Pharmacology 2nd Lec PDF

Dr. Dlawer Abdul Hammed AL Jaff Ph.D Pharmacology and toxicology 3/10/2016  The fourth family of receptors differs considerably from the other three in that the receptor is entirely intracellular and, therefore, the ligand must diffuse into the cel...

Dr. Dlawer Abdul Hammed AL Jaff Ph.D Pharmacology and toxicology 3/10/2016  The fourth family of receptors differs considerably from the other three in that the receptor is entirely intracellular and, therefore, the ligand must diffuse into the cell to interact with the receptor  This places constraints on the physical and chemical properties of the ligand in that it must have sufficient lipid solubility to be able to move across the target cell membrane 3/10/2016  Because these receptor ligands are lipid soluble, they are transported in the body attached to plasma proteins, such as albumin.  Binding of the ligand with its receptor follows a general pattern in which the receptor becomes activated  The activated ligandâ€―receptor complex migrates to the nucleus, where it binds to specific DNA sequences, resulting in the regulation of gene expression. 3/10/2016  The time course of activation and response of these receptors is much longer than that of the other mechanisms  Because gene expression and, therefore, protein synthesis is modified, cellular responses are not observed until considerable time has elapsed (thirty minutes or more), and the duration of the response (hours to days) is much greater than that of other receptor families 3/10/2016  Radioligand binding studies have shown that the receptor numbers do not remain constant but change according to circumstances.  When tissues are continuously exposed to an agonist, the number of receptors decreases (down-regulation) and this may be a cause of tachyphylaxis (loss of efficacy with frequently repeated doses), e.g. in asthmatics who use adrenoceptor agonist bronchodilators excessively. Prolonged contact with an antagonist leads to formation of new receptors (up-regulation). 3/10/2016  Indeed, one explanation for the worsening of angina pectoris or cardiac ventricular arrhythmia in some patients following abrupt withdrawal of a (beta-adrenoceptor blocker is that normal concentrations of circulating catecholamines now have access to an increased (up-regulated) population of beta- adrenoceptors 3/10/2016  Drugs that activate receptors do so because they resemble the natural transmitter or hormone, and so to act for longer than the natural substances (endogenous ligands); for this reason  bronchodilation produced by salbutamol lasts longer than that induced by adrenaline 3/10/2016  Antagonists (blockers) of receptors are sufficiently similar to the natural agonist to be 'recognised' by the receptor and to occupy it without activating a response, thereby preventing (blocking) the natural agonist from exerting its effect.  Drugs that have no activating effect whatever on the receptor are termed pure antagonists 3/10/2016 A receptor occupied by a low efficacy agonist is inaccessible to a subsequent dose of a high efficacy agonist, so that, in this specific situation, a low efficacy agonist acts as an antagonist. This can happen with opioids. 3/10/2016  Partial agonists. Some drugs, in addition to blocking access of the natural agonist to the receptor, are capable of a low degree of activation, i.e. they have both antagonist and agonist action. Such substances are said to show partial agonist activity (PAA).  The beta- adrenoceptor antagonists pindolol and oxprenolol have partial agonist activity (in their case it is often called intrinsic sympathomimetic activity) (ISA), while propranolol is devoid of agonist activity, i.e. it is a pure antagonist 3/10/2016  A patient may be as extensively '(3- blocked' by propranolol as by pindolol, i.e. exercise tachycardia is abolished, but the resting heart rate is lower on propranolol; such differences can have clinical importance. 3/10/2016  Inverse agonists. Some substances produce effects that are specifically opposite to those of the agonist.  The agonist action of benzodiazepines on the benzodiazepine receptor in the CNS produces sedation, anxiolysis, muscle relaxation and controls convulsions; substances called –beta carbolines which also bind to this receptor cause stimulation, anxiety, increased muscle tone and convulsions; they are inverse agonists. 3/10/2016  Receptor binding (and vice versa).  If the forces that bind drug to receptor are weak (hydrogen bonds, van der Waals bonds, electrostatic bonds), the binding will be easily and rapidly reversible; if the forces involved are strong (covalent bonds), rests on their greater capacity to resist degradation then binding will be effectively irreversible.  An antagonist that binds reversibly to a receptor can by definition be displaced from the receptor by mass action of the agonist (and vice versa). If the concentration of agonist increases sufficiently above that of the antagonist the response is restored. 3/10/2016  This phenomenon is commonly seen in clinical practice — patients who are taking a beta-adrenoceptor blocker, and whose low resting heart rate can be increased by exercise, are showing that they can raise their sympathetic drive to release enough noradrenaline (agonist) to diminish the prevailing degree of receptor blockade. 3/10/2016  Increasing the dose of beta-adrenoceptor blocker will limit or abolish exercise induced tachycardia, showing that the degree of blockade is enhanced as more drug becomes available to compete with the endogenous transmitter.  Since agonist and antagonist compete to occupy the receptor according to the law of mass action, this type of drug action is termed competitive antagonism. 3/10/2016  When receptor-mediated responses are studied either in isolated tissues or in intact man, a graph of the logarithm of the dose given (horizontal axis), plotted against the response obtained (vertical axis), commonly gives an S-shaped (sigmoid) curve, the central part of which is a straight line.  If the measurements are repeated in the presence of an antagonist, and the curve obtained is parallel to the original but displaced to the right, then antagonism is said to be competitive and the agonist to be surmountable. 3/10/2016  Drugs that bind irreversibly to receptors include phenoxybenzamine (to the a- adrenoceptor). Since such a drug cannot be displaced from the receptor, increasing the concentration of agonist does not fully restore the response and antagonism of this type is said to be insurmountable 3/10/2016  The log-dose-response curves for the agonist in the absence of and in the presence of a noncompetitive antagonist are not parallel. Some toxins act in this way, e.g. bungaro toxin, a constituent of some snake and spider venoms, binds irreversibly to the acetylcholine receptor and is used as a tool to study it. Restoration of the response after irreversible binding requires elimination of the drug from the body and synthesis of new receptor, and for this reason the effect may persist long after drug administration has ceased. Irreversible agents find little place in clinical practice 3/10/2016  Physiological (functional) antagonism  An action on the same receptor is not the only mechanism by which one drug may oppose the effect of another. Extreme bradycardia following overdose of a p-adrenoceptor blocker can be relieved by atropine which accelerates the heart by blockade of the parasympathetic branch of the autonomic nervous system, the cholinergic tone of which (vagal tone) operates continuously to slow it.  Bronchoconstriction produced by histamine released from mast cells in anaphylactic shock can be counteracted by adrenaline (epinephrine), which relaxes bronchial smooth muscle (P2-adrenoceptor effect) or by theophylline. In both cases, a pharmacological effect is overcome by a second drug which acts by a different physiological mechanism, i.e. there is physiological or functional antagonism. 3/10/2016  ENZYMES  Interaction between drug and enzyme is in many respects similar to that between drug and receptor.  Drugs may alter enzyme activity because they resemble a natural substrate and hence compete with it for the enzyme. For example, enalapril is effective in hypertension because it is structurally similar to that part of angiotensin I which is attacked by angiotensin-converting enzyme (ACE); by occupying the active site of the enzyme and so inhibiting its action enalapril prevents formation of the pressor angiotensin II. 3/10/2016  Carbidopa competes with levodopa for dopa decarboxylase and the benefit of this combination in Parkinson's disease is reduced metabolism of levodopa to dopamine in the blood (but not in the brain because carbidopa does not cross the blood-brain barrier). Ethanol prevents metabolism of methanol to its toxic metabolite, formic acid, by competing for occupancy of the enzyme alcohol dehydrogenase; this is the rationale for using ethanol in methanol poisoning.  The above are examples of competitive (reversible) inhibition of enzyme activity.  Irreversible inhibition  occurs with organophosphorus insecticides which combine covalently with the active site of acetylcholinesterase; recovery of cholinesterase activity depends on the formation of new enzyme.  Covalent binding of aspirin to cyclo-oxygenase (COX) inhibits the enzyme in platelets for their entire lifespan because platelets have no system for synthesising new protein and this is why low doses of aspirin are sufficient for antiplatelet action. 3/10/2016  Continuous or repeated or administration of a drug is often accompanied by a gradual diminution of the effect it produces.  Tolerance is said to have been acquired when it becomes necessary to increase the dose of a drug to get an effect previously obtained with a smaller dose  By contrast, the term tachyphylaxis describes the phenomenon of progressive lessening of effect (refractoriness) in response to frequently administered doses it tends to develop more rapidly than tolerance. 3/10/2016  Tolerance is readily observed with opioids Tolerance is acquired rapidly with nitrates used to prevent angina, possibly mediated by the generation of oxygen free radicals from nitric oxide  it can be avoided by removing transdermal nitrate patches for 4-8 h, e.g. at night. 3/10/2016  The order of reaction or process  In the body, drug molecules cross cell membranes, are transported across cells, and many are altered by being metabolised.  These movements and changes involve interaction with membranes, carrier proteins and enzymes.  The rate at which these movements or changes can take place is subject to important influences that are referred to as the order of reaction or process. 3/10/2016  In biology generally, two orders of such reactions are recognised First-order processes by which a constant fraction of drug is transported/metabolised in unit time. Zero-order processes by which a constant amount of drug is transported/metabolised in unit time. 3/10/2016  In the majority of instances the rates at which absorption, distribution, metabolism and excretion of a drug occur are directly proportional to its concentration in the body.  In other words, transfer of drug across a cell membrane or formation of a metabolite is high at high concentrations and falls in direct proportion to be low at low concentrations (an exponential relationship). 3/10/2016  This is because the processes follow the Law of Mass Action, which states that the rate of reaction is directly proportional to the active masses of reacting substances.  In other words, at high concentrations, there are more opportunities for crowded molecules to interact with each other or to cross cell membranes than at low, uncrowded concentrations.  Processes for which rate of reaction is proportional to concentration are called first- order. In doses used clinically, most drugs are subject to first-order processes of absorption, distribution, metabolism and elimination. The knowledge that a drug exhibits first-order kinetics is useful. 3/10/2016  As the amount of drug in the body rises, any metabolic reactions or processes that have limited capacity become saturated. In other words, the rate of the process reaches a maximum amount at which it stays constant, e.g. due to limited activity of an enzyme, and further increase in rate is impossible despite an increase in the dose of drug. 3/10/2016  Clearly, these are circumstances in which the rate of reaction is no longer proportional to dose, and processes that exhibit this type of kinetics are described as rate-limited or dose-dependent or zero-order or as showing saturation kinetics. In practice enzymemediated metabolic reactions are the most likely to show rate-limitation because the amount of enzyme present is finite and can become saturated. 3/10/2016  Alcohol (ethanol) is a drug whose kinetics has considerable implications for society as well as for the individual, as follows. Alcohol is subject to first-order kinetics with a t1/2 of about one hour at plasma concentrations below 10 mg/dl [attained after drinking about two thirds of a unit (glass) of wine or beer]  Above this concentration the main enzyme (alcohol dehydrogenase) that converts the alcohol into acetaldehyde approaches and then reaches saturation, at which point alcohol metabolism cannot proceed any faster. 3/10/2016  Thus if the subject continues to drink, the blood alcohol concentration rises disproportionately, for the rate of metabolism remains the same (at about 10 ml or 8 g/h for a 70 kg man), i.e. a constant amount is metabolised in unit time, and alcohol shows zero-order kinetics. 3/10/2016