertension itself, hypertension is aided by the use of prazosin, a selective α1 adrenoreceptor antagonist. Phentolamine is not suitable for hypertension treatment because it causes an unacceptable

tachycardia due to an increased NA secretion. With prazosin, NA secretion is regulated, resulting in an acceptable reflex tachycardia. However, although it is successful in being used where other therapy has proved ineffective, it does provide some unwanted effects such as postural hypotension, urinary incontinence and also retrograde ejaculation due to a weakening of the bladder neck. β

adrenoreceptor antagonists include propranolol; a competitive non-selective β antagonist, which is relatively lipid-soluble and atenolol; a competitive selective β1 antagonist, which is relatively water-soluble. Propranolol therefore can penetrate the CNS and can cause vivid dreams.

Anti-hypertensive β antagonists decrease cardiac output, renin (reenin) release and sympathetic tone, a basal level of sympathetic activity in the body. β receptor antagonists also lead to unwanted effects such as bronchoconstriction, precipitation of heart failure or heart block, hypoglycaemia or cold extremities.

Lectures 10+11: Basic Mechanisms in HypertensionDiuretics produce increased Na+, Cl- and H2O excretion, producing more urine. Their effects can be additive or synergetic and the maximum response depends on the site of action.

Osmotic diuretics, such as mannitol, filters water at the glomerulus but doesn’t reabsorb it, urine osmolarity is therefore increased The drug is given either orally or intravenously and is used in the treatment of renal failure. Loop diuretics, such as frusemide and bumetanide inhibit the Na +/K+/2Cl-

cotransporter in the ascending loop of Henlé. Because the ion gradient in the medulla is not maintained, water stays in the nephron. These are the most powerful diuretics and are used to combat heart failure, renal failure, pulmonary oedema and hypertension with renal failure, but not in the treatment of hypertension itself. Thiazide diuretics, like bendroflumethazide and chlortalidone, act by inhibiting Na+/Cl- cotransport in the distal convoluted tubule, leading to a lesser ability to reabsorb water in the more distal portions. Thiazide diuretics are mild and used to treat oedema and hypertension.

The major problem with loop and thiazide diuretics is that it can lead to hypokalemia, low potassium levels. More and more NaCl is lost by passage through the nephron, increasing the transport across principal cells which increases the lumen negative potential, leading to potassium loss as the gated ion channels open. Potassium sparing diuretics, like spironolactone, amiloride and triamterene

decrease trans-principal cell Na+ movement and decrease the negative lumen potential. Spironolactone inhibits the effect of aldosterone (which increases reabsorption of ions and water in the kidney) and decreases sodium absorption. Amiloride and triamterene block Na+ channels in the lumenal membrane. These three drugs are very weak on their own but are used in combination with other diuretics. Fast control of blood pressure is achieved through sympathetic and parasympathetic activity of the ANS. Slow “compensatory” control is achieved through the hormone aldosterone, which increases Na+ absorption in the collecting duct by increasing the number of Na+/K+ ATPases, and the number of sodium channels, and stimulation of channels via a protein mediator.

Renin (reenin) release leads to a decrease in Na+ concentration and activation of the SNS, as it is secreted into the bloodstream it provides a much more general effect than ACE which only locally activates Angiotensin II. ACE inhibitors include captopril, enalapril and ramipril, but produce unwanted effects such as initial dose hypertension and a cough. Captopril was the first designer drug. ACE antagonists such as losartan, valsartan and candesartan do not produce coughs. Angiotensin receptors are G-Protein Coupled Receptors.

Lecture 12+13 – Cardiac Arrhythmias and Antidysrhythmic DrugsArrhythmias are classified by their site of origin, which can be atrial, ventricular or junctional, and the type of heartbeat, tachycardias, bradycardias and true arrhythmias, which show a disturbed rhythm. Tachycardias can take the form of atrial/ventricular fibrillation/flutter. Ventricular flutter can be quickly fatal. Multifocal atrial tachycardia results from electrical impulses arriving from multiple atrial locations, paroxysmal supraventricular tachycardia (PSVT) occurs from time to time with a rapid but regular heartbeat, and an ectopic heartbeat happens where the electrical impulses governing the heart rate originate in the wrong place, leading to an irregular rhythm with extra or skipped heartbeats. Bradyarrhythmias include heart block, where damage to the AV node, such as from fibrosis, causes the atria and ventricles to beat independently. Asystolic arrest is a complete cessation of electrical activity. People at a higher risk of arrhythmias include those suffering from CAD, heart valve disorders and blood chemistry disorders, or those taking drugs such as β blockers, caffeine, amphetamines, cocaine and some antidysrhythmic drugs.

Cardiac arrhythmias can be due to disorders of impulse generation or conduction. Atrial flutter is an abnormally high heart rate of over 250 bpm, due to ectopic foci in the atrial myocardium. Because the maximum conduction rate of the AVN is about 200 bpm, some degree of heart block may occur due to the danger of thrombus formation. An ECG trace shows many P waves and no T waves. Atrial

fibrillation is produced by no co-ordination in atrial contraction. QRS complexes occur at irregular intervals on an ECG trace and the ventricular rate is also very high and irregular. With ventricular fibrillation, an ECG shows no QRS waves and this is rapidly fatal. DC electric shock may be the only way of restoring a normal heart rate.

Antidysrhythmic drugs can be classified according to the Vaughan-Williams system.

Weaknesses of the system include that it excludes some potential sites of antidysrhythmic drug action, such as adenosine A receptors, muscarinic M2 receptors, Na+/K+ ATPase and digoxin. The system also doesn’t allow for the fact that drugs may have multiple mechanisms of action (such as Solatol, which can be seen as a class 2 or 3 drug) or that the effects of the drugs on healthy and unhealthy people may differ.

Antidysrhythmic drugs can also be classified by clinical utility. The classes include drugs for arrhythmias of supraventricular origin such as adenosine, drugs of either supraventricular or ventricular origin such as propranolol or quinidine, and of ventricular origin such as lidocaine.

Amiodarone is useful for both supraventricular and ventricular arrhythmias and is useful in treating Wolff-Parkinson-White syndrome. According to the Vaughan-Williams classification it can be considered a class 1, 3 and 4 drug. Amiodarone has the structural analogue of a thyroid hormone, it is very lipophilic and deposits microcrystals in the tissues; phototoxic reactions in the skin can turn it a grey-colour and deposits in the cornea can cause dazzling from bright lights. Amiodarone has a half-life of 10 to 100 days and can be administered orally or by IV injection into a central vein. It is used to treat atrial/ventricular fibrillation/flutter and PSVT by prolonging action potentials and

increasing the heart rate without depressing the force of contraction. It can also lead to hepatotoxicity, bradycardias and conduction disturbances.

Adenosine is useful for treating supraventricular arrhythmias, but is Vaughan-Williams unclassified. It binds to and activates α1 purinoreceptors on cardiac myocytes, leading to an opening of K+ Ach channels, causing hyperpolarisation and the inhibition of Ca2+ channels and shortening the action potential duration. This leads to a lower discharge rate of the SAN, reduced conduction and an increased refractory period in the AVN. It is useful in the suppression of PSVT, ventricular tachycardia associated with Wolff-Parkinson-White syndrome and supraventricular tachyarrhythmias that may occur during general anaesthesia. Adenosine is a naturally-occurring purine nucleotide with a plasma half-life of 10 seconds. It can, however, lead to severe bradycardias, facial flushing, chest pains and dyspnoea and bronchospasm in severe cases.

β blockers block β1 adrenoreceptors in the SAN, AVN and ventricular tissue, they reduce depolarisation of the SAN and AVN, slow sinus rhythm and slow conduction through the AVN.

Suppression of arrhythmias can be induced by excessive catecholamine release, increased tissue sensitivity to catecholamines, and also after a myocardial infarction has occurred. Catecholamines are derived from the amino acid tyrosine, include NA, adrenaline and dopamine and circulate in the blood. Unwanted effects of β adrenoreceptor antagonists include bronchoconstriction, hypoglycaemia, cold extremities, vivid dreams and precipitation of cardiac failure or heart block. Drugs used to treat dysrhythmias alter ion channel activity and intracellular Ca2+

concentration.

There are two main types of neuron; Aδ neurons provide fast impulse transmission and hence produce sharp pains, C neurons provide slow impulse transmission and burning pains.

Local anaesthetics lidocaine, procaine and cocaine all have aromatic, linker and amine groups, they are only active inside the cells, providing inhibition of impulses by binding to Na + channels and causing them to remain open, this is known as direct use dependence.

Vaughan-Williams Class 4 drugs are calcium channel blockers, which slow SA and AVN conduction and suppress ectopic pacemakers. They decrease atrial and ventricular fibrillation, but can lead to Wolff-Parkinson-White Syndrome, cardiodepression, hypotension, AVN block, oedema, headaches and constipation. Nifedipine is used for treatment of hypotension and angina, not dysrhythmias.

Type L and T Ca2+ channels are found in the heart, types N and P on neurons.

Lectures 14+15 – Drugs used to treat Angina and Cardiac Failure Drugs used to treat Angina and Cardiac Failure include organic nitrates, K + channel activators, β-blockers and Ca2+ antagonists. Angina pectoris produces a crushing pain in the chest that may radiate to the arm, neck, or jaw, due to the convergence of nerves. The pain results from cardiac ischaemia due to the heart not receiving enough oxygen to meet its demand. When oxygen demand increases due to an increased amount of cardiac work, coronary blood flow increases, but due to factors such as atherosclerosis, thrombus formation and vasospasm, angina sufferers cannot increase blood flow. Atherosclerosis is a type of arteriosclerosis that occurs when plaque is deposited in arteries due to high cholesterol, this narrowing also makes it more likely that a thrombus may form, or break off and lodge itself elsewhere in the body.

Stable angina (angina of effort) is the most common type of angina, caused by atherosclerosis of coronary arteries and is triggered by exercise, excitement and cold weather. Stable angina is easily treatable with rest and relaxation, but therapeutic treatment includes aspirin (reduces platelet aggregation) and statins (to lower cholesterol) as well as organic nitrates, β-antagonists and Ca 2+

blockers. It is also surgically treatable with Coronary Artery Bypass Graft surgery (CABG) or Percutaneous Transluminal Coronary Angioplasty (PTCA). Unstable/ brittle angina is associated with the disruption of pre-existing atherosclerotic plaque or superimposition of a thrombus and attacks occur at rest. Variant/ Prinzmetal's angina is rare, it is caused by vasospasm when at rest and at the same time in the mornings. All three forms of angina can easily lead to myocardial infarction.

Organic Nitrates, such as nitroglycerine, are prodrugs, which need to be metabolised before being able to function as drugs. Most cardiac drugs seem to work by reducing cardiac work and thus reducing the cardiac oxygen demand. Nitrates reduce cardiac work by reducing preload and afterload through dilation of capacitance vessels and a decrease in central venous blood pressure. Because of this decreased pressure, less blood returns to the heart, leading to a decreased EDV (preload), decreased myocardial stretch and contractile force, and this produces decreased cardiac work, relieving some anginal pain. Large doses of nitrates also cause arteriolar dilation and a fall in peripheral resistance, also reducing cardiac work.

GTN is ineffective if swallowed because it is metabolised in the liver, so tablets are taken sublingually, or medication is taken via a buccal spray, skin patches, ointments and IV injection. GTN only has an affect for 20-30 minutes and is therefore used to suppress acute attacks. Isorbadide dinitrate is effective when swallowed and, as with all nitrates, depends on the metabolism rate to

yield mononitrate. The duration of the action of sustained release tablets can last up to 12 hours, but tolerance of the drug is likely to result with time. Unwanted effects of nitrates include flushing of the skin, headaches, orthostatic hypotension (fainting from hypotension) and a reflex tachycardia in response to vasodilation. β blockers decrease the heart rate and promote diastole, allowing more blood to flow around the coronary circuit, but the primary intention is to reduce cardiac work, and hence O2 demand.

There are three types of voltage gated Ca2+ channel; L, T and N. Only L-type channels are sensitive to the drugs verampanil and nifedipine.

Verampanil is use-dependent and only blocks the channels when they are active, whilst nifedipine blocks the channels regardless. Verampanil is more effective in the heart because it selectively blocks the more active Ca2+ channels, reducing heart rate and cardiac output. Nifedipine is more potent on vascular smooth muscle than in the heart and so reduces cardiac preload and afterload. Unwanted effects of verampanil include constipation, heart block and precipitation of cardiac failure, while nifedipine produces headaches, flushing, dizziness and gravitational oedema.

Early palliative treatment of myocardial infarction includes hospitalisation and IV administration of morphine, an analgesic, which also reduces centrally mediated sympathetic tone. Death of heart cells is also limited by the use of thrombolytics, which restore blood flow, and organic nitrates, which decrease preload and chest pain. “hypertrophy” refers to filling problems with the heart and “congestive heart failure” refers to pumping problems. Common causes include hypotension, myocardial infarction and valvular disease. In the short term many factors arise to compensate for cardiac failure, but in the long term these effects become problematic, so these must be controlled.

Congestive heart failure leads to the person becoming easily tired, peripheral cyanosis due to underperfusion (lack of nutrition via capillary beds) of skin, and salt and water retention due to underperfusion of the kidney, which leads to oedema; pulmonary hypertension, dyspnoea and engorgement of the liver result. Treatment strategies include a reduction in cardiac work with rest, a reduction of salt in one’s diet and the usage of ACE inhibitors, organic nitrates and thiazide and loop diuretics.

A positive inotropic agent, such as digoxin, can be used to increase cardiac output. This improves symptoms in patients with atrial fibrillation, but doesn’t change the mortality rate. Digoxin increases Na+ concentration, inhibits Ca2+ afflux and increases sarcoplasmic reticulum Ca2+ concentration, allowing an increased force of cardiac muscle contraction without an increase in O 2 requirements. At pharmacotherapeutic doses, digoxin increases vagal nerve activity, slowing the SAN firing rate. At toxic doses it produces arrhythmias and inhibits Na+/K+ ATPase, leading to depolarisation and ectopic heartbeats. Digoxin has a low 2:1 therapeutic dose, signs of toxicity include nausea and vomiting, disturbances of visual acuity and colour and ventricular tachyarrhythmias.

Other treatments of congestive heart failure include phosphodiesterases (PDE) inhibitors and β 1

agonists and antagonists. Other treatments of congestive heart failure include phosphodiesterases (PDE) inhibitors and β1 agonists and antagonists.

Lectures 16, 17+18 – Drugs for AsthmaBronchial asthma is a disease characterised by the widespread narrowing of peripheral airways in the lung, varying in severity over short periods of time either spontaneously or in response to treatment. Genetic factors can be an issue, as well as environmental influences in early life, such as maternal smoking, intrauterine nutrition, avoidance of dietary and environmental allergens in early life etc. Specific asthma triggers include excreta of dust mites, pollens, exercise or emotion, cold air, respiratory tract infections, animal fur, dander, saliva, fungal spores etc.

Dendritic cells present antigens to lymphocytes, which differentiate into specific cells. Sensitised mast cells and eosinophils release mediators in response to allergens. Mast cells are responsible for the release of early preformed mediators, including histamine (which causes contraction of smooth muscle in the airways and increased vascular permeability and bronchial secretions), eosinophil and neutrophil chemotactic factor and the release of later mediators synthesised “de novo” and attracted eosinophils release a protein, later leading to epithelial desquamation. Later mediators include secretions of leukotriene C4, D4 and E4 and those of prostaglandin D2, which regulate the body’s inflammatory response as mentioned above.

Anti-asthma drugs include relievers, or bronchodilators, for short-term use, and preventers, or prophylactic agents, for long-term use. Drugs for short-term use include agonists at β2

adrenoreceptors (bronchodilators), alkylxanthines, such as theophylline, which bears a structural similarity to caffeine and antagonists at muscarinic Ach receptors. Non-selective agonists at β adrenoreceptors include isoprenaline > adrenaline > noradrenaline. A β1 agonist is dobutamine, and a β2 agonist is salbutamol. Propranolol is a non-selective β antagonist, atenolol is a β1 antagonist.

Β1 adrenoreceptor activation causes an increased heart rate and force, a relaxed GI tract, stimulation of lipolysis and glycolysis and renin production. β2 adrenoreceptor activation causes relaxation of airway smooth muscle, dilation of blood vessels, an increased glycolysis rate and skeletal muscle contraction. β antagonists with a greater lipophilicity produce longer-term effects. Salmeterol has longer-term effects than does Salbutamol.

β antagonist bronchodilators, however, can produce some adverse side effects, such as a tremor, due to interference with muscle spindle function (The muscle spindle's functions are to send proprioceptive information (one's own perception) about the muscle to the central nervous system, and to respond to muscle stretching). Other side-effects include tachycardia, nervous tension due to its effect on the CNS, and hypokalemia, a low K+ concentration due to the stimulation of Na+/K+

ATPase in skeletal muscle. These may be minimised by inhalational, rather than oral administration.

Theophylline is an alkylxanthine that is very structurally similar to that of caffeine. Theophylline stops cAMP being broken down to AMP and so prolongs the suppression of inflammation and the relaxation of airway smooth muscle. Although theophylline has been around for many years there is still some debate as to whether or not it actually works. During an asthma attack, adenosine release causes bronchoconstriction and theophylline can act as a competitive antagonist to stop this from happening. Aminophylline is a water soluble complex of theophylline and ethylenediamene and is administered intravenously. Theophylline is taken either orally, with sustained release capsules, or intravenously, to make it last longer and avoid side effects from high concentrations, especially as the therapeutic window is low. Its half-life is affected by cardiac and liver diseases, as well as smoking and many drugs, plasma or salivary assay can help determine the correct dosage. Unwanted effects of theophylline include nausea, headaches, fainting, tachycardia, cardiac dysrhythmias and convulsions (seizures due to effects on the CNS).

At muscarinic Ach receptors, agonists Ach, methacholine and muscarine are of high potency, while nicotine is of low potency. The antagonist atropine is of high potency and tubocurarine of low potency, but the drugs have different effects in different parts of the body. Some people suffer Ach release during an asthma attack and in the past atropine was used as a competitive antagonist to stop increased goblet cell secretion and bronchoconstriction, but it was found that atropine had widespread unwanted effects and so this was found not to be practical. Ipatropium has a very similar structure to atropine, but is used in conjunction with other drugs by inhalation and since it is positively charged, it cannot be well absorbed and can therefore give many unwanted effects as with atropine, through antagonism at other muscarinic Ach receptors to stop salivary secretion and produce dry mouth. Rarely it also causes urine retention and blurring of vision.

Drugs for long-term use include glucocorticosteroids, sodium cromoglicate and nedocromil, and cysteinyl leukotriene antagonists. Glucocorticosteroids such as hydrocortisone modulate protein and carbohydrate metabolism at low concentrations and lead to suppression of inflammation and the immune response at high concentrations.

Glucocorticosteroids bind to a hormone response element on a gene, through the same mechanism as with a nuclear hormone receptor, and decrease the amount of mRNA produced through gene repression, leading to a decreased protein production. Glucocorticosteroids prevent the formation of promoters of bronchoconstriction, mucus secretion and capillary permeability. They also prevent cytokine release, to avoid attracting lymphocytes to the affected area. A short-term rescue therapy to regain control of asthmatic effects lasts for about 7 days with oral prednisolone, a continued administration is used for chronic and severe asthma. One major problem with glucocorticosteroids is that they lead to the growth of the opportunist Candida albicans (oral thrush), through local immunosuppression and local effects on the vocal cords can result in dysphonia (hoarseness). The incidence of these unwanted effects can be reduced by using a spacer device, or by rinsing the

mouth with water after administration. The more serious effects of glucocorticosteroids do not occur so much nowadays, but can include muscle wasting, osteoporosis, poor wound healing, increased abdominal fat, thinning of the skin, hypertension and the presence of a buffalo hump and a moon face. These are Cushingoid features.

Sodium cromoglicate was found to be the compound that worked in alleviating the symptoms of asthma, after 150 compounds were produced from the active ingredient in the plant Ammi visnaga, which was previously commonly known as a traditional asthma remedy. Sodium cromoglicate is administered by inhalation, but is not easily absorbed because is highly charged. It reduces the early phases of asthma but is slow in the later phase and is therefore used prophylatically. It is also only effective in a minority of patients, more so children than adults.

Leukotrienes are produced by eosinophils, basophils and macrophages and are important mediators in asthma. They are agonists at CysLT receptors and cause contraction of bronchial smooth muscle, stimulate mucus secretion and increase microvascular permeability. Competitive antagonists such as montelukast and zafirlukast are administered orally as additional prophylactic therapy in mild to moderate asthma. It reduces exercise-induced and aspirin-induced asthma. Unwanted effects include abdominal pain, nausea and headaches and zafirlukast may also cause hepatotoxicity.