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ASBASJSM COLLEGE OF PHARMACY (AN AUTONOMOUS COLLEGE) BELA
Name of Unit General Pharmacology Subject /Course name Pharmacology-I Subject/Course ID BP404T Class: B.Pharm. Semester IV Course coordinator Devinder Kumar Mobile No. 8219193104 Email id devinderkumar1994.dk@gmail.com
Learning Outcome of Module-
LO Learning Outcome Course Outcome Code LO 1 To Understand the principles and mechanism of drug action BP404. LO 2 To Understand the receptor theories &receptors classification. BP404. LO 3 To Understand the dose response relationship, therapeutic index and factor modifying drug action drug action.
BP404.
LO 4 To understand the Adverse drug reactions and Drug Interactions
BP404.
LO 5 To Understand the Drug discovery and Clinical evaluation of new drug, Pharmacolvigilance
BP404.
Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial
COLLEGE OF PHARMACY
(An Autonomous College)
BELA (Ropar) Punjab
Content Table Topic Pharmacodynamics- principles and mechanisms of drug action. Receptor theories and classification of receptors, regulation of receptors. Drug receptors interactions signal transduction mechanisms, G-protein-coupled receptors, ion channel receptor, transmembrane enzyme linked receptors, Transmembrane JAK-STAT binding receptor and receptors that regulate transcription factors. Dose response relationship, therapeutic index. Combined effects of drugs and factors modifying drug action. Adverse drug reactions, drug interactions. Drug discovery and clinical evaluation of new drugs - drug discovery phase, preclinical evaluation phase, clinical trial phase, phases of clinical trials. Pharmacolvigilance.
insulin in case of insulin dependent diabetes; here insulin is given by injection to maintain the requirement Cytotoxic- When there is entry of any parasite, or there is no other option to control the growth of own body cell then Cytotoxic drugs are used. They kill the microorganism of kill the uncontrolled and excessive growing cells.
Mechanism of Drug Action Only a handful of drugs act by virtue of their simple physical or chemical property; examples are:
- Bulk laxatives (ispaghula)—physical mass
- Dimethicone, petroleum jelly—physical form, opacity
- Para amino benzoic acid—absorption of UV rays
- Activated charcoal—adsorptive property
- Mannitol, mag. sulfate—osmotic activity
- 131I and other radioisotopes—radioactivity
- Antacids—neutralization of gastric HCl
- Pot. Permanganate—oxidizing property
- Chelating agents (EDTA, dimercaprol)—chelation of heavy metals.
- Cholestyramine—sequestration of bile acids and cholesterol in the gut
- Mesna—scavenging of vasicotoxic reactive metabolites of cyclophosphamide Majority of drugs produce their effects by interacting with a discrete target biomolecule, which usually is a protein. Such mechanism confers selectivity of action to the drug Functional proteins that are targets of drug action can be grouped into four major categories, viz. Enzymes Ion channels Transporters Receptors
ENZYMES Almost all biological reactions are carried out under catalytic influence of enzymes. Drug can either increase or decrease the rate of enzymatically mediated reactions Enzyme Inhibition: Selective inhibition of particular enzyme is common mode of action. Such inhibit on is either competitive or non-competitive.
Competitive Inhibitions: When the active site or catalytic site of an enzyme is occupied by the substance other than the substrate of that enzyme. Its activity is inhibited. This type of inhibition is also known competitive inhibition.
In such inhibition both ES and ET complex are formed during their reaction. With the increase in conc. Of inhibitors, lowers the rate of enzymatic reaction, Such inhibitors increase the kM but the Vmax remains unchanged. However when the concentration of substrate is increased the effect of inhibitor can be reversed forcing it out from EI complex.
Non-Competitive Inhibitions: These are not influenced by the concentration of the substrate of inhibits by binding irreversibly to the enzyme but not at the active site. They also bind with same affinity to the free enzyme and form the enzyme substrate complex It changes the shape of enzyme and active site
They are operated by specific signal molecules either directly and are called ligand gated channels (e.g. nicotinic receptor,) or through G-proteins and are termed G-protein regulated channels (e.g. cardiac adrenergic receptor activated Ca2+^ channel. Drugs can also act on voltage operated and stretch sensitive channels by directly binding to the channel and affecting ion movement through it, e.g. local anesthetics which obstruct voltage sensitive Na+^ channels. Quinidine blocks myocardial Na+^ channels. Dofetilide and amiodarone block myocardial delayed rectifier K+^ channel. Nifedipine blocks L-type of voltage sensitive Ca2+^ channel. Nicorandil opens ATP-sensitive K+^ channels. Sulfonylurea hypoglycaemics inhibit pancreatic ATP-sensitive K+^ channels. Amiloride inhibits renal epithelial Na+^ channels. Phenytoin modulates (prolongs the inactivated state of) voltage sensitive neuronal Na+channel. Ethosuximide inhibits T-type of Ca2+^ channels in thalamic neurons
TRANSPORTERS: Several substrates are translocate across membranes by binding to specific transporters (carriers) which either facilitate diffusion in the direction of the concentration gradient or pump the metabolite/ion against the concentration gradient using metabolic energy. Many drugs produce their action by directly interacting with the solute carrier (SLC) class of transporter proteins to inhibit the ongoing physiological transport of the metabolite/ion. Ex: Desipramine and cocaine block neuronal reuptake of noradrenaline by interacting with norepinephrine transporter. Fluoxetine (and SSRIs) inhibit neuronal reuptake of 5-HT by interacting with serotonin transporter (SERT).
RECEPTORS
It is defined as a macromolecule or binding site located on the surface or inside the effector cell that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function. OR Receptors are macromolecules involved in chemical signaling between & with in the cells. They may be located on the cell surface membrane or within cytoplasm. The largest number of drug that do not bind directly to the effectors like Enzyme, Channels, Transport structural protein, template biomolecule. But act through specific regulatory macromolecules or the site which bind and interact with the drug are called ― Receptor ‖
RECEPTOR THEORIES
RECEPTORS – A receptor is the specific chemical constituent of the cell with which a drug interacts to produce its Pharmacological effects. Some receptor sites have been identified with specific parts of proteins and nucleic acids. The term drug receptor or drug target denotes the cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular response, i.e., a change in cell function. D + R D-R Drug Response A Receptor is analogous to a switch that it has two configurations: ―ON‖ and ―OFF‖ Receptor: Any cellular macromolecule that a drug binds to initiate its effects. Drug: A chemical substance that interacts with a biological system to produce a physiologic effect. All drugs are chemicals but not all chemicals are drugs. The ability to bind to a receptor is mediated by the chemical structure of the drug that allows it to interact with complementary surfaces on the receptor. Once bound to the receptor an agonist activates or enhances cellular activity. Examples of agonist action are drugs that bind to beta receptors in the heart and increase the force of myocardia contraction or drugs that bind to alpha receptors on blood vessels to increase blood pressure. The binding of the agonist often triggers a series of biochemical events that ultimately leads to the alteration in function.
THEORIES FOR DRUG RECEPTOR INTERACTION Over the years a number of hypotheses have been proposed to account for the ability of a drug to interact with a receptor and elicit a biological response. Several of the more important proposals are: OCCUPATION THEORY The occupancy theory of Gaddum and Clark states that the intensity of the pharmacological effect is directly proportional to the number of receptors occupied by the drug. Maximal response occurs when all the receptors are occupied. D + R ↔ DR ⇒ RESPONSE The concept of drug–receptor interactions involve two stages: first, there is a complexation of the drug with the receptor, which termed the affinity; second, there is an initiation of a biological effect, which termed the intrinsic activity and the efficacy. Affinity is a measure of the capacity of a drug to bind to the receptor. Intrinsic activity (α) or Efficacy is the property of a compound that produces the maximum response or the ability of the drug– receptor complex to initiate a response.
THE TWO-STATE (MULTISTATE) MODEL OF RECEPTOR ACTIVATION
It was developed on the basis of the kinetics of competitive and allosteric inhibition as well as through interpretation of the results of direct binding experiments. It postulates that a receptor, regardless of the presence or absence of a ligand, exists in two distinct states: the R (relaxed, active or on) and T (Tense, inactive or off) states, which are in equilibrium with each other. In the absence of the natural ligand or agonist, receptors exist in equilibrium (defined by equilibrium constant L; Figure 4) between an active state (R), which is able to initiate a biological response, and a resting state (R), which cannot. In the absence of a natural ligand or agonist, the equilibrium between R and R defines the basal activity of the receptor. A drug can bind to one or both of these conformational states, according to equilibrium constants Kd and Kd for formation of the drug– receptor complex with the resting (D•R) and active (D•R) states, respectively.
Full agonists bind only to R* Partial agonists bind preferentially to R* Full inverse agonists bind only to R Partial inverse agonists bind preferentially to R Antagonists have equal affinities for both R and R* (no effect on basal activity)
RATE THEORY The response is proportional to the rate of drug-Receptor complex formation. Effect is produced by the drug molecules based on the rates of association and dissociation of drugs to and from the receptors. As an alternative to the occupancy theory, Paton proposed that the activation of receptors is
Resting Active
K d K d*
D R (^) D (^) R*
D. R D.R**
could result: A specific conformational perturbation makes possible the binding of certain molecules that produce a biological response (an agonist). A non- specific conformational perturbation accommodates other types of molecules that do not elicit a response (e.g., an antagonist). If the drug contributes to both macromolecular perturbations, a mixture of two complexes will result. This theory offers a physicochemical basis for the rationalization of molecular phenomena that involve receptors, but does not address the concept of inverse agonism
CLASIFICATION OF RECEPTORS Receptor is a membrane bound or soluble proteins or proteins complex which exerts a physiological effect after binding its natural ligand. The drugs can acts though various types of receptors with their signal Transduction Mechanism, The receptors are classified on the basis of nature of receptor and regulate path
TRANSDUCTION MECHANISM
G protein- coupled receptors Enzyme linked receptor Voltage dependent ion channels Other member receptors Nuclear receptors
G - Protein- Coupled Receptors (GPCRs) GPCRS are the largest family of membrane proteins and mediate most cellular responses to hormones and neurotransmitters, as well as responsible for vision, olfaction and taste. GPCRS are characterized by the presence of seven membrane spanning alpha helical segments separated by alternating intra and extracellular loop regions. If agonist and antagonist bind to Gpcr iI cause the receptor and g-protein change conformation. The alpha subunits exchange the guanosine triphosphate (GTP) for guanosine diiphosphate (GDP) and dissociates from the other subunits, where it interacts with an effectors proteins (adenylate cyclase and phospholipase c) This effector protein can stimulate or inhibit second massager molecules to produce a physiological effect. The alpha subunit then hydrolysis the bound GTP to GDP and reassociates with the other subunits. Gs protein activate cAMP Gi proteins inhibit cAMP Gq protein activate phospholipase C, which increase DAG and IP 3 When G protein is activated, GTP replaced GDP on the alpha subunit. Following activation of Protein, GTP is rapidly degraded to inactive GDP by Activte of the alpha subunit GTPase
G. protein couple receptor regulates through Adenylyl cyclase: cAMP pathway Agonist or ligand bind to GPCR that activate Gs stimulate Adenylate cyclase to convert ATP to the cAMP Cyclic adenosine monophosphate.
G PCR, action through Adenylate cyclase system. Stimulation/Inhibition depend upon nature of agonist and antagonist
Ligand Gated Ion Channels It is made up of five multi subunit proteins (2ά,β,γ and δ) It is a large group of intrinsic transmembrane proteins that allow the passage of ion upon activation by specific chemical. Most endogenous ligand bond to distinct from the ion conduction pore and binding directly causes opening or closing of the chemical. Ligand can bind extracellular eg Glutamate, ACH and GABA or intracellular Ca2+^ on Ca2+ activated K+^ channels. It is important to note that the ligand itself is not transported across cell membrane.
Diagram represented the ligand gated ion channel Ligand binding causes a drastic change in the permeability of the channels to a specific ion or ions; effectively no ions can pass through the channel when it is inactive but to 10^7 ions per second can allow trough upon ligand binding. This ligand gated ion channel, a type of ion tropic receptor, allows specific ions (like Na+^ K+ Ca2+^ and Cl-) to flow in and out of the membrane. Examples of ligand gated ion channels include ach receptors , serotonin, GABAA and Glutamate receptor.
Voltage Dependent Ion Channels Voltage dependent ion channels are a class of transmembrane proteins that form ion channel that are activated by change in the electrical membrane potential near the channel. The membrane potential alters the confirmation of the channel positive proteins, regulating their opening and closing. It is normally open or close in response to changes in the membrane potential, but they can also function receptors for drugs.
Example: The Calcium channel blockers bind to voltage-dependent Ca2+/Na2+^ channels and block Ca2+,Na2+^ entry into the cells when stimulated. This cause decreased contractility in target tissues, such as cardiac and smooth muscle.
A systematic diagram of movement of ions and their effects Transmembrane Enzyme-linked receptor It is the class of receptor themselves is enzymatic proteins. When a drug binds to this type receptor, it causes an enzyme to become ―switched on‖ intercelluarly. This enzyme then catalyzes the formation of other signal proteins that ultimately lead to the cellular response. Some peptide hormones and cytokines act through this class of receptors. The enzyme in most cases is a tyrosine proteins kinase.
Enzyme Linked insulin receptors Eg. Insulin bind to the tyrosine kinase receptor cause the enzyme to phosphorylate tyrosine residues in proteins. The proteins can then signal other proteins to be formed resulting in glucose uptake.
Transmembrane JAK-STAT binding
Nuclear Receptor The lipid-soluble drugs diffuse through cell membrane and bind either in the cellular cytosol or in the nucleus. Gene expression is altered, and protein synthesis is either increased or decreased, which causes the cellular response. This mechanism is the slowest and effects can usually be measured in term of hours rather than minutes or seconds.
Nuclear Receptor Various drug acts through nuclear receptor. Lipophilic substances, such as steroid hormones and thyroid hormones, can diffuse through the cell membrane and interact with receptors in the cytoplasm or nucleus. The hormone receptors complex than alters gene transcription, causing the synthesis of effector proteins mRNA. The hormone complex interacts with DNA in pairs; these may be identical (homodimeric) or non-identical (heterodimeric) pairs
FUNCTION OF RECEPTORS To propagate regulatory signals from outside to inside the effector cell when the molecular speciescarrying the signal can‘t itself penetrate the cell membrane To amplify the signals To integrate various extracellular and intracellular regulatory signals. To adapt to short term and long term changes in the regulatory melieu and maintain homeostasis.
DOSE RESPONSE RELATIONSHIP
DOSE – Amount of drug administered in the patient. e.g If 500 mg of paracetamol is taken dose is 500mg. RESPONSE - Effect shown by the body to a particular drug e.g Paracetamol is antipyretic drug so response is it should bring body temperature to normal. Drug +Receptor Drug-Receptor Complex Response
Dose Response Relationship A relationship used to analyze a kind of response obtained after administering specific dose of drug e.g If 10mg of ILLAPRAZOLE is administered response is it should inhibit formation of proton pumps at 10mg specifically Dose response relationship has two components Dose plasma concentration relationship Plasma concentration response relationship Dose Response Curve Relationship of dose to response can be illustrated by a graph which is called as dose response curve. Dose response curve is required:- Deciding dose of drug Comparing dosage to percentage of people showing different effects Intensity of response increases with increase in dose and dose response curve is rectangular hyperbola Dose response and log dose-response curves Dose response curve is rectangular hyperbola This is because drug-receptor interaction obeys law of mass action, accordingly E = Emax × [D] /Kd × [D] Where E = Observed effect of dose of drug Emax = maximal response Kd = dissociation constant of drug receptor complex
