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By R. Aila. Conway School of Landscape Design. 2018.
Nutritional (pathology from too much/too little food intake) Deficiency (vitamin deficiency secondary to reduced intake) Excess (obesity leading to diabetes) 9 actonel 35mg lowest price medications vitamins. Developmental (pathology in the chemistry of heredity) Inborn errors of metabolism (Fanconi’s syndrome purchase actonel 35 mg fast delivery medications made from animals, cystinuria) Genetic diseases (Huntington’s disease) 10. Degenerative (pathology from age-related tissue breakdown) Protein misfolding diseases (Alzheimer’s dementia, prion diseases) Apoptosis (pre-programmed cell death) Mechanical “wear-and-tear” (osteoarthritis [or, more correctly, osteoarthropathy]) This classification system is based on a traditional pathology approach to disease with emphasis on etiology (causative factors) and pathogenesis (mechanism of disease, particularly at a cellular level). For example, drug design that targets neoplasia may lead to drugs with many applications, including lung cancer, bowel cancer, or brain cancer. Likewise, drug design that targets inflammation could have applications to many dif- ferent diseases, affecting many organ systems. Nevertheless, this approach focuses more on cellular targets than on molecular targets. Neuropeptides and peptidergic receptors Opioid peptides Neurokinins Neuropeptide Y Galanin Cholecystokinin j. Steroid hormones and their receptors Estrogens Progestins Androgens Adrenal steroids b. Peptide hormones and their receptors Pituitary neurohormones Oxytocin and vasopressin Insulin and glucagon Renin–angiotensin hormones 3. Cytoplasmic organelle targets Mitochondrial targets Rough endoplasmic reticulum Smooth endoplasmic reticulum c. Proteins Enzyme proteins Hydrolases Amidases (proteases) Esterases (lipases) Ligases Carboxylases Synthetases Lyases Decarboxylases Dehydrases Oxidoreductases Oxidases Reductases Dehydrogenases Transferases Kinases Transaminases Enzyme cofactors Vitamins Non-enzyme proteins Abnormal folding proteins (amyloid) Growth factors (nerve growth factor) Endogenous proteins from other animals (snail conotoxins) b. Environmental toxins Biological Chemical Organic Inorganic Physical Within each of these categories there is a further refinement of targets. As discussed in chapter 9, for example, possible druggable targets for antifungal drug design may be subdivided as follows: 1. Fungal cell wall disruptors These subclassifications are given in detail in the corresponding chapters (4–9). Drug molecules were divided into acyclic and cyclic structures, which were then further subdivided. For example, the cyclic mol- ecules were categorized into steroids, heterocycles, and so on. These were then subcat- egorized; for instance, heterocycles had many subcategories including benzodiazepines, imidazolidinediones, dihydropyridines, etc. Regrettably, this classification system is too extensive and too cumbersome to be useful. It starts at the level of the biomolecule and works up to the pathological processes (traumatic, toxic, …), then to the physiological systems (cardiovascular, endocrine, …) and ultimately to the diseases affecting these systems. Because of its molecular-based approach, it offers def- inite advantages for drug design. The goal of medicinal chemistry is to design novel chemical compounds that will favorably influence ongoing biochemistry in the host organism in some beneficial manner. As discussed in chapters 4–6, one of the most obvious approaches is to either mimic or block endogenous messengers used by the organism itself to control or alter its own bio- chemistry. These endogenous messengers may be neurotransmitters (fast messengers), hormones (intermediate), or immunomodulators (slow), working at the electrical, mole- cular, or cellular levels, respectively. However, not all pathologies that afflict the human organism can be addressed by manipulation of these messengers. Accordingly, it becomes necessary to directly target other cellular components and/or endogenous macromolecules that are not normally directly controlled through binding to endogenous messengers. These endogenous macromolecules are the catalysts and molecular machinery that enable the cell to perform its normal metabolic functions; accordingly, they afford numerous druggable targets. Finally, if that approach is not sufficient, it would next be necessary to attack the agent causing the disease process, perhaps a bacterium or virus. Design the drug to manipulate endogenous messengers that would normally respond to the disease process. Design the drug to influence endogenous targets involved in the disease but not influenced by messenger systems. For example, when confronted with the task of designing drugs for systemic arterial hypertension and atherosclerosis, there are many targets. Following Step 1, drugs could be designed to interact with messenger neurotransmitter (adrenergic) receptors (e.
It achieves this in two ways proven 35mg actonel medicine vs medication, both of which involve closure of K channels (see Chapter 2 and Brown 1983; Brown et al generic actonel 35 mg with mastercard treatment 2 degree burns. The first is a voltage- dependent K conductance called the M conductance, Gm or Im. The slow epsp was selectively potentiated by the anticholinesterase drugeserine (2 mM) with the generation of action potentials. This firing and the slow epsp, but not the fast epsp or ipsp, were eliminated by the muscarinic antagonist atropine (0. This is not voltage activated but is switched on by Ca2 entry through channels opened during the initial depolar- isation. It is inhibited by activation of muscarinic receptors and so its reduction will also lead to repetitive firing. Unfortunately it does not appear to be affected by pirenzapine, the M1 antagonist. This appears to be because the hyperpolarisation counters the inactivation of a low- threshold Ca2 current which is then activated by the depolarisation to give a burst of action potentials (McCormick and Prince 1986b). Pilocarpine, arecoline and, of course, muscarine itself are naturally occurring muscarinic agonists, while oxotremorine is a synthetic one, which, as its name implies, can cause muscle tremor through a central effect. Acetylcholine has the structure to activate both muscarinic and nicotinic receptors. Carbachol retains these actions but is longer acting because it lacks the terminal methyl group and is not so readily hydrolysed by cholinesterase (see Fig. Methacholine with the methyl side chain lacks nicotinic activity but can be hydrolysed while bethanechol has a similar action but, like carbachol, is not easily hydrolysed. Suxamethonium is like two acetylcholine molecules joined together and has transient nicotinic activity at the neuromuscular junction before desensitising (blocking) those receptors. Perhaps not surprisingly, it is initially an agonist that causes a depolarisation of muscle fibres and actual twitching, before producing a depolarisation block of transmission. There are a large number of competitive antagonists apart from curare, such as gallamine, pancuronium and atracurium, while decamethonium works like suxamethonium as a depolarising agent. Drugs that block the nicotinic receptors on autonomic ganglia, such as hexamethonium, probably do so by actually blockingthe Na ion channel rather than the receptor. In contrast to the nicotinic antagonists and indeed both nicotinic and muscarinic agonists, there are a number of muscarinic antagonists, like atropine, hyoscine (scopolamine) and benztropine, that readily cross the blood±brain barrier to produce central effects. Somewhat surprisingly, atropine is a central stimulant while hyoscine is sedative, as least in reasonable doses. Generally these compounds are effective in the control of motion but not other forms of sickness (especially hyoscine), tend to impair memory (Chapter 18) and reduce some of the symptoms of Parkinsonism (Chapter 15). Much effort has been expended in the search for more specific muscarinic agonists and antagonists and while a few compounds have emerged which, from binding studies at least, show some (but never dramatic) selectivity, the results have been somewhat disappointing. Even then the peripheral effects of the M2 antagonist such as dry mouth and blurred vision can be unpleasant. Such possible permutations of agonist and antagonists in the treatment of dementia are considered in more detail in Chapter 18. In the striatum it is released from intrinsic interneurons and in the cortex from the terminals of ascendingaxons from subcortical neurons in defined nuclei. Such collaterals innervate (drive) an interneuron (the Renshaw cell) in the ventral horn of the spinal cord, which provides an inhibitory feedback onto the motoneuron. Also the activation of Renshaw cells, by such stimulation, is not only potentiated by anticholinesterases but is also blocked by appropriate antagonists. Stimulation produces an initial rapid and brief excitation (burst of impulses), which is blocked by the nicotinic antagonist dihydro-b-erythroidine, followed, after a pause, by a more prolonged low-frequency discharge that is blocked by muscarinic antagonists and mimicked by muscarinic agonists. This nucleus, together with the diagonal band, forms the sub- stantia innominata and the dorsal neurons of this band also join with those in the medial septum to provide a distinct cholinergic input to the hippocampus (Fig. Certainly antimuscarinic drugs like atropine are well known to impair cognitive function in both animals and humans. In the former antimuscarinic drugs appear to impair both the acquisition and retention of some learned tasks, as in the Morris water maze.
Their major advantage is that discount actonel 35mg with amex 8h9 treatment, in markedcontrast to the other Class I drugs buy actonel 35mg free shipping medicine engineering, they have a lowpotential for causing proarrhy- thmia. Their major electrophysiologic effect istodecrease the duration 64 Chapter 3 Figure 3. Lidocaine Lidocaine has beenusedclinically since1943 whenit was introduced as a local anesthetic agent. In the 1950s, it gradually came into use for the acute treatmentofventricular arrhythmias, and itremains the drug of first choice for ventricular arrhythmias in manyacute situations. Clinical pharmacology Althoughlidocaine is well absorbedinthe gut, it issubject to exten- sive first-pass metabolisminthe liver, so it is normally administered Class I antiarrhythmic drugs 65 Table 3. Very little of the drug isexcreted by the kidneys even after intravenousadministration. Further, the proteins that bind lidocaine are acute-phase reactants; that is, during periods of stress, suchasacute myocardial infarction, the proteins that bind lidocaine increase in plasma. In- creasedplasmabinding during stress canprolong the elimination half-life from 1or2 hours to as long as 4 hours, and thus cancause lidocaine levels to increase evenduring a constant infusion. When lidocaine is given acutely, it israpidly distributed to the target or- gans(phase 1 distribution), but within 20 minutes, it is distributed throughout the rest of the body(phase 2distribution); the initial immediate efficacy of the drug falls off during phase 2. Thus, twoor three additional boluses are usually given at 10-minute intervals af- ter the original bolus; the dosage of the additional boluses is usually half that of the initial bolus. However, at fast heart rates or during ischemia, hypokalemia, or acidosis, lidocaine can substantially slowdepolarization and conduc- tion velocity. The duration of the actionpotential and the refractory period are shortened by lidocaine in ventricular tissuebut not in atrial tissue. Lidocaine can suppress both normal and abnormal au- tomaticity, which can lead to asystole when lidocaine is giveninthe setting ofaventricular escape rhythm. Class I antiarrhythmic drugs 67 Hemodynamic effects Lidocaine has little or nohemodynamic effect. Therapeutic uses Lidocaine is effective for ventricular tachyarrhythmias and is often the drug of choice for the emergent therapy of these arrhythmias because therapeutic plasma levels can be obtained rapidly. The drug has been shown to decrease the incidenceofventricular fibrillation in the setting of acute myocardial infarction but does not improve mortality. Adverse effects and interactions The predominantside effects relate to the central nervous sys- tem. Slurred speech, dizziness, perioral numbness and paresthesias, seizures, and respiratory arrest can all occurand are generally asso- ciatedwith toxic plasma levels. Propranolol, metoprolol, and cimetidine(but not ranitidine) decrease hepatic blood flow and result in increased levels of lidocaine. Clinical pharmacology Mexiletine is nearly completely absorbed from the gutand displays minimal first-pass hepatic clearance. Peak plasma levels occur in 4–6 hours, and the drug isapproximately 70% protein bound. The drug is mainly metabolized by the liver, and the elimination half-life is from 8to16hours. Dosage Because of the variable metabolism and because therapeutic and toxic doses of mexiletinetend to overlap, dosage must be individu- alized. If there is no response after several days (at least 3 days) and if toxicity is not present, dosage can be increased to 200 mg every 8 hours. Dosage can be further increased after several 68 Chapter 3 more days unless toxicity is present, but rarely canmore than 750 mg/day be administeredwithoutsignificantside effects. Electrophysiologic effects The electrophysiologic effects of mexiletine are virtually identical to those of lidocaine. Hemodynamic effects Mexiletine has little or no effecton bloodpressure or cardiac func- tion. Therapeutic uses The therapeutic profile of mexiletine issimilar to that of lidocaine; that is, it effectively suppresses ventricular arrhythmias. Unlike lido- caine, however, mexiletine is not particularly suitable for the treat- mentofemergentoracute arrhythmias because titrating the drug to an effective dose may take many days. Although mexiletine is effective in suppressing premature ventricular complexes and non- sustained ventricular tachycardia, these arrhythmias shouldgener- ally not be treatedunless they are producing significantsymptoms. On the basis of serial drug testing in the electrophysiology laboratory, mexiletine rarely suppresses inducible sustained ventricular tachy- cardia; the drug is estimated to be effective for suchsuppressionin only 5–10% of patients tested.
Booster doses are recommended for persons exposed to permanent or frequent contact with the virus buy 35mg actonel with visa medications given during labor. However cheap actonel 35mg fast delivery treatment viral pneumonia, at least 12 hours before reconstitution of the vaccine, the diluent must be refrigerated between 2°C and 8°C so that the diluent and lyophilised powder are at the same temperature: a temperature difference during reconstitution may reduce vaccine efficacy. Contra-indications, adverse effects, precautions – No contra-indication (including during pregnancy and breast-feeding). Remarks – Immunocompetent patients are considered as correctly vaccinated against rabies if they present a document confirming pre-exposure vaccination with 3 doses of cell culture rabies vaccine. After delivery, continue vaccination as described in the table above until the required five doses have been administered. Contra-indications, adverse effects, precautions – Do not administer in the event of significant reactions to a previous dose of tetanus vaccine. Do not freeze – 4 tetAnus AntItoxIn (equIne) ⚠⚠ equine tetanus antitoxin should no longer be used, as there is a risk of hypersensitivity and serum sickness. Tetanus antiserum provides temporary passive immunity against tetanus for 2 weeks. Dosage and duration – Prevention of tetanus Tetanus antiserum is administered in the event of tetanus-prone wounds, e. Child and adult: 1500 Iu as a single dose; 3000 Iu if more than 24 hours has elapsed It is administered as soon as possible after injury, along with the tetanus vaccine, in a separate syringe and injection site. In children between 6 and 9 months, vaccination is only recommended in epidemics, as the risk of virus transmission may be very high. Contra-indications, adverse effects, precautions – Do not administer to patients with history of an allergic reaction to a previous injection of yellow fever vaccine, true allergy to egg, immunodeficiency (e. However, given the severity of yellow fever, the vaccine is administered 4 when the risk of contamination is very high (epidemics, unavoidable travel to regions of high endemicity). However, at least 12 hours before reconstitution of the vaccine, the diluent must be refrigerated between 2°C and 8°C so that the diluent and lyophilised powder are at the same temperature: a temperature difference during reconstitution may reduce vaccine efficacy. Drugs for external use, antiseptics and disinfectants Aciclovir, eye ointment Alcohol-based, solution or gel Artesunate rectal Benzoic acid + Salicylic acid, ointment Benzyl benzoate Calamine Chlorhexidine 5% solution Chlorhexidine 7. There must be no residual powder on hands (use powder-free gloves) and hands must be dry. Rub hands for 20-30 seconds, palm to palm, palm over dorsum, between fingers (fingers interlaced), around the thumbs and nails, until hands are completely dry. Contra-indications, adverse effects, precautions – Do not use if: • hands are visibly dirty or soiled with organic matter (wash hands); • there is residual powder on hands (wash hands); • hands are wet (water dilutes alcohol and impedes drying). Remarks – Dose required and duration of handrubbing may vary depending on the product used. Remarks – Buttocks should be held together for at least 1 minute to ensure retention. If capsules are expelled from the rectum within 30 minutes of insertion, re-administer the treatment. When it is absolutely impossible to transfer a patient to a facility where parenteral antimalarial treatment can be administered, artesunate rectal capsules should be administered once daily until the patient is able to take a 3-day course of an artemisinin-based combination. Child > 12 years Child < 2 years Child 2-12 years and adult 1 part of 25% lotion 1 part of 25% lotion Undiluted Preparation + + 25% lotion 3 parts of water 1 part of water 12 hours (6 hours Contact time 24 hours 24 hours in children < 6 months) – Apply the lotion to the whole body, including scalp, postauricular areas, palms and soles. Contra-indications, adverse effects, precautions – Do not apply to broken or infected skin. In the event of secondary bacterial infection, administer an appropriate local (antiseptic) and/or systemic (antibiotic) treatment 24 to 48 hours before applying benzyl benzoate. In case of ingestion: do not induce vomiting, do not perform gastric lavage; administer activated charcoal. Remarks – Close contacts should be treated at the same time regardless of whether they have symptoms or not. The treatment may be repeated if specific scabies lesions (scabious burrows) are still present after 3 weeks. Remarks – Storage: below 25°C – Once diluted, the solution must be used immediately; do not store the diluted solution (risk of contamination). Therapeutic action – Antiseptic Indications – Antisepsis of umbilical cord in maternity units Presentation – 7.
