Pharmacology: How Drugs Act

• Basic principles of pharmacology are being reviewed

How Drugs Act: Chemical Mediators and Drug Targets

• Drugs can act by one or more mechanisms to produce their effects
• Pharmacologists allocate drugs to one of a few groups based on their mechanism of action
• Knowledge of a drug's mechanisms has implications for its beneficial and adverse effects
• Mechanism knowledge underlies methods to quantify drug effects
• Mechanism knowledge has resulted in progress being made in understanding diseases and in the development of new classes of drugs

Communication, Control, and Co-ordination

• The activities of cells, tissues, and organs should be regulated and integrated for an organism to survive
• The system of communication to survive includes inter- and intracellular communication
• Communication is mediated by substances in solution diffusing through internal fluid compartments
• Chemicals produce specific actions at high dilution and only on certain cells or tissues
• Communication requires that the message transmits at the right time; be clear; be received only by receiver; evoke response; cease when response is achieved

Chemical Mediators

• At the heart of communication are chemical mediators, how cells receive and respond
• Pharmacology began on these three elements and is now including drug action

Examples of Chemical Mediators: Neurotransmitters and Hormones

• There are two groups of chemical mediators present in body
• Synthesis, storage, release, and metabolism should be controlled properly
• Shows structural diversity
• A chemical mediator is required to bind to a specific site for effect with binding occurring at dilutions @ 10^-8 and 10^-12M
• Chemical mediators do not produce permanent effects so binding should be reversible
• Not all tissues respond to every chemical mediator so there cannot be binding sites and mediator selectivity
• Agents that bind are ligands but not all ligands are drugs

Receptors

• Macromolecules mainly have protein in composition that binds an endogenous mediator reversibly
• A sequence of events begin ending in specific change in cell
• Receptors are selective receivers of the communication system + coupled to transducers or amplifiers for promulgation of the message
• Receptors are found in cell membranes

Selective Receptors

• Most receptors are proteins with unique 3D structure
• Domains have different properties like charged and hydrophobic sites/flexibility
• Combinations of properties makes each receptor highly selective / capable of binding a single mediator
• Receptors bind mediators at very low concentrations with high affinity
• Receptors can be saturated by mediator which occurs at low concentrations distinguishing receptors from other non-specific binding sites

Binding Requirements: Drug Binding

• Binding requires complementary relationship: molecular geometry, arrangement of reactive groups, molecular flexibility
• Drug binding does not involve the F/B of covalent bonds so non-covalent bonds are important
• Bonding interaction types: hydrogen, Van der Waal forces(Dispersion), ionic, charge transfer, ion-dipoles and dipole-dipole bonds
• Bond types/close proximity of molecules @ binding site produces the high affinity reversible binding that is typical of drug-receptor interactions

Production of Receptors

• Protein production instructions are encoded in DNA
• Selective distribution among different cell and tissue types shows selective DNA expression for cell/tissue function
• A hormone/neurotransmitter rc may exist in receptor sub-types based on slight variations

Location of Receptors

• Location of receptors in cells varies by mediator type with four main types
• Three of the receptors are in the cell membrane and one is inside the cell

Cell Membrane

• Receptors on the cell membrane's outer face must be oriented to bind mediators from outside
• These receptors typically have hydrophilic mediators
• Location is verified by autoradiography, by comparing the activity of extracellular mediator(effective) and intracellular(ineffective) and covalently bound polymer beads

Receptor Isolation and Purification

• Receptors can be isolated from membrane fragments and purified by affinity chromatography
• Receptors isolated/purified can be reconstituted in lipid membranes/ functionally equivalent

Cytoplasm

• Receptors are found within the location of the cytoplasm cell and are not stored in the membrane.
• The interaction receptors tend to be lipophilic combining with dissolving fats allowing cells to pass
• Examples are steroid and thyroid messengers that pass into cell nucleus

From Receptor Binding to Cellular Response

• Binding a mediator to receptor initiates a response in a cell
• Several response ways that vary from mediator to mediator and between tissues affected by mediator
• There are three response mechanisms with cell membrane receipts
• Receptor channels, G-protein and enzyme-linked receptors are the characterized means of the receptors

Receptor Operated Channels/Ligand-gated Ion Channels

• Ion channels link to neurotransmitter receptors
• Neurotransmitter combinations opening channel in membrane allows passage of a particular ion to take place
• This leads to altered membranes/cell membranes to change
• Nerves/muscles are cells which get electrical stimulus from neurotransmitters/receptor linked which leads to the occurrence of cell communication

G-protein-linked Receptors

• Linked operate using production, intracellular messaging and the second messenger.
• G-protein linkage extends to three variants
• The link: receptor, G-protein and the enzyme adenylate cyclase

G-protein-linked Receptors (2/7)

• Mediator binding causes a change to the receptor exposing a G-protein binding site causing receptor and G-protein to move/complex in membrane
• The G-protein bound to: cyclic nucleotide, guanosine diphosphate (GDP) which will be displaced by GTP when a receptor and G-protein complex.
• GTP binding causes dissociation from G-protein subunits, binding to adenylate cyclase

Activated G-protein Stimulates Effector to Produce Second Messenger

• Protein subunits and adenylate cyclase form complex activating enzyme + convert ATP to cyclic adenosine monophosphate (cyclic AMP)
• GTP has hydrolysis (GDP), G-protein subunits return and cease activating a cyclase binding subunit; unless a receptor remains it becomes inactive

Second Messenger Promotes Signalling Inside the Cell

• AMP from mediator receptor produces effects by activating AMP-dependent protein kinase enzyme
• Catalyzes a transfer of phosphate group (ATP) for serine or threonine on target proteins
• A receptor G-protein action is adrenaline on beta-adrenergic of skeletal muscle cells stimulating breakdown of stored energy

Inhibitory G-protein-linked Receptors

• Receptors results in adenylyl cyclase inhibition
• The G protein involved is an independent unit that will exist as membrane in the cellular structure.
• The receptors are used in the noradrenaline combining in the combination with Alpha Adrenergic.

G-protein-linked to Membrane Phospholipid Conversion to Second Messenger

• Linking causes activation of Phospholipase C whose substrate: phospholipid, phosphatidylinositol (PIP2) found on the membrane
• Phosphatidylinositol biphosphate broken down into inositol triphosphate and diacylglycerol (DAG) which will then produce calcium-sensitive proteins for more activity
• Mechanisms are distinct of AMP

Second Messengers and Intracellular Signalling

• Receptor mechanisms are 2nd messenger which transduces messages (mediator) to membrane messenger.
• AMPs show messenger distributors and various other signals

Enzyme-linked Receptors or Catalytic Receptors

• Transducer linkage is from catalytic
• Receptor makes a mediator site with glycoprotein for outer cells
• Mediator combos induce the domain's changes
• Cytoplasmic domains give evidence to enzyme activity
• Insulin receptor link gets phosphorylation and action results

Intracellular Receptors

• Interact with DNA in nucleus for effect with binding activating receptors for proteins
• Activated receptors form an complex in cell nucleus with affinity for sequences
• Transcription forms RNA which determines the production patterns
• Action done after cells exposure to steroid and beta oestradiol, hormone action based on cell type

Biological Membranes and Drugs

• Other binding sites allow drug action when there are no endogenous mediators.
• Lipids in membranes help lipophilic drugs with a number of drug actions due entering membranes packing and space between cells.
• Reduces fluidity and selective effects. Cell nerve membranes have shown success with some selectivity

Biological Membranes and Drugs: Ion Channels

• Presents the receptors to the cellular membrane without binding of electric potential to muscle and nerves
• The Channels are used for elements such as calcium and potassium.
• Their structure types can adjust within cells
• Channels are influential even with other messengers.

Biological Membranes and Drugs: Membrane Binding

• Some drugs act by binding to components and will change permeation
• Kill fungal for sterol molecules which have ergosterol
• Action seen across antibiotics which creates surface disruption

Enzymes and Drugs

• Enzyme and receptors have requirements of ligands
• Acting drugs are inhibitors
• Some of enzymes can produce products from enzyme-cox production
• Enzymes compete with substrates such as captopril for enalapril/solfamides production

Enzymes and Drugs: Interaction

• React in 2 ways, that will supplies enzymes for cell inhibitor such as triphosphase
• Uses enzymes and breaks down extras like tissue for blockages

Other Sites and Drug Action

• Other protein can act as targets for drugs
• Compounds are not immediate transmitters for messenger production
• Drugs have function with cells.

Ion Channels

• Nerves present ions that open response to change(operates)
• Site where have drugs and binds
• Effect channel from Na and Ca to K

Transporters and Pumps

• Lipid barrier use movement that protein will use some functions in the membrane.
• Compounds bind molecules for a act
• Used carriers depending on cell that will then exchange with the transport functions
• pumps use energy depending ATP will move
• Drugs effects use functions of (Na,K,2CI) and cells depend cell with transport

Protein Binding Drugs

• Proteins bind in cells and binds to ribosomes and drugs
• Bind functions of cell then disruption to the inhibitors.
• Antibiotics aminoglycosides and macroides will disrupt with ribosomes

Protein Binding Drugs (2/3)

• Cell fuctions can be important for nutrients .
• Micro protein are for nutrients with the tubulin helps worms
• Drugs bind within cells that creates process production.

Protein Binding Drugs

• Drugs bind micro , the disruption effects forms dividing mitosis and stabilizes while removal effects
• act as anti protein for drugs.

DNA Binding Drugs

• DNA that prevent its structure which will then protect its type to avoid damage for cell effects
• Mutine prevents reactions and prevent transcript cells

Summary

• The text has discussed ways that drugs affect health ,but they still have actions unclear of which will depend.
• Have identify actions for the clinical to improve.
• Two agent not only improve therapy, but supplement deficiencies for produce immunity.