Pharma Final PDF

7 Dynamics of Drug Actions ILOs By the end of this lecture, students will be able to: 1. Appraise the importance of efficacy versus potency in therapeutic selection. 2. Compare the quantitative distinction in response of different drugs when either acting on the same recep...

7 Dynamics of Drug Actions ILOs By the end of this lecture, students will be able to: 1. Appraise the importance of efficacy versus potency in therapeutic selection. 2. Compare the quantitative distinction in response of different drugs when either acting on the same receptors or on different ones. 3. Explain the importance of potentiation & antagonism in fields of therapy. 4. Predict relative drug safety and drugs to be monitored upon analysing the quantal dose-frequency curves considering its effective and toxic responses. 5. Appraise implications of variation of drug response, in fields of therapy. GRADED DOSE-RESPONSE CURVE IS USED FOR:  Quantitative Comparison of Effect of Different Drugs Acting on SAME RECEPTOR: E A B  Comparing agonistic action of B, C, D, E, F to the full agonist “A” C as shown in Figure 1 which reveals: a. Drugs B, C, E are of same efficacy as “A” i.e., Full Agonists. D F b. It also reveals that potency of E> “A” while “A”>B>C in potency. c. Drugs D & F have less efficacy than “A” i.e., Partial Agonists. D>F in efficacy, while F> D in potency.  Comparing the effect of addition of another drug to “A” a. If this drug causes a slope shift to the left “like the effect of E”: it is called “ POTENTIATION “. b. If this drug causes a slope shift to the right“like the effect of B” it is called “ANTAGONISM”.  Comparing the effect of addition of an antagonist to “A” as shown in Figure 2 which reveals: a. If it causes a right parallel shift and appears to decrease potency of an agonist as in “B” and can be overcome by increasing concentration of the agonist, it is a Competitive Reversible Antagonist. b. If it causes a nonparallel shift to the right and appears to decrease efficacy of an agonist as in “C” and cannot be overcome by increasing concentration of the agonist, it is either a Competitive Irreversible Antagonist or a Non- Competitive Antagonist. A B Competitive – Potency Antagonism Efficacy  Quantitative Comparison of Effect of Different Drugs C Irreversible - Acting on DIFFERENT RECEPTORS: Competitive Antagonism Non--Competitive Antagonism Fig 1: Comparing effects of Different Agonists. Fig 2: Dose-Response-Curve of Different Antagonists  Comparing the action of drugs, A, B, C, D, on different receptors, shown in Figure 3 reveals: They can vary in efficacy; Drug B >A >D >C in efficacy. They could not be compared in potency as they do not act on same receptor. N.B. If one drug acting on a receptor increases the action of another drug acting on a different receptor; this is termed “SYNERGISM” or “ SUMMATION” , the new curve induced by both drugs will be more efficacious than that of the first drug alone. This is to differentiate from the forestated “POTENTIATION”, where the new curve induced by both drugs will be of more potency than that of the first drug alone. N.B. The Graded-Dose-Response-Curve gives information about the relation of drug concentration/dose in a particular tissue or whole body, but it does not reflect the relation between the drug dose and the proportion of population that therapeutically responded or that developed side effects. Alternatively, a QUANTAL DOSE-RESPONSE-CURVE (figure 4) has become of major clinical importance in justifying that. It is quantal because for any individual in the population the response is always all or none, i.e., - Therapeutically [a drug for sleep; induce sleep or not / a drug lowering cholesterol; dropped it to target level or not] - Adversely, e.g., hypoglycaemia, hepatic injury, hypertension, etc. or not]. QUANTAL DOSE-RESPONSE CURVE IS USED FOR:  Predicting the relative DRUG SAFETY by: 1. Determining from this dose-response-frequency curve: Median-Effective-Dose, ED50: the drug dose that induces a specific therapeutic response in half the population. Median-Toxic -Dose, TD50: the drug dose that induces a special (adverse) toxic response in half the population. 2. Calculating the relative measure of drug safety, termed “THERAPUTIC INDEX” [TI] = TD50 / ED50 whereby if: TI is low  drug is = not safe, as Digoxin. TI is high  drug is = safe, as Penicillin (regarding the high doses).  Determining Drugs that need THERAPEUTIC MONITORING: In clinical practice, determination of blood drug concentration is recommended for certain therapeutics. This is termed Therapeutic Drug Monitoring and is indicated when a drug has narrow therapeutic window, i.e., when the difference between Fig 3: Comparable Dose-Response of Different Fig. 4: Quantal Dose-Response-Curve the dose causing Drugs acting on different receptors.  toxicity and therapeutic effect is very small, i.e., unsafe drugs as Warfarin. Drugs with wide therapeutic window, are safe and do not need monitoring as Ampicillin as shown in Figure 5. Fig. 5: Narrow versus Wide Therapeutic Window of drugs. VARIATION IN DRUG RESPONSE In certain instances, the response of drugs may become reduced, increased, or altered.  If responsiveness to a drug becomes REDUCED gradually, in consequence to repeated administration, this is “TOLERANCE”. It indicates a need to increase the dose of a drug, to maintain the attained response. It could be caused by down regulation of receptors, or decrease in response effectiveness. “TACHYPHYLAXIS” is an acute rapidly developed tolerance, when doses of a drug are repeated in quick succession. N.B. “REFRACTORINESS” signifies the loss of therapeutic efficacy of a drug. “RESISTANCE” signifies the complete loss of effectiveness to antibiotics or anticancer…etc.  If responsiveness to a drug becomes INCREASED: as the exaggeration in vasodilatation produced by Nitrates when it induces syncope; this is “HYPER-SUSCEPTIBILITY” (DRUG INTOLERANCE).  If responsiveness to a drug becomes ALTERED:  When an abnormal response to a therapeutic dose of a drug develops due to a genetic defect, this is “IDIOSYNCRASY” as with Sulphonamide developing haemolytic anaemia in patients with glucose-6- phosphate deficiency.  When an immune response develops due to formation of antigen-antibody reaction, this is “HYPERSENSITIVITY REACTION” as with Penicillin developing skin reaction, bronchial asthma, or even anaphylaxis.  When an adaptive state develops to repeated drug administration and upon its cessation, withdrawal manifestations appear, this is “DEPENDENCE” as with Habituation; developing to Nicotine in Cigarettes or Cannabis or as Physical Dependence “Addiction”; developing to Diazepam or Morphine.  27 Drugs Affecting Mediators & Transmitters of Communication ILOs By the end of this lecture, students will be able to 1. Deduce the therapeutic utility of drugs modulating some mediators. 2. Predict how modulation of transmitters can serve in control of many diseases From previous lectures, it was clear that signals of communication can PASS LOCALLY from the signaling cell to the target cell by Direct Contact, or by acting in an Autocrine or Paracrine manner. When that Paracrine Communication occurs between a. Neurons, i.e., then their action occurs via the synapse at the SYNAPTIC CLEFT. b. A nerve and a skeletal muscle, i.e., then their action occurs via MOTOR END PLATE The mediator then is considered a NEUROTRANSMITTERS. N.B. Some of these local mediators can still find access and exert also systemic effects. If a signal of communication passes directly to blood and is CONVEYED SYSTEMICALLY to distant targets via the circulation, then that signal is considered a HORMONE and its signaling cell belongs to an endocrine gland. Examples of different NON-ENDOCRINE MEDIATORS are shown in figure 1: Fig. 1: Different types of non-endocrine mediators ATP & ADP; Adenosine tri- & di-phosphate - NO; Nitric Oxide - AT; Angiotensin - ET; Endothelin - NPY; Neuropeptide Y - ANP; Atrial natriuretic peptide - VIP; Vaso-active intestinal peptide In many disease states, such mediators may be upregulated/increased, downregulated/ suppressed or malfunctioning. That is why we use DRUGS accordingly to reverse the situation and set balance back to normal. N.B. DRUG EXAMPLES ONLY WRITTEN IN PURPLE MUST BE KNOWN BY THEIR NAMES Example of such drugs and their modality of action in some diseases will be stated. ____________________ Page 1 of 3  DRUGS that suppress mediators or block their action, if found in excess, in some diseases is achieved by: ▪ Inhibiting their synthesis ▪ Blocking their receptor interaction by receptor antagonists ▪ Increasing their degradation ▪ Inhibiting their Synthesis as: Using Angiotensin Converting Enzyme Inhibitors [Ramipril] to suppress increased Angiotensin-II [AgII] level to lower the blood pressure when treating hypertension or manifestations of heart failure. ▪ Blocking their Receptors by Receptor Antagonists as: Using the Angiotensin-1 Receptor Blockers [Valsartan] to block the effect of Angiotensin-II; thus, helping in treatment of hypertension and heart failure. ▪ Increase their degradation: Using the Cholinesterase Reactivators [Oximes] to set the enzyme Acetylcholinesterase [Ach-E] active again in order to degrade excess Acetylcholine (ACh) at the synaptic cleft during insecticide (organophosphorus) poisoning. ____________________ DRUGS that increase mediators or mimic their action if found suppressed or malfunctioning in some diseases by: ▪ Giving the mediator itself or its analogues ▪ Giving a drug that can mimic the mediator’s action ▪ Stimulating mediator synthesis ▪ Increasing mediator release from stores ▪ Decreasing mediator breakdown ▪ Inhibiting the uptake of the mediator ▪ Activating the receptors’ interaction by a receptor agonist: ▪ Giving the mediator itself or its analogues: Using an Insulin Analogue to overcome the existing reduction in insulin release & action in cases of diabetes. ▪ Giving a drug that can mimic the mediator’s action: Using Nitric Oxide [NO] donners as organic nitrates [Nitroglycerine], which can cause venous and arterial dilatation that is demanded for treatment of angina pectoris and relieving symptoms of heart failure. ▪ Stimulating mediator synthesis: Using the beta 2-adrenoreceptor [2-ADR] blocker [Nebivolol] to activate Nitric Oxide Synthase that will increase NO production and lower the blood pressure when treating hypertension or manifestations of heart failure. Page 2 of 3  ▪ Increasing mediator release from stores: Using the Dual Acting Sympathomimetics [Pseudoephedrine] that (beyond its direct action) can indirectly release catecholamines as epinephrine (adrenaline) from stores to activate alpha 1-adrenoreceptor [1-ADR] causing vasoconstriction, thus used as nasal drops in flue remedy. ▪ Decreasing mediator breakdown: Using a Reversible Anticholinesterase Inhibitor [Ach-E Is] [Neostigmine] that will prevent degradation; so, will increase ACh at the motor end plate to increase skeletal muscle contraction in cases of myasthenia gravis. ▪ Inhibiting the uptake of the mediator: Using Selective Serotonin Reuptake Inhibitors [SSRIs] [Fluoxetine] to prevent 5-HT presynaptic re-uptake; so, increases 5-HT within the synaptic cleft that is needed to elevate mood and treat depression. ▪ Activating the receptors’ interaction by a receptor agonist: Using the beta 1-adrenoreceptor [1-ADR] Agonist [Dobutamine] to activate the cardiac muscle; like that induced by epinephrine (adrenaline) to treat cardiogenic shock. 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