Pharmacodynamics

Pharmacodynamics

1. PHARMACODYNAMICS Muhammad Usman Khalid DPT,MS-NMPT

2. PHARMACODYNAMIC Pharmacodynamics refers to the relationship between the drug concentration at the site of action (receptor) and pharmacologic response, including biochemical and physiologic effects that influence the interaction of drug with the receptor. The interaction of a drug molecule with a receptor causes the initiation of a sequence of molecular events resulting in a pharmacologic or toxic response .

3. RECEPTORS 'Receptor' is sometimes used to denote any target molecule with which a drug molecule (i.e. a foreign compound rather than an endogenous mediator) has to combine in order to elicit its specific effect. For example, the voltage-sensitive sodium channel is sometimes referred to as the 'receptor' for local anesthetics , or the enzyme dihydrofolate reductase as the 'receptor' for methotrexate . The term drug target is preferable in this context.

4. CONTINUED In the more general context of cell biology, the term receptor is used to describe various cell surface molecules (such as T-cell receptors) involved in the immunological response to foreign proteins and the interaction of cells with each other and with the extracellular matrix.

5. CONTINUED Various carrier proteins are often referred to as receptors, such as the low-density lipoprotein receptor that plays a key role in lipid metabolism and the transferrin receptor involved in iron absorption. These entities have little in common with pharmacological receptors.

6. LIGAND (Latin: ligare -to bind) Any molecule which attaches selectively to particular receptors or sites. The term only indicates affinity or binding without regard to functional change.

7. CHEMISTRY OF RECEPTORS AND LIGANDS Interaction of receptors with ligands involves the formation of chemical bonds, most commonly electrostatic and hydrogen bonds, as well as weak interactions involving van der Waals forces. The mechanism of the “lock and key” is a useful concept for understanding the interaction of receptors with their ligands. The precise fit required of the ligand echoes the characteristics of the “key,” whereas the opening of the “lock” reflects the activation of the receptor. The interaction of the ligand with its receptor thus exhibits a high degree of specificity.

8. AFFINITY & INTRINSIC ACTIVITY(Efficacy) The ability to bind with the receptor designated as affinity, and the capacity to induce a functional change in the receptor designated as intrinsic activity (IA) or efficacy.

9. AGONIST An agent which activates a receptor to produce an effect similar to that of the physiological signal molecule. Agonists , which 'activate' the receptors. High Affinity + High Intrinsic activity e:g Morphine, Adrenaline

10. INVERSE AGONIST An agent which activates a receptor to produce an effect in the opposite direction to that of the agonist. It has the full affinity towards the receptors but produces effect just opposite to that of an agonist. e:g benzodiazepines produces anti-anxiety and anti- convulsant effects by interacting with their receptors, but β - carbolines acts as inverse agonist at benzodiazepines receptors and produce anxiety and convulsions.

11. ANTAGONIST Antagonist , which may combine at the same site without causing activation, and block the effect of agonists on that receptor . An agent which prevents the action of an agonist on a receptor or the subsequent response, but does not have any effect of its own. High affinity without intrinsic activity E:g Naloxone, atropine

12. PHYSICAL ANTAGONISM The opposing action of the two drugs is due to their physical property. E:g activated charcoal absorb toxic substances in case of poisoning

13. CHEMICAL ANTAGONISM The opposing action of two drugs is due to their chemical property. E:g antacids are weak bases which neutralize gastric acid

14. PHYSIOLOGICAL ANTAGONISM Two drugs act on the same physiological system and produce opposite effects E:g adrenaline and histamine on bronchial smooth muscle Histamine produces bronchoconstriction hence adrenaline helps to reverse bronchospasm in anaphylactic shock

15. RECEPTOR ANTAGONISM The antagonist binds to the same receptor as the agonist and inhibits its effects it can be competitive or non-competitive.

16. COMPETITIVE ANTAGONISM A  competitive antagonist  is a receptor  antagonist  that binds to a receptor but does not activate the receptor. The  antagonist  will compete with available agonist for receptor binding sites on the same receptor . E:g Acetylcholine & Atropine The competitive antagonism can be overcome by increasing the conc. Of the agonist.

17. NON-COMPETITIVE ANTAGONISM The antagonist binds ta a different site or to the same site with higher affinity so that the agonist cannot displace if from the receptor. E:g P henoxybenzamine and noradrenaline binds to the same site on receptors. In this type antagonistic effects cannot be overcome by increasing the concentration of the agonist.

18. PARTIAL AGONIST Drugs that has affinity to the receptor but less intrinsic activity is called partial agonist. Affinity + less intrinsic activity E:g pindolol , buprenorphine

19. AGONISTS have both affinity and maximal intrinsic activity ( lA = 1), e.g. adrenaline, histamine, morphine. COMPETITIVE ANTAGONISTS have affinity but no intrinsic activity ( lA = 0), e.g. propranolol, atropine, chlorpheniramine, naloxone. PARTIAL AGONISTS have affinity and submaximal intrinsic activity ( lA between 0 and 1), pentazocine (on µ opioid receptor ). INVERSE AGONISTS have affinity but intrinsic activity with a minus sign ( lA between 0 and -1 ), e.g. DMCM   (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) (on benzodiazepine receptor).

20. MAJOR RECEPTOR FAMILIES Pharmacology defines a receptor as any biologic molecule to which a drug binds and produces a measurable response. Thus, enzymes and structural proteins can be considered to be pharmacologic receptors. These receptors may be divided into four families: 1 ) ligand-gated ion channels, 2 ) G protein–coupled receptors, 3 ) enzyme-linked receptors, and 4 ) intracellular receptors

21. LIGAND-GATED ION CHANNELS The first receptor family comprises ligand-gated ion channels that are responsible for regulation of the flow of ions across cell membranes. The activity of these channels is regulated by the binding of a ligand to the channel . Response to these receptors is very rapid, having durations of a few milliseconds. The nicotinic receptor and the γ- aminobutyric acid (GABA) receptor are important examples of ligand-gated receptors, the functions of which are modified by numerous drugs. Stimulation of the nicotinic receptor by acetylcholine results in sodium influx, generation of an action potential, and activation of contraction in skeletal muscle. Benzodiazepines, on the other hand, enhance the stimulation of the GABA receptor by GABA, resulting in increased chloride influx

22. G PROTEIN–COUPLED RECEPTORS A second family of receptors consists of G protein–coupled receptors. These receptors are comprised of a single peptide that has seven membrane-spanning regions, and these receptors are linked to a G protein ( G s and others) having three subunits, an α subunit that binds guanosine triphosphate (GTP) and a βγ subunit. Binding of the appropriate ligand to the extracellular region of the receptor activates the G protein so that GTP replaces guanosine diphosphate (GDP) on the α subunit . Dissociation of the G protein occurs, and both the α-GTP subunit and the βγ subunit subsequently interact with other cellular effectors, usually an enzyme or ion channel.

23. G PROTEIN–COUPLED RECEPTORS These effectors then change the concentrations of second messengers that are responsible for further actions within the cell. Stimulation of these receptors results in responses that last several seconds to minutes. SECOND MESSENGERS: These are essential in conducting and amplifying signals coming from G protein–coupled receptors. A common pathway turned on by G s , and other types of G proteins, is the activation of adenylyl cyclase by α-GTP subunits, which results in the production of cyclic adenosine monophosphate ( cAMP )—a second messenger that regulates protein phosphorylation. G proteins also activate phospholipase C, which is responsible for the generation of two other second messengers, namely inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). These effectors are responsible for the regulation of intracellular free calcium concentrations, and of other proteins as well.

24. ENZYME-LINKED RECEPTORS A third major family of receptors consists of those having cytosolic enzyme activity as an integral component of their structure or function. Binding of a ligand to an extracellular domain activates or inhibits this cytosolic enzyme activity. Typically , upon binding of the ligand to receptor subunits, the receptor undergoes conformational changes, converting from its inactive form to an active kinase form. The activated receptor auto phosphorylates, and phosphorylates tyrosine residues on specific proteins. The addition of a phosphate group can substantially modify the three-dimensional structure of the target protein, thereby acting as a molecular switch.

25. INTRACELLULAR RECEPTORS 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. Because these receptor ligands are lipid soluble, they are transported in the body attached to plasma proteins, such as albumin. For example, steroid hormones exert their action on target cells via this receptor mechanism. Binding of the ligand with its receptor follows a general pattern in which the receptor becomes activated because of the dissociation of a small repressor peptide. The activated ligand–receptor complex migrates to the nucleus, where it binds to specific DNA sequences, resulting in the regulation of gene expression.

26. Protease-Activated Receptor Signaling Some receptors are not presented by the cell in a form readily accessible to agonist. Proteases that are anchored to the plasma membrane or that are soluble in the extracellular fluid (e.g., thrombin) can cleave ligands or receptors at the surfaces of cells to either initiate or terminate signal transduction. Peptide agonists often are processed by proteolysis to become active at their receptors. Tumor necrosis factor ( TNF- α )– converting enzyme (TACE) cleaves the precursor of TNF- α at the plasma membrane, releasing a soluble form of this pro-inflammatory cytokine. Similarly, angiotensin-converting enzyme (ACE), which is also an integral membrane protein preferentially expressed by endothelial cells in the blood vessels of the lung, converts angiotensin I to angiotensin II ( Ang II), thereby generating the active hormone near receptors for Ang II on vascular smooth muscle.

27. Cytoplasmic Second Messengers Binding of an agonist to a receptor provides the first message in receptor signal transduction to effector pathways and an eventual physiological outcome. The first messenger promotes the cellular production or mobilization of a second messenger, which initiates cellular signaling through a specific biochemical pathway. Physiological signals are integrated within the cell as a result of interactions between and among second-messenger pathways. S econd messengers include cyclic AMP, cyclic GMP, cyclic ADP–ribose, Ca2+, inositol phosphates, diacylglycerol , and nitric oxide.

28. Cyclic AMP Cyclic AMP is synthesized by adenylyl cyclase under the control of many GPCRs ; stimulation is mediated by Gs ; inhibition, by Gi . There are nine membrane-bound isoforms of adenylyl cyclase (AC) and one soluble isoform found in mammals. The membrane-bound ACs are glycoproteins of approximately 120 kDa with considerable sequence homology: a small cytoplasmic domain; two hydrophobic transmembrane domains , each with six membrane-spanning helices; and two large cytoplasmic domains. Membrane-bound ACs exhibit basal enzymatic activity that is modulated by binding of GTP- liganded α subunits of the stimulatory and inhibitory G proteins ( Gs and Gi ).

29. Cyclic GMP Cyclic GMP is generated by two distinct forms of guanylyl cyclase (GC). Nitric oxide (NO) stimulates soluble guanylyl cyclase ( sGC ), and the natriuretic peptides, guanylins , and heat-stable Escherichia coli enterotoxin stimulate members of the membrane-spanning GCs ( e.g. , particulate GC).

30. Cyclic Nucleotide–Dependent Protein Kinases PKA holoenzyme consists of two catalytic(C) subunits reversibly bound to a regulatory (R) subunit dimer . The holoenzyme is inactive. Binding of four cyclic AMP molecules, two to each R subunit , dissociates the holoenzyme, liberating two catalytically active C subunits that phosphorylate serine and threonine residues on specific substrate proteins. PKA can phosphorylate both final physiological targets (metabolic enzymes or transport proteins) and numerous protein kinases and other regulatory proteins in multiple signaling pathways.

31. Cyclic Nucleotide–Gated Channels In addition to activating a protein kinase, cyclic AMP also directly regulates the activity of plasma membrane cation channels referred to as cyclic nucleotide–gated (CNG) channels. CNG ion channels have been found in kidney, testis, heart, and the CNS. These channels open in response to direct binding of intracellular cyclic nucleotides and contribute to cellular control of the membrane potential and intracellular Ca2+ levels. The CNG ion channels are multisubunit pore-forming channels that share structural similarity with the voltage-gated K+ channels.

32. Cyclic AMP–Regulated GTPase Exchange Factors (GEFs) The small GTP-binding proteins are monomeric GTPases and key regulators of cell function. They integrate extracellular signals from membrane receptors with cytoskeletal changes and activation of diverse signaling pathways, regulating such processes as phagocytosis, progression through the cell cycle, cell adhesion, gene expression, and apoptosis.

33. Calcium The entry of Ca2+ into the cytoplasm is mediated by diverse channels: Plasma membrane channels regulated by G proteins, membrane potential, K+ or Ca2+ itself, and channels in specialized regions of endoplasmic reticulum that respond to IP3 or, in excitable cells, to membrane depolarization and the state of the Ca2+ release channel and its Ca2+ stores in the sarcoplasmic reticulum. Ca2+ is removed both by extrusion (Na+–Ca2+ exchanger and Ca2+ ATPase) and by reuptake into the endoplasmic reticulum (SERCA pumps). Ca2+ propagates its signals through a much wider range of proteins than does cyclic AMP, including metabolic enzymes, protein kinases, and Ca2+-binding regulatory proteins (e.g., calmodulin) that regulate still other ultimate and intermediary effectors that regulate cellular processes as diverse as exocytosis of neurotransmitters and muscle contraction. Drugs such as chlorpromazine (an antipsychotic agent) are calmodulin inhibitors.

34. DOSE-RESPONSE RELATIONSHIP The pharmacological effect of a drug depends on its concentration at the site of action, which in turn determined by the dose of the drug administered, such a relationship is called dose-response relationship.

35. GRADED DOSE RESPONSE This curve when plotted on a graph takes the form of a rectangular hyperbola, whereas log-response curve is sigmoid shape

36. THERAPEUTIC INDEX Therapeutic index (TI) is an index of drug safety TI = Median lethal dose (LD50)/Median effective dose (ED50)

37. LD50 It is the dose of a drug required to kill 50% of the animal population. ED50 It is the dose of drug which produces desired effect in 50% of population.

38. QUANTAL DOSE RESPONSE Certain pharmacological effects which cannot be quantified but can only be said to be present or absent are called as quantal response. E:g drugs causing vomiting etc

39. DRUG POTENCY The quantity of a drug required to produced a desired response is potency of the drug. The lower the dose required for a given response the more potent is the drug.

40. DRUG EFFICACY It is the maximum effect of a drug.

41. COMBINED EFFECTS OF DRUGS Additive effect Potentiation Synergism

42. ADDITIVE EFFECT The combined effect of two or more drugs is equal to the sum of their individual effect. Effect of drugs A+B= effect of drug A+ effect of drug B E:g ibuprofen and paracetamol

43. POTENTIATION The enhancement of action of one drug by another drug which is inactive is potentiation Effect of drug A+B > Effect of drug A + Effect of drug B E:g levodopa + carbidopa Carbidopa inhibits the breakdown of levodopa thus enhancing their effects.

44. SYNERGISM When two or more drugs are administered simultaneously their combined effect is greater than that elicited by either drug alone. E:g sulphamethoxazole + trimethoprim

45. PLACEBO EFFECT Placebo ( latin word) means I will please It is the dummy medicine having no pharmacological activity. The effect produced by placebo called the placebo effect.

46. IDIOSYNCRACY It is usually genetically determined adverse reaction. It is the unusual response of the drug. E:g aplastic anemia caused by chloramphenicol.

47. TOLERANCE Repeated administration of certain drugs can result in a decrease in their pharmacological effect. Hence higher doses of such drugs are needed to produce a given response. E:g ephedrine, organic nitrates, opoids etc. Tolerance develop to nasal decongestant effect of ephedrine on repeated dose.

48. TYPE OF TOLERANCE Natural tolerance ( Blacks tolerant to mydriasis) Acquired tolerance (Morphine tolerance on analgesic effect not on miotic effect)

49. TACHYPHYLAXIS When a drug is administered repeatedly at short intervals, the response diminish rapidly. This is commonly seen with non-catecholamine e:g ephedrine

50. IATROGENIC DISEASE Physician induced disease due to drug therapy. E:g acute gastritis and peptic ulcer due to NSAID’s

51. ADVERSE DRUG REACTION A dverse drug reaction as "an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product."

52. CONTINUED Adverse drug reactions are classified into six types (with mnemonics): D ose-related (Augmented), N on-dose-related (Bizarre), D ose-related and time-related (Chronic), T ime-related (Delayed), W ithdrawal (End of use), and failure of therapy (Failure). 

53. SIDE EFFECTS Problems that occur when treatment goes beyond the desired effect. Or problems that occur in addition to the desired therapeutic effect . Unintended effect occurring at normal dose related to the pharmacological properties Example -- A hemorrhage from the use of too much anticoagulant (such as heparin) is a side effect caused by treatment going beyond the desired effect. Example -- The common side effects of  cancer  treatment including  fatigue , nausea, vomiting, decreased blood cell counts,  hair loss , and mouth sores are instances of side effects that occur in addition to the desired therapeutic effect.

54. DRUG INTERACTION An interaction is said to occur when the effects of one drug are changed by the presence of another drug, herbal medicine, food, drink or by some environmental chemical agent. Much more colorful and informal definitions by patients are that it is “. . . when medicines fight each other.

55. Jazak Allah!