Dynamics of Drug Actions 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 receptors...

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 Comparing agonistic action of B, C, D, E, F to the full agonist SA_ B C as shown in Figure 1 which reveals: a. Drugs B, C, E are of same efficacy ^A_]XX , Full Agonists. D F b. It also reveals that potency of EAE ^A_ `Z]o ^A_AEBAEC ]v potency. c. Drugs D & F have less ((]˙Zv^A_]XX , Partial Agonists. D>F in efficacy, while F> D in potency. Comparing the effect of addition of another drug }^A_ a. If this drug causes a slope shift to the left ^o]lZ((}(E_W]]oo SPOTENTIATIONS. b. If this drug causes a slope shift to the right^o]lZ((}(_ B ]]oo SANTAGONISM_X Comparing the effect of addition of an antagonist }^A_ as shown in Figure 2 which reveals: a. If it causes a right parallel shift and appears to decrease potency }( v P}v] ]v ^B_ v v 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 SSYNERGISM_ or SSUMMATION_ , 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 STHERAPUTICINDXE _ [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 ^TOLERANC_E X 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. STACHYPHYLAXIS _ is an acute rapidly developed tolerance, when doses of a drug are repeated in quick succession. N.B. SREFRACTORINESS_ signifies the loss of therapeutic efficacy of a drug. ^RESISTANCE_ signifies the }uoo}}(((]v}v]]}]}v]vYX 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 SDEPENDENCE_ as with Habituation; developing to Nicotine in Cigarettes or Cannabis or as Physical Dependence SAddiction_; developing to Diazepam or Morphine. 9 NUCLEOTIDES & NUCLEIC ACIDS ILOs By the end of this lecture, students will be able to 1. Describe types & structure of nucleotides and nucleic acids 2. Explain function of nucleotides and nucleic acids 3. Interpret why the structure and organization of nucleic acids best fits their function What are nucleic acids? Nucleic acids are the most important of all biomolecules. They function to create and encode and then store information in the nucleus of every living cell of every life-form organism on earth. They represent the hard-disk of our body. The term nucleic acid is the overall name for Deoxyribonucleic acid (DNA) and Ribonucleic acid (RNA). They are composed of nucleotides, which are the monomers made of three components: 5-carbon sugar (pentose): If the sugar is ribose, the nucleic acid is termed RNA; if the sugar is deoxyribose, the nucleic acid is termed DNA. Phosphoric acid: PZ}Z}]]] Z }OHP} ;}v }(}˘˙]} P ]v}vvo}]vOHP}æ;}v of deoxyribose sugar in adjacent nucleotide. Nitrogenous bases: They are organic molecule with a nitrogen atom that has the chemical properties of a base. The main biological function of a nitrogenous base is to bond nucleic acids together. Nitrogenous bases are typically classified as the derivatives of two parent compounds: pyrimidines and purines (Figure1) Pyrimidines are formed of 1 cyclic ring. These include: Cytosine, thymine, uracil Purines are formed of 2 heterogeneous rings. These include: Adenine, Guanine Purines are present in both DNA and RNA. As for pyrimidines, the distribution is different. DNA contains cytosine and thymine while RNA contains cytosine and uracil. Thus, in summary, DNA and RNA are polymers of nucleotides. A nucleotide is composed of a nitrogenous base bound to a pentose sugar (both together form what is called NUCLEOSIDE), in addition to phosphate group. 1  Figure 1: Nitrogenous bases present in nucleic acids The number of phosphate groups can be either one group (nucleoside monophosphate), or 2 groups (nucleoside diphosphate), or 3 groups (nucleoside triphosphate) Formation of nucleotide polymers (Figure 2) Nucleotides are attached to each other through a [ -æ[Z}Z}]}v. This bond links carbon number 3 of the sugar and carbon number 5 in the sugar of the next nucleotide. Carbon number 5 links to this bond through sharing by its phosphate group. After polymerization, the formed chain will Z [ v ~]v `Z]Z}v vu ]v the sugar is free and not involved in any }v v æ[ v ~]v `Z]Z }v number 5 in the phosphate group of the sugar is free and not involved in any bond). Figure 2: Formation of Deoxyribonucleic acid (DNA) phosphodiester bond to link nucleotides to form nucleic acids To form DNA, the 2 strands of deoxyribonucleotides wind around each other in a clockwise direction, forming a structure called double helix. This structure is linear. In the double helix, the sugar and phosphates are located to the exterior, forming the backbone, while the nitrogenous bases are located to the interior for better protection from degradation. DNA is located within the nucleus of cell. It is associated with basic proteins and forms chromosomes. This is called nuclear DNA. 2  DNA is also located within mitochondrial matrix (mitochondrial DNA (mtDNA) and takes a circular double stranded form. Properties of DNA strands 1- Polarity Each DNA strand has polarity, with a ;Ev~ prime) which is the terminal of DNA strand where C3 of deoxyribose sugar is not linked and is free, and æ; Ev ~æ ]u which is the end of DNA strand where C5 of deoxyribose sugar is not linked and is free. Therefore, the two DNA strands show polarity, `Z Z v Z}` v ]Z ]v ; t æ; ]]}v}æ; t ;]]}vX 2- Anti-polarity (antiparallel strands) In DNA helix, two strands run in antiparallel ]]}vV}vvv(}u[ -æ[ ]]}v `Z]oZ}Zv(}uæ[ -[]]}vX 3- Base Pairing Base pair signifies two nitrogenous bases held together through hydrogen bonding. Each pair of base consists of purine in one strand and pyrimidine in another strand. Figure 3: base pairing and antipolarity in DNA Particular purine always pairs with particular pyrimidine. This is called Complementary base pairing, where adenine pairs with thymine with double hydrogen bond and guanine pairs with cytosine with tripe hydrogen bond (A=T, GYC) Eukaryotic DNA organization To fit the 2 meter long DNA in the nucleus, it is wrapped around the basic proteins called histones (5 types designated H1, H2A, H2B, H3, and H4) that, along with ions such as Mg 2+ , help neutralize the negatively charged DNA phosphate groups. The N-terminal ends of these histones can be acetylated, methylated, or phosphorylated. These reversible covalent modifications influence how tightly the histones bind to the DNA, thereby affecting the expression of specific genes. Histone modification is an example of epigenetics, or heritable changes in gene expression caused without alteration of the nucleotide sequence.(Refer to regulation of gene expression lecture) 3 Functions of DNA 1. DNA carries the genetic material of the cell and is responsible for transmission of this material to newly divided cells through making exact copies on itself. (Refer to DNA replication lecture) 2. DNA is responsible for protein synthesis through the process of gene expression. (Refer to transcription and translation lectures) Ribonucleic acid (RNA): RNA is present mainly in the cytoplasm of the cell and has three types: 1. Messenger RNA (mRNA): It constitutes 5% of all RNA. It is synthesized in the nucleus by DNA and then sent to the ribosomes in the cytoplasm. The mRNA carries a ^}_ message from DNA in the nucleus, where it is synthesized, to the ribosomes in the cytoplasm, where it is going to direct the synthesis of a specific protein. The letters of the message are the nitrogenous bases, the sequence of which is complementary to that of the DNA from which it was copied. mRNA contains adenine, guanine, cytosine and URACIL. Each 3 successive bases in the mRNA are called a ^}}v_ because they code for a specific amino acid. These codons are responsible for arranging the amino acids in proper order in the polypeptide chain to be synthesized. The process of synthesis of mRNA in the nucleus under the directions of DNA is called ^v]]}v_X (Refer to transcription lecture) 2. Transfer RNA (tRNA): (Figure 5) It constitutes 15% of all RNA. It is present in the cytoplasm and may be also known as soluble RNA (sRNA).It is composed of 74 to 95 nucleotides. It has a hairpin structure and is stabilized by hydrogen bonds. tRNA molecules function as carriers for the amino acids and transfer them to the machinery site of protein synthesis in the cell ( Ribosome ). There is, at least, a specific tRNA for each amino acid. This means that there are, at least, 20 different tRNA molecules in every cell, each of which is specialized to carry one of the 20 different amino acids required for the process of protein synthesis. TZ ] v u]v} ] ]v]vP ] }v Z [ u]voX Iv ]]}v Z ] v v]}}v site for recognition of codons on mRNA. 3. Ribosomal RNA (rRNA): It constitutes 80% of total RNA. It is present in the ribosomes of the cytoplasm. 4 The ribosome is a cytoplasmic nucleoprotein structure which acts as the machinery for the synthesis of proteins. On the ribosomes, the mRNA and tRNA molecules interact to translate a specific protein. (Refer to the protein machinery lecture). Figure 5: Transfer RNA 5