Pharmacology: Drug Action and Receptors

• Pharmacology involves studying substances affecting living systems through chemical processes, typically increasing or decreasing normal regulatory activities.
• A drug is any substance taken into a biological system for non-nutritive reasons, including chemicals, biologicals, and herbals.
• Pharmacodynamics studies what drugs do to the body, including their effects and mechanisms of action.
• Pharmacokinetics studies how the body handles drugs, including their absorption, distribution, metabolism, and excretion.
• Drugs are administered to achieve a beneficial or selectively toxic effect on an individual.

Drug Action and Receptors

• Drug action is mediated by binding to receptors, thus influencing biological systems.
• Receptors are typically bound and activated by endogenous ligands found in the body like hormones or neurotransmitters
• Drugs can modify the interaction between receptors and endogenous ligands, increasing or decreasing receptor activity.
• The location of receptors determines where a drug will act and the outcome of the action, whether beneficial or detrimental.

Types of Receptor

• Regulatory proteins mediate the actions of endogenous chemical signals like neurotransmitters and transmembrane signaling.
• Signal transduction occurs when a ligand or drug binds to and activates a receptor, causing biochemical events that create a pharmacological effect.
• Drug-Receptor signaling reveals response speed and selectivity.

Common Signaling Pathways

• Ligand-gated ion channels are regulatory proteins used to transport ions and span cell membranes, where binding leads to channel protein changes for ion flow.
• An example of this is the nicotinic receptor.
• The endogenous neurotransmitter acetylcholine binds to muscle receptors to open channels and allow sodium ions to enter.
• This depolarizes the cell, which then results in muscle contraction. It gives a rapid response.
• G-protein coupled receptors span the cell membrane where binding changes the protein shape and activates the G-protein.
• The G-protein then activates systems that activate an enzyme or ion channel that will then amplify the effect. This is a slower process
• Regulated transmembrane enzymes have receptors on the outside of the cell linked to enzymes on the inside.
• When binding to the receptor occurs, it changes the receptor drug and activates the enzyme, which leads to reactions and biological effects.
• Intracellular or nuclear receptors are located inside the cell where they are activated by lipid-soluble drugs.
• They exist as inactive protein complexes used for gene expressions.
• The drug binds and activates the receptor, where it will then move to the nucleus to bind to specific genes that increase gene expression and protein synthesis. This process is slower, with longer lasting effects.

Other Receptor Types

• Transporters are proteins that transport endogenous substances across cell membrane, where drugs often will inhibit transporter Ex SSRIs are used to treat depression by blocking the transporter responsible for removing serotonin from the synaptic cleft, which enhances serotonin
• Enzymes catalyze biological reactions, where drugs inhibit catalytic functions, for example statins inhibit HMG-CoA reductase that makes cholesterol
• Structural proteins contribute to cell structure, where drugs disrupt normal function for example anticancer drugs bind to microtubules to inhibit mitosis

Drug Actions not Mediated by Receptors

• Some drugs interact directly with the biological systems.
• This is less common. An example of this is antacids; these neutralize stomach acid through an acid-base process. Another example is Chemotherapy drugs, which disrupt a cell function to kill cells

Drug Classification

• Drugs are classified by binding location and binding effect
• Drug interaction affects ligand-receptor activity and are usually reversible.

Drug Classifications

• Agonists will bind to a receptor and activate the receptor to desired effect or response, can be endogenous or drug, an example is Beta 2 agonist to dilate bronchioles in the lung.
• Partial Agonists will bind to a receptor and activate it, but produce a weaker response than an agonist. An example for beta 2 will dilate bronchioles but not as much.
• Allosteric Activators binds to different area than agonist, which allows for the receptor to be activated, this leads to an increased ability for an agonist to activate the receptor and increase effects.
• Competitive Antagonist binds to the receptor as a agonist but doesn't activate it instead; blocks the agonist from binding. An example of this is it binds to the beta 2 receptor, blocking dilation of the bronchioles, this can only occur with a high amount of an agonist.
• Non-Competitive Antagonist binds irreversibly to a receptor at the same site or allosteric site, leading to conformational change where it is less able to bind.

Graded dose-response relationship

• The intensity of the pharmacological effects made by a drug is always proportional to the dosage.
• To achieve the desired effect of the drug, multiple receptors will have to be activated at once.
• Dose is represented graphically by the dose response curve
• Efficacy shows maximum pharmacological response that can be produced by the drug (vertically)
• Potency is the dose concentration to produce a response to a set magnitude
• Therapeutic range is the dosage level above the minimum concentration for the desired results without producing toxicity

Recommended Dose

• The amount of drug will cause desried effects in most people but not all; some will see desiredeffects and others will experience toxicity.
• Doses should be adjusted based on response of individual
• A qualtal dosage indicates effect is binary for example, present or absent across people.

Drug Disposition and Pharmacokinetics

• For a drug to have effects of substance must:
• reach cellular site of action, exert an effect and remove substance from the body
• Disposition is substance movement throughout body
• Pharmakinetics: is the disposition quantitively.
• ADME
• Absorption to blood, distribution throughout body, metabolism through enzymes to create different body and excretion out of the body.

Phisio Chemical Properties of Drugs

• Can be soldiquid or gas and dictated based on administration.
• Must be able to cross in biological membranes. Is determined by by physio chemical properties.
• Bio availability is percentage of an ADME dose that reaches the blood
• IV is 100% bio available.
• Other routes are 5 to 100% based on dose.

Routes of Administrations

• Routes vary based on area:
• Mouth, Rectum, Under the tongue and cheek- all enteral
• Skin, vagina, eye, ear, nose and lungs- topical
• Veins, muscle and skin- parenteral
• Absorption is movement from administration into the blood with breakdown, dissolution in GI fluids and crossing of biological membranes
• Lipids require diffusion and so do aqueous pores.
• Most drugs are weak acid or base and ionize in fluids.
• Acidity will have ionized form and weak acid, basic few protons will have base.
• Acids are absorbed from acidic conditions
• Bases absorbed from basic conditions

Distribution

• Sites of absorption to other areas of the body.
• Most drugs reach all areas of body- indicator of pharmacology expected is in the blood.
• When blood concentration will drop below concentration.
• Dependent of rate and blood flow to a location.
• Depends on perfusion of body
• Drugs existing in free drugs and protein bond.
• Proteins cannot cross over and reduce ability to work.
• Most penetration is not equal in all organs; some are limitesd by brain, cord and placenta

Metabolism

• Aka bio-transformation to a different compound.
• needs to be metabolized in order to have desired affect, can result on toxics and nontoxic creation.
• Most happen in the liver.
• Divided into phases 1 & 2.
• Phase 1 either adds functional reaction, phase 2 is adding water based part to aid in excretion.
• Oxidation of the drug happens in Cyps and is 18 family member of enzymes that act on drugs.
• Gene variability results into metabolism in fast or slow results.
• Other oxidative and hydrolysis
• reactions add large molecular structure for metabolic action

Drug Interactions

• First pass effext is transformation of drug during absorption
• Drugs with oral pass will be absorbed by transformation.
• Reduce active drug to reach rest of the circulating body
• Disease and drug interactions effeteness the birstranfofmration and effectiveness of a drug'
• Amount deacres are during birth and increase with elderly 60+, disease will result with liver.

Excretion

• Move of drug through metabolites out of the body- Kidney , Gl tract are the.main ones.
• Glomerulus will capsule and bowman capsule that filters the substance.
• Loop of henle reabsorbs water and solutes
• Process will pass Bowman's, pass to be absorbed and exretred by drug
• High gfr, high flow will dictate ability to excretion
• Body fluids are minor- but will be detected- lungs will be volatile.

Clinical Pharmacokinetics

• is study of a function with time, what it should be quanitative- goal is to detemie dose in an ivinduals therapy- theres a minimal add verse effect .
• Body is made of fluid components, or can be desributed to fluid copartments. VDs is volume is appears it desitubed.
• 42 liters is total, 28 intra,, 14 extra
• Clearance is process from drugs remving in the body.

Pharmakinetics

• Most drugs are related constant over concnteration and not saruate
• Time need for liver and kidney to remove the time for blood or liver and thekidens to remove 50%of the drug..
• If adminstrated are plasma concertion will increase intial the adminstraikion is equal to
• Plateau priplnce states, plasma will acumlate and concnetin will stay the same, time may double by hlaf if it does atimiste new idose.
• If given more body or is there is a diffrenence , you would then have to detemine dosage adminstriation based on wiegh and is metric

Clinical trials

• Have increased effort to estabilised dose for kids
• Can get does by age size what dose is need but it is bsa. Which can be detrimned.
• Some pt wont take medication correctly = no admerince
• May forget and have a effect of minor

Adverse drug reaction

• Assed on the Therputic dose, = if dose effect to benficla to undesire effect
• Diffcult to predict due ot rare and some toxic reations after prougned effect- due to toxic aniamis unqie cricumstance.
• Averse, not ntwneded extension of drug , not intended issue/receptors the drug will take on- but the biastfrnmtiom wil alos
• Alllergey reation, what type of admenration was not supposed to do.

What can occur.

• Torelance , unsedied psycholy
• Generic or unusal repsine
• tergoinsis defect, risks
• age for those and sensitve
• multi desiese

Drig and driugg intearcations

• Modication by presnte
• alter abdromption distubance
• consquennces and inteactions
• added, comined
• pharmo and effects
• disutribution and bio transormaton

Drug development

• idenifcation
• more sudy , if so to lead compound
• 2-8 years up to 2600 chemical compund

Drugs

• testing prior to testing in humans
• cell and tissue - determine mechansim, sefetty, depends on the type
• time, species , dose

Clinical traisl

• companys that pasd the procced with the intital trial that company is needed
• procced through trial 12
• dose to determing the dose
• safeth
• and how it will elimation in body