General action of drugs
Action of Drugs (Pharmacodynamics)
Pharmacodynamics is the study of drug effects and modification of the action of one drug by another drug at the therapeutic dose in the body
Principles of Drug Action
Drugs do not impart new functions to any system, organ or cell; they only alter the pace of ongoing activity. The basic types of drug action can be broadly classed as:
1. Stimulation- It refers to selective enhancement of the level of activity of specialized cells, e.g. adrenaline stimulates heart, pilocarpine stimulates salivary glands.
2. Depression- It means selective diminution of activity of specialized cells, e.g. barbiturates depress CNS, quinidine depresses heart. Certain drugs stimulate one type of cells but depress the other, e.g. acetylcholine stimulates intestinal smooth muscle but depresses SA node in heart. Thus,. most drugs cannot be simply classed as stimulants or depressants.
3. Irritation - This means a nonselective, often noxious effect and is particularly applied to less specialized cells (epithelium, connective tissue). Mild irritation may stimulate associated function, e.g. bitters increase salivary and gastric secretion, counterirritants increase blood flow to the site. But strong irritation results in inflammation, corrosion, necrosis and morphological damage.
4. Replacement- This refers to the use of natural metabolites, hormones or their congeners in deficiency states, e.g. levodopa in parkinsonism, insulin in diabetes mellitus, iron in anaemia.
5. Cytotoxic action -Selective cytotoxic action for invading parasites or cancer cells, attenuating them without significantly affecting the host cells is utilized for cure/palliation of infections and neoplasms, e.g. penicillin, chloroquine, zidovudine, cyclophosphamide, etc.
MECHANISM OF DRUG ACTION Majority of drugs produce their effects by interacting with a discrete target biomolecule, which usually is a protein. Functional proteins that are targets of drug action can be grouped into Jour major categories, viz. enzymes, ion channels, transporters and receptors.
I. ENZYMES Enzymes are a very important target of drug action. Drugs can either increase or decrease the rate of enzymatically mediated reactions. However, in physiological systems enzyme activities are often optimally set. Thus, stimulation of enzymes by drugs, that are truly foreign substances, is unusual. Several enzymes are stimulated through receptors and second messengers, e.g. adrenaline stimulates hepatic glycogen phosphorylase through β-receptors and cyclic AMP. Inhibition of enzymes is also a common mode of drug action. (A)
II. ION CHANNELS Proteins which act as ion selective channels participate in transmembrane signaling and regulate intracellular ionic composition. Drugs can affect ion channels either through specific receptors or by directly binding to the channel and affecting ion movement through it. e.g. 1. local anaesthetics which physically obstruct voltage sensitive Na+ channels. 2. Nicorandil opens ATP-sensitive K+ channels. (B) .
Ill. TRANSPORTERS (CARRIERS) Several substrates are translocated 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. For example Amphetamines selectively block dopamine reuptake in brain neurons by dopamine transporter. (C)
IV. RECEPTORS Receptors are 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. (D)
The following terms are used in describing drug-receptor interaction:
Agonist An agent which activates a receptor to produce an effect similar to that of the physiological signal molecule. E.g. adrenaline
Inverse agonist An agent which activates a receptor to produce an effect in the opposite direction to that of the agonist. E.g. DMCM (on benzodiazepine receptor).
Antagonist 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. e.g. propranolol.
Partial agonist An agent which activates a receptor to produce submaximal effect but antagonizes the action of a full agonist. E.g. pentazocine
ACTION-EFFECT SEQUENCE
Drug action It is the initial combination of the drug with its receptor resulting in a conformational change in the latter (in case of agonists), or prevention of conformational change through exclusion of the agonist (in case of antagonists).
Drug effect It is the ultimate change in biological function brought about as a consequence of drug action, through a series of intermediate steps (transducer).
Enzymes
Many drugs are targeted on enzymes.
Here the drug molecule is a substrate analogue that acts as a competitive inhibitor of the enzyme either reversibly (e.g. Neostigmine, acting on acetylcholinestrase) or the binding is irreversible and non-competitive (e.g. Aspirin, acting on cyclo-oxygenase).
Drugs may also act as false substrates, where the drug molecule undergoes chemical transformation to form an abnormal product that disrupts the normal metabolic pathway.
Example is the anticancer drug fluorouracil Enzymes
Ion Channels
Some ion channels (known as ligand-gated ion channels or ionotropic receptors) incorporate a receptor and open only when the receptor is occupied by an agonist;
others are gated by different mechanisms, e.g. voltage-gated ion channels are particularly important.
In general, drugs can affect ion channel function by interacting either with the receptor site of ligand-gated channels, or with other parts of the channel molecule.
The interaction can be indirect, involving a G-protein and other intermediaries, or direct, where the drug itself binds to the channel protein and alters its function.
Example : Voltage gated-sodium channels are blocked by local anesthetics.
Examples of drugs that bind to accessory sites on the channel protein and thereby affect channel gating include: Dihydropyridine, vasodilator drugs, which inhibit the opening of L-type calcium channels.
benzodiazepine tranquillizers , these drugs bind to a region of the GABA receptor-chloride channel complex .
Sulfonylureas (Antidiabetics), which act on ATP-sensitive potassium channels of pancreatic β-cells and thereby enhance insulin secretion.
Carrier molecules (transporters)
The transport of ions and small organic molecules across cell membranes generally requires a carrier protein, because the permeating molecules are often too polar (i.e. insufficiently lipid-soluble) to penetrate lipid membranes on their own.
There are many examples of such carriers : Glucose and amino acid transporter, Ion & organic molecule transporters, neurotransmitter precursors (such as choline) or of neurotransmitters (Noradrenaline, 5-HT, glutamate uptake).
The amine transporters belong to a well-defined structural family, distinct from the corresponding receptors.
The carrier proteins embody a recognition site that makes them specific for a particular permeating species.
These recognition sites can also be targets for drugs whose effect is to block the transport system. e.g. TCA, Cocaine, Omeprazole, Cardiac Glycosides
Receptors
They are protein structure present on the mammalian cell or within the cells.
Receptors are the sensing elements in the system of chemical communications that coordinates the function of all the different cells in the body.
The chemical messengers being the various
Hormones
Neurotransmitters
other mediators (e.g. Autocoids: Histamine, 5HT, etc)
Many therapeutically useful drugs act, either as agonists or antagonists, on receptors for known endogenous mediators.
TYPES OF RECEPTOR
Receptors elicit many different types of cellular effect. Based on molecular structure and the nature of transduction mechanism four receptor types can be distinguished.
Type 1: Ligand-gated ion channels (ionotropic receptors).
These are membrane proteins with a similar structure to other ion channels, and incorporate a ligand-binding (receptor) site, usually in the extracellular domain.
On these receptors fast neurotransmitters act.
Examples include the nicotinic acetylcholine receptor; GABAA receptor; glutamate receptors of the NMDA.
These ion channels have same structural features e.g. Nicotinic Ach Receptor
It is assembled from 4 different types of subunit α β γ δ.
These subunits are inserted into the membrane.
The oligomeric structure possesses two Ach binding sites, each lying at the interface between one of the 2 subunits and its neighbor.
Both must bind Ach molecules in order for the receptor to be activated.
Type 2: G-protein-coupled receptors (GPCRs).
metabotropic receptors They are membrane receptors that are coupled to intracellular effector systems via a G-protein .
They constitute the largest family, and include receptors for many hormones and slow transmitters.
Example the muscarinic acetylcholine receptor, Adrenoceptors & Chemokine receptors.
Subtypes are also present and all have same basic structure.
Type 3: Kinase-linked and related receptors.
This is a large and heterogeneous group of membrane receptors responding mainly to protein mediators.
They comprise an extracellular ligand-binding domain linked to an intracellular domain by a single transmembrane helix.
In many cases, the intracellular domain is enzymic in nature (with protein kinase or guanylyl cyclase activity).
Examples: Type 3 receptors includes for those insulin and for various cytokines and growth factors.
Type 4: Nuclear receptors.
These are receptors that regulate gene transcription.
The term nuclear receptors is something of a misnomer, because some are actually located in the cytosol and migrate to the nuclear compartment when a ligand is present.
They include receptors for steroid hormones, thyroid hormone, and other agents such as retinoic acid and vitamin D.
Receptor Concept
The concept of drugs acting on receptors generally is credited to John Langley (1878). While studying the antagonistic effects of atropine against pilocarpine -induced salivation.
The word receptor was introduced in 1909 by Paul Ehrlich. Ehrlich postulated that a drug could have a therapeutic effect only if it has the "right sort of affinity." Ehrlich defined a receptor in functional terms: ". that combining group of the protoplasmic molecule to which the introduced group is anchored will hereafter be termed receptor.
“ The receptors are specialized target macromolecules present on the cell surface or intracellularly. Receptors bind drugs & initiate events leading to alterations in biochemical and/or biophysical activity of a cell and consequently, the function of an organ.
Drug Receptors From a numerical standpoint, proteins form the most important class of drug receptors. Examples include the receptors for hormones, growth factors, transcription factors, neurotransmitters; the enzymes (e.g., dihydrofolate reductase, acetylcholinesterase, and cyclic nucleotide phosphodiesterases)
Drug-Receptor Interaction
The binding of drugs to receptors can involve all known types of interactions-ionic, hydrogen bonding, hydrophobic, vander Waals, and covalent. Most interactions between drugs and their receptors involve bonds of multiple types. If binding is covalent, the duration of drug action is frequently, but not necessarily, prolonged. Noncovalent interactions of high affinity also may be essentially irreversible.
The magnitude of the responses is proportional to the number of drug-receptor complexes. Drug + K1 Drug-receptor complex K3 (Response) Receptor K2
Where K1, K2 and K3 are rate constants. The rate at which the drug molecule combines with a receptor site is K1. Similarly, the rate at which the drug-receptor complex dissociates is given by K2. The rate at which a response is generated following a drug-receptor interaction is given by rate constant K3. These constants are used to define some basic concepts related to drug-receptor interactions.
In general, the drug-receptor interaction is characterized first by binding of drug to receptor and second by generation of a response in a biological system. The first function is governed by the chemical property of affinity, ruled by the chemical forces that cause the drug to associate reversibly with the receptor.
Affinity It describes the ability of a drug to form and subsequently maintain a complex with a receptor site.
Intrinsic Activity It describes the ability of a drug to evoke a pharmacologic response on combining with a receptor. E.g. Acetylcholine acts as a cholinergic agonist.
Potency & Efficacy
Potency: A drug is said to be potent when it possesses high intrinsic activity at low unit weight doses. Knowledge of a drug’s potency is important for finding out the appropriate dosage level to be administered .
Efficacy: It refers to the maximal or peak response produced by a drug, and is an important determinant in the drug selection process.
Some important terms related to drugs and receptors:
Agonist: It is a drug (or hormone or neurotransmitter) which combines with its specific receptor, activates it and initiate a response e.g. acetylcholine, noradrenaline activate cholinoceptors and adrenoceptors respectively.
Antagonist: It is a drug which binds to the receptor, but does not activate it. Moreover, it prevents the action of the agonist by rendering the receptor unavailable for interaction with the agonist e.g. atropine antagonizes acetylcholine. A pure antagonist has no action of its own, but acts only by interfering with the action of an agonist e.g. the opioid antagonist naloxone.
Partial Agonist: It is a drug that binds to the receptor, but activates it weakly and prevent the action of a full agonist. This drug acts on the receptor with an intrinsic activity or efficacy of less than one.
A unique feature of these drugs is that, under appropriate conditions, a partial agonist may act as an antagonist of a full agonist. e.g. Aripiprazole, an atypical neuroleptic agent, is a partial agonist at selected dopamine receptors. Dopaminergic pathways that were overactive would tend to be inhibited by the partial agonist, whereas pathways that were underactive may be stimulated.
Inverse Agonist: It is a drug that causes an effect opposite to that of the agonist, in contrast to a competitive antagonist that simply blocks the agonist, but has no inherent action of its own. E.g. The agonist action of benzodiazepines on the GABA receptor produces sedation, anxiolysis, muscle relaxation and controls convulsions. The inverse agonist: The β-carbolines (e.g. n-butyl-β-carboline-3-carboxylate) also binds to GABA receptor causing stimulation, anxiety, increased muscle tone and convulsions. Thank you
Pharmacodynamics is the study of drug effects and modification of the action of one drug by another drug at the therapeutic dose in the body
Principles of Drug Action
Drugs do not impart new functions to any system, organ or cell; they only alter the pace of ongoing activity. The basic types of drug action can be broadly classed as:
1. Stimulation- It refers to selective enhancement of the level of activity of specialized cells, e.g. adrenaline stimulates heart, pilocarpine stimulates salivary glands.
2. Depression- It means selective diminution of activity of specialized cells, e.g. barbiturates depress CNS, quinidine depresses heart. Certain drugs stimulate one type of cells but depress the other, e.g. acetylcholine stimulates intestinal smooth muscle but depresses SA node in heart. Thus,. most drugs cannot be simply classed as stimulants or depressants.
3. Irritation - This means a nonselective, often noxious effect and is particularly applied to less specialized cells (epithelium, connective tissue). Mild irritation may stimulate associated function, e.g. bitters increase salivary and gastric secretion, counterirritants increase blood flow to the site. But strong irritation results in inflammation, corrosion, necrosis and morphological damage.
4. Replacement- This refers to the use of natural metabolites, hormones or their congeners in deficiency states, e.g. levodopa in parkinsonism, insulin in diabetes mellitus, iron in anaemia.
5. Cytotoxic action -Selective cytotoxic action for invading parasites or cancer cells, attenuating them without significantly affecting the host cells is utilized for cure/palliation of infections and neoplasms, e.g. penicillin, chloroquine, zidovudine, cyclophosphamide, etc.
MECHANISM OF DRUG ACTION Majority of drugs produce their effects by interacting with a discrete target biomolecule, which usually is a protein. Functional proteins that are targets of drug action can be grouped into Jour major categories, viz. enzymes, ion channels, transporters and receptors.
I. ENZYMES Enzymes are a very important target of drug action. Drugs can either increase or decrease the rate of enzymatically mediated reactions. However, in physiological systems enzyme activities are often optimally set. Thus, stimulation of enzymes by drugs, that are truly foreign substances, is unusual. Several enzymes are stimulated through receptors and second messengers, e.g. adrenaline stimulates hepatic glycogen phosphorylase through β-receptors and cyclic AMP. Inhibition of enzymes is also a common mode of drug action. (A)
II. ION CHANNELS Proteins which act as ion selective channels participate in transmembrane signaling and regulate intracellular ionic composition. Drugs can affect ion channels either through specific receptors or by directly binding to the channel and affecting ion movement through it. e.g. 1. local anaesthetics which physically obstruct voltage sensitive Na+ channels. 2. Nicorandil opens ATP-sensitive K+ channels. (B) .
Ill. TRANSPORTERS (CARRIERS) Several substrates are translocated 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. For example Amphetamines selectively block dopamine reuptake in brain neurons by dopamine transporter. (C)
IV. RECEPTORS Receptors are 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. (D)
Agonist An agent which activates a receptor to produce an effect similar to that of the physiological signal molecule. E.g. adrenaline
Inverse agonist An agent which activates a receptor to produce an effect in the opposite direction to that of the agonist. E.g. DMCM (on benzodiazepine receptor).
Antagonist 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. e.g. propranolol.
Partial agonist An agent which activates a receptor to produce submaximal effect but antagonizes the action of a full agonist. E.g. pentazocine
ACTION-EFFECT SEQUENCE
Drug action It is the initial combination of the drug with its receptor resulting in a conformational change in the latter (in case of agonists), or prevention of conformational change through exclusion of the agonist (in case of antagonists).
Drug effect It is the ultimate change in biological function brought about as a consequence of drug action, through a series of intermediate steps (transducer).
Enzymes
Many drugs are targeted on enzymes.
Here the drug molecule is a substrate analogue that acts as a competitive inhibitor of the enzyme either reversibly (e.g. Neostigmine, acting on acetylcholinestrase) or the binding is irreversible and non-competitive (e.g. Aspirin, acting on cyclo-oxygenase).
Drugs may also act as false substrates, where the drug molecule undergoes chemical transformation to form an abnormal product that disrupts the normal metabolic pathway.
Example is the anticancer drug fluorouracil Enzymes
Ion Channels
Some ion channels (known as ligand-gated ion channels or ionotropic receptors) incorporate a receptor and open only when the receptor is occupied by an agonist;
others are gated by different mechanisms, e.g. voltage-gated ion channels are particularly important.
In general, drugs can affect ion channel function by interacting either with the receptor site of ligand-gated channels, or with other parts of the channel molecule.
The interaction can be indirect, involving a G-protein and other intermediaries, or direct, where the drug itself binds to the channel protein and alters its function.
Example : Voltage gated-sodium channels are blocked by local anesthetics.
Examples of drugs that bind to accessory sites on the channel protein and thereby affect channel gating include: Dihydropyridine, vasodilator drugs, which inhibit the opening of L-type calcium channels.
benzodiazepine tranquillizers , these drugs bind to a region of the GABA receptor-chloride channel complex .
Sulfonylureas (Antidiabetics), which act on ATP-sensitive potassium channels of pancreatic β-cells and thereby enhance insulin secretion.
Carrier molecules (transporters)
The transport of ions and small organic molecules across cell membranes generally requires a carrier protein, because the permeating molecules are often too polar (i.e. insufficiently lipid-soluble) to penetrate lipid membranes on their own.
There are many examples of such carriers : Glucose and amino acid transporter, Ion & organic molecule transporters, neurotransmitter precursors (such as choline) or of neurotransmitters (Noradrenaline, 5-HT, glutamate uptake).
The amine transporters belong to a well-defined structural family, distinct from the corresponding receptors.
The carrier proteins embody a recognition site that makes them specific for a particular permeating species.
These recognition sites can also be targets for drugs whose effect is to block the transport system. e.g. TCA, Cocaine, Omeprazole, Cardiac Glycosides
They are protein structure present on the mammalian cell or within the cells.
Receptors are the sensing elements in the system of chemical communications that coordinates the function of all the different cells in the body.
The chemical messengers being the various
Hormones
Neurotransmitters
other mediators (e.g. Autocoids: Histamine, 5HT, etc)
Many therapeutically useful drugs act, either as agonists or antagonists, on receptors for known endogenous mediators.
TYPES OF RECEPTOR
Receptors elicit many different types of cellular effect. Based on molecular structure and the nature of transduction mechanism four receptor types can be distinguished.
These are membrane proteins with a similar structure to other ion channels, and incorporate a ligand-binding (receptor) site, usually in the extracellular domain.
On these receptors fast neurotransmitters act.
Examples include the nicotinic acetylcholine receptor; GABAA receptor; glutamate receptors of the NMDA.
These ion channels have same structural features e.g. Nicotinic Ach Receptor
It is assembled from 4 different types of subunit α β γ δ.
These subunits are inserted into the membrane.
The oligomeric structure possesses two Ach binding sites, each lying at the interface between one of the 2 subunits and its neighbor.
Both must bind Ach molecules in order for the receptor to be activated.
metabotropic receptors They are membrane receptors that are coupled to intracellular effector systems via a G-protein .
They constitute the largest family, and include receptors for many hormones and slow transmitters.
Example the muscarinic acetylcholine receptor, Adrenoceptors & Chemokine receptors.
Subtypes are also present and all have same basic structure.
Type 3: Kinase-linked and related receptors.
This is a large and heterogeneous group of membrane receptors responding mainly to protein mediators.
They comprise an extracellular ligand-binding domain linked to an intracellular domain by a single transmembrane helix.
In many cases, the intracellular domain is enzymic in nature (with protein kinase or guanylyl cyclase activity).
Examples: Type 3 receptors includes for those insulin and for various cytokines and growth factors.
These are receptors that regulate gene transcription.
The term nuclear receptors is something of a misnomer, because some are actually located in the cytosol and migrate to the nuclear compartment when a ligand is present.
They include receptors for steroid hormones, thyroid hormone, and other agents such as retinoic acid and vitamin D.
The concept of drugs acting on receptors generally is credited to John Langley (1878). While studying the antagonistic effects of atropine against pilocarpine -induced salivation.
The word receptor was introduced in 1909 by Paul Ehrlich. Ehrlich postulated that a drug could have a therapeutic effect only if it has the "right sort of affinity." Ehrlich defined a receptor in functional terms: ". that combining group of the protoplasmic molecule to which the introduced group is anchored will hereafter be termed receptor.
“ The receptors are specialized target macromolecules present on the cell surface or intracellularly. Receptors bind drugs & initiate events leading to alterations in biochemical and/or biophysical activity of a cell and consequently, the function of an organ.
Drug Receptors From a numerical standpoint, proteins form the most important class of drug receptors. Examples include the receptors for hormones, growth factors, transcription factors, neurotransmitters; the enzymes (e.g., dihydrofolate reductase, acetylcholinesterase, and cyclic nucleotide phosphodiesterases)
Drug-Receptor Interaction
The binding of drugs to receptors can involve all known types of interactions-ionic, hydrogen bonding, hydrophobic, vander Waals, and covalent. Most interactions between drugs and their receptors involve bonds of multiple types. If binding is covalent, the duration of drug action is frequently, but not necessarily, prolonged. Noncovalent interactions of high affinity also may be essentially irreversible.
The magnitude of the responses is proportional to the number of drug-receptor complexes. Drug + K1 Drug-receptor complex K3 (Response) Receptor K2
Where K1, K2 and K3 are rate constants. The rate at which the drug molecule combines with a receptor site is K1. Similarly, the rate at which the drug-receptor complex dissociates is given by K2. The rate at which a response is generated following a drug-receptor interaction is given by rate constant K3. These constants are used to define some basic concepts related to drug-receptor interactions.
In general, the drug-receptor interaction is characterized first by binding of drug to receptor and second by generation of a response in a biological system. The first function is governed by the chemical property of affinity, ruled by the chemical forces that cause the drug to associate reversibly with the receptor.
Affinity It describes the ability of a drug to form and subsequently maintain a complex with a receptor site.
Intrinsic Activity It describes the ability of a drug to evoke a pharmacologic response on combining with a receptor. E.g. Acetylcholine acts as a cholinergic agonist.
Potency & Efficacy
Potency: A drug is said to be potent when it possesses high intrinsic activity at low unit weight doses. Knowledge of a drug’s potency is important for finding out the appropriate dosage level to be administered .
Efficacy: It refers to the maximal or peak response produced by a drug, and is an important determinant in the drug selection process.
Some important terms related to drugs and receptors:
Agonist: It is a drug (or hormone or neurotransmitter) which combines with its specific receptor, activates it and initiate a response e.g. acetylcholine, noradrenaline activate cholinoceptors and adrenoceptors respectively.
Antagonist: It is a drug which binds to the receptor, but does not activate it. Moreover, it prevents the action of the agonist by rendering the receptor unavailable for interaction with the agonist e.g. atropine antagonizes acetylcholine. A pure antagonist has no action of its own, but acts only by interfering with the action of an agonist e.g. the opioid antagonist naloxone.
Partial Agonist: It is a drug that binds to the receptor, but activates it weakly and prevent the action of a full agonist. This drug acts on the receptor with an intrinsic activity or efficacy of less than one.
A unique feature of these drugs is that, under appropriate conditions, a partial agonist may act as an antagonist of a full agonist. e.g. Aripiprazole, an atypical neuroleptic agent, is a partial agonist at selected dopamine receptors. Dopaminergic pathways that were overactive would tend to be inhibited by the partial agonist, whereas pathways that were underactive may be stimulated.
Inverse Agonist: It is a drug that causes an effect opposite to that of the agonist, in contrast to a competitive antagonist that simply blocks the agonist, but has no inherent action of its own. E.g. The agonist action of benzodiazepines on the GABA receptor produces sedation, anxiolysis, muscle relaxation and controls convulsions. The inverse agonist: The β-carbolines (e.g. n-butyl-β-carboline-3-carboxylate) also binds to GABA receptor causing stimulation, anxiety, increased muscle tone and convulsions. Thank you
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