Pharmacodynamics Principles

Pharmacology Basics

• Pharmacology studies drugs' actions, predicts interactions, manages comorbidities, and determines appropriate doses.
• Pharmacology also helps to understand drug effects related to aging, pregnancy, and organ dysfunction.
• Pharmacodynamics refers to the effect of drugs on the body via concentration and effect.
• Pharmacokinetics refers to how the body affects drugs over time and concentration.
• Pharmacokinetics guide dosing, frequency, dose adjustments, and understanding interactions.
• Effective drugs must be present in the right place, at the right concentration, and in the right amount.

Pharmacokinetics

• Pharmacokinetics involves absorption, distribution, metabolism, and excretion.
• Cmax represents the maximum drug concentration in blood.
• Cmin represents the lowest drug concentration in blood.
• Tmax represents the time at which maximum drug concentration occurs.
• T1/2 represents the time taken for tissue drug concentration to fall to half its original peak concentration.
• You can calculate T1/2 using the formula: T1/2 = (0.693 x Vd) / CL, where CL is clearance.

Absorption

• Absorption refers to a drug's passage from the administration site into the plasma.
• Order of transit: Gut → Liver → Vein → Heart → Lungs → Heart → Artery
• Drugs can enter the body via enteral, parenteral, subcutaneous, intramuscular, sublingual, topical, or inhalation routes.
• IV administration is the most direct route, giving 100% bioavailability and skipping first-pass metabolism.
• Different administration routes can lead to different Cmax and Tmax values, but not half lives.
• Most drugs absorb in the intestine using passive diffusion, moving from high to low concentration until equilibrium.
• Absorption rate depends on the concentration gradient, absorptive surface area, and drug's fat solubility.
• Fat-soluble molecules pass directly through the cell membrane's phospholipid bilayer.

Factors Affecting Absorption

• GI tract function, blood supply, pH, and absorption surface area are all body related factors.
• Food and disease also affect absorption
• Drug properties include lipid solubility, particle size, and concentration.
• Dosage form, formulation, administration route, and dosage are also factors.

First Pass Metabolism

• First pass metabolism takes place before the drug reaches systemic circulation.
• Drugs from the digestive tract pass to the liver for metabolism by P450 enzymes before entering circulation.
• The extent of first pass metabolism determines a drug's bioavailability.
• Some drugs undergo almost complete liver metabolism, leading to low bioavailability and ineffective action.
• First pass metabolism occurs mainly in the liver, but also in the intestinal mucosa, lungs, and skeletal muscle.
• Prodrugs require liver metabolism to become active.

Distribution

• Distribution involves a drug's movement throughout the body to exert its therapeuticeffect.
• Drugs must move from the bloodstream (plasma compartment) to the tissue.
• Blood serves an primary distribution, and poor blood supply means poor distribution.
• Free drug molecules distribute evenly through fluid compartments.
• Drug properties like lipid/water solubility, particle size, and protein binding affinity affect the distribution.
• Drugs must be free to move, act, and be unbound to move from plasma to tissues.

Plasma Protein Binding

• Many drugs bind to plasma proteins, particularly albumin; only free drugs exert therapeutic effects.
• Low plasma binding drugs: a drop in protein levels has minimal impact on the unbound fraction.
• High plasma binding drugs: changes in protein levels significantly alter the unbound fraction.
• Changes in plasma protein binding are significant for drugs with greater than 90% bound.
• Renal impairment, low albumin levels, chronic liver disease, malnutrition and late pregnancy affect plasma protein binding.
• Bioavailability = the fraction of administered drug that enters the circulation intact and available to exert its desired effect.
• Use the formula: Bioavailability (F) = AUC (oral) / AUC (IV) to determine bioavailability.

Volume of Distribution

• Volume of distribution estimates the extent of drug distribution.
• Drugs distribute unevenly based on their physical and chemical properties.
• Low volume of distribution means the drug is confined to plasma and body water with little distribution to tissue.
• High volume of distribution means the drug is widely distributed to the tissues.
• Lipid-soluble drugs have a higher volume of distribution than water-soluble ones.
• Volume of distribution = Amount of drug in the body (dose) / Concentration in plasma
• Loading Dose = Vd x target concentration

Metabolism

• Metabolism occurs regardless of administration route, occurring earlier for oral drugs.
• Liver metabolism can produce active metabolites, reduce drug activity, or activate prodrugs.
• The aim of metabolism is to make drugs more water-soluble for easier kidney excretion.

Phase 1 Metabolism

• Phase 1 metabolism occurs in liver hepatocytes, involving cytochrome P450 enzymes (CYP).
• These enzymes catalyze oxidation, reduction, and hydrolysis.
• P450 enzyme activity can be induced or inhibited by other drugs.

Phase 2 Metabolism

• Phase 2 metabolism involves adding chemical groups to increase water solubility via these processes:
  • conjugation
  • methylation
  • glucuronidation (most common)
  • acetylation
  • sulfation
  • conjugation with glutathione.
• Liver disease, genetics, age, and nutritional status affect metabolism.
• Enzyme inhibitors and inducers affect metabolism rate by cytochrome P450.
• CYP inhibition slows drug metabolism, increasing serum plasma concentration to potentially toxic levels.
• CYP induction speeds up metabolism, decreasing serum plasma concentration and potentially causing treatment failure.
• CYP450 enzymes metabolize drugs by oxidation, hydrolysis, hydroxylation.
• Hepatic clearance is the volume of blood perfusing the liver cleared of drug per unit of time.

Cytochrome P450 Inducers & Inhibitors

• Common Inducers = CRAP GPS:
  • Carbemazapines
  • Rifampicin
  • Alcohol
  • Phenytoin
  • Griseofulvin
  • Phenobarbitone
  • Sulphonylureas
• Common Inhibitors = SICKFACES.COM:
  • Sodium Valproate
  • Isoniazid
  • Cimetidine
  • Ketoconazole
  • Fluconazole
  • Alcohol/grapefruit juice
  • Chloramphenicol
  • Erythromycin
  • Sulfonamides
  • Ciprofloxacin
  • Omeprazole
  • Metronidazole

Excretion

• Most drugs are excreted by the kidneys, with some processed by the hepatic biliary system and excreted in the faeces.
• The rate of elimination is important for determining the duration of response and time interval between doses.
• Water solubility is key for renal excretion; lipid-soluble drugs are reabsorbed into the renal tubules.

Clearance

• The formula for clearance is: Clearance = (concentration of drug in urine x volume of urine produced) / concentration of drug in plasma.
• Concentration of drug in plasma (Cp) relates to the drug dose given.
• Volume of urine produced (Vu) relates to the glomerular filtration rate (GFR).
• Drug reabsorption from nephrons will decrease the concentration of drug in urine and therefore clearance.
• Drug secretion into nephrons will increase concentration and therefore clearance.
• Half-life - the time taken for the concentration of drug in the plasma to fall by half.
• Half Life (T1/2) can be affected by the rate of metabolism and efficiency of excretion.
• Steady state is achieved after 5 half-lives and drug is eliminated after 5 half-lives. -T1/2 = 0.693 x VD / CL
• Where CL = (clearance)
• If the total clearance of a drug increases, then half life will decrease.
• If total clearance decreases, half-life will increase. Clearance represents the sum of all elimination processes (renal, hepatic, biliary, exhalation).
• Clearance is the volume of plasma cleared of drug per unit time, not the amount of drug cleared in that time.

Orders of Kinetics

• First Order Kinetics: The rate of elimination is proportionate to the current concentration.
• Higher concentration = faster excretion or more in plasma, more in filtrate.
• Half-life remains constant. This is the case for most drugs.
• Zero Order Kinetics (Saturation Kinetics): When the metabolizing enzyme is saturated there is too much drug and not enough enzyme to metabolize it.
• This creates a bottleneck and creates constant elimination regardless of the plasma concentration.
• The rate of excretion is now independent of the concentration of drug in the plasma.
• The half-life is no longer a constant value and is not dependent on the current concentration of the drug.
• These drugs are more easily overdosed as the rate of excretion does not increase at higher doses.
• Once the enzyme is no longer saturated, the elimination pattern will follow first-order kinetics.
• In zero order kinetics, the relationship between dose and steady state becomes unpredictable.
• Time to steady state (TSS) = 5 x T1/2 (i.e., 5 half-lives, this is the same for elimination).

Pharmacodynamics:

• Pharmacodynamics looks at The effects of a drug on the body at the cellular level.
• This includes the biochemical and physiological effects that drugs can exert on the body.
• Considers where and how drugs act, what effects they have, and how dose affects response.
• Helps understand drug action mechanisms, drug targets, therapeutic effects, side effects, drug potency, dosing, and response.

Drug Effects on Cells:

• Most drugs work by interacting with a receptor.
• Non-steroidal anti-inflammatory drugs work by blocking the action of specific enzymes.
• Antidepressants work by inhibiting cell transport mechanisms.
• Oncology drugs and disease modifying anti-rheumatic drugs work by modifying the cell's physical or chemical environment.
• Antibacterials, antifungals & antivirals act of invading organisms

Drug Targets:

• Most drug targets are protein molecules, mimicking natural substances and hormones to reach receptor sites.
• Four categories of drug targets: receptors, enzymes, carrier molecules, and ion channels.
• Drugs bind with their target such as a receptor to form a drug-receptor complex.

Specificity

• Most drug targets show high specificity for binding molecules, ignoring closely related molecules.
• Specificity between drugs and receptor sites is reciprocal; closer fit means greater chance of complex formation and response.
• NOTE:no drug is specific in its action.

Affinity and Efficacy

• Drug-receptor interactions involve electrostatic bonding, hydrogen bonding, and Van der Waals forces.
• The ability of a drug to bind at the receptor site depends on the receptor's shape and electrical charge.
• Once bound, the drug's effect depends on its affinity (how tightly it binds) and efficacy. (the ability of the drug to elicit a response – intrinsic activity)

Receptors

• Receptors are specific proteins on the cell surface or in the cell membrane that sense and respond to substances.
• Four types of receptors:
  • Agonist (Ligand) or voltage gated lon channels
  • G-Protein coupled receptors
  • Nuclear receptors
  • Kinase linked receptors

Receptor Regulation

• Upregulation increases receptor density and sensitivity, often caused by denervation or prolonged deprivation of/long term administration of an antagonist.
• Downregulation decreases receptor density and sensitivity, often caused by an increase in a long term admin/exposure to an agonist.
• Decreasing agonist exposure results in upregulation, while increased exposure results in downregulation.

Enzymes & Transporters

• Enzymes speed up chemical reactions:
  • the Enzyme binds to a substrate and breaks it down into new molecules.
• Inhibiting enzymes have profound effect on biochemical pathways.
• Transporters release neurotransmitters into a synapse and then they will bind to receptors on the postsynaptic neurone.
• They will elicit a response – Activation/Inhibition, the neurotransmitter is then transported back into the presynaptic neurone by a transporter.

Agonists

• Full agonists mimic naturally occurring messengers, binding tightly to receptors (high affinity) and producing equivalent responses (high efficacy).
• Full agonists activate receptors, resulting in a maximal biological response, with 100% efficacy.
• Partial agonists do not fully activate receptors but still result in a similar response to the natural chemical messenger.

Inverse Agonists

• Inverse agonists bind to the same site as agonists, and also reduce the max effect by inactivating the receptor to below its basal activity.

Antagonists

• Antagonists block receptors from activation, binding tightly (high affinity) but producing no response (no efficacy).
• Competitive antagonism - agonist can still attach and activate the site if the site is displaced
• Non-competitive antagonists - distort the site, preventing agonist binding; cannot be overcome by increasing agonist concentration
• Orthosteric = binding that occurs to the active receptor binding site
• Allosteric - binding that occurs to an alternative receptor binding site which alters the shape of the receptor

Allosteric Modulators

• An allosteric modulator indirectly influences an agonist's effects by binding to a distinct site
• A positive allosteric modulator (enhancer) amplifies agonist effect.
• A negative allosteric modulator (inhibitor) reduces binding of ligands, decreasing activity

Drug Response

• Drugs reach a sufficient level - therapeutic level.
• The Length of time taken for drug to reach minimum effective level - onset of action.
• The duration of the action - termination of action.

Dose-Response Curve

• More potent drugs require lower doses for the same response, with EC50 measuring agonist potency.
• A change in potency does not signify a change in efficacy; high-potency drugs can mirror low-potency drugs if dosed correctly.
• If potency curve shifts right and EC50↑ there is a decrease.
• If potency ↑ curve shifts left and EC50↓ there is an increase.

Therapeutic Index

• Therapeutic index (TI) is the range of doses for effective medication without unacceptable adverse events.
• Therapeutic index (TI) is based on a % of the patient population.
• Drugs with a narrow therapeutic index have a narrow margin between effective and toxic doses.
• Wider therapeutic index drugs are safer with higher margin of error.

Calculating Therapeutic Index

• TI = Toxic Dose (TD50) / Therapeutic Dose (ED50) -TD50 = the dose of drug that causes a toxic response in 50% of the population -ED50 = the dose of drug that is therapeutically effective in 50% of the population
• . The larger the therapeutic index (TI), the safer the drug is.
• If the Tl is small (the difference between the two concentrations is very small), the drug must be dosed carefully and the person receiving the drug should be monitored closely for any signs of drug toxicity.
• Examples of Narrow Therapeutic Index Drugs:
  • Gentamycin
  • Warfarin
  • Theophylline
  • Digoxin
  • Phenytoin
  • Lithium

Adverse Drug Reactions

• Adverse drug reactions (ADRs) are harmful, unintended responses to a medicine or vaccine.
• Pharmacovigilance collects ADR data through national reporting to ensure medicines have positive benefits and risk.
• Pharmacovigilance provides an early warning system for identifying previously unrecognized ADRs.
• The medicines regulator can then try to identify and understand risk factors that may affect the clinical management of the patient, issuing regulations that may include restrictions on use, refinement of dosage, introduction of specific warnings or withdrawal of a medicine from the market to protect patients from harm
• Most ADRs are reported by HCPs but parents, carers can also report them.

Classification of ADRs

• Type A - augmented reactions; predictable, usually dose/pharmacology related from knowledge about how the drug works.
• Type B - bizarre reactions; unpredictable, not related to pharmacological action of the drug and often linked to genetic variation - occur far less frequently.
• Type C - continuing reactions; less common, persist for a relatively long time.
• Type D - delayed reactions; become apparent sometime after the use of a medicine.
• Type E – 'end of use' reactions; associated with withdrawal of a medicine.
• Type F - Failure of treatment.

Reporting ADRs

• You can report any medicine; prescribed, from pharmacy or OTC as well as vaccines and complementary therapies.
• Reports should be made to regulator when a medicine or vaccine is suspected to have caused an ADR – you do not need to be certain. In the UK; Yellow Card Scheme run by MHRA. Reports can be made:
  • Online
  • Yellow card mobile app
  • Paper forms
  • Members of the public

Information to Include When Reporting

Reports should be made if ADR is serious, medically significant, or results in harm to the patient. Required information for reporting:

• Patient identifier – maintain anonymity but allow you to identify patient in the future
• The name of the medicine suspected to have caused the ADR
• Brief description of the suspected reaction
• Your contact details to allow the report to be acknowledged, you to be contacted if further information is required.

Other Information About Reporting ADRs

• If any of these elements are missing, the report will be invalid.
• All ADRs from medicines under additional monitoring must be reported, regardless of severity.
• Some medicines, mainly new ones, are put under extra monitoring to learn more about their ADR patterns.

Prescribing Safely

• Prescriptions must be legible, in indelible ink, dated, with the patient's name and address.
• The prescriber's address, type, and signature in ink are required.
• Patient age/DOB is preferable, legally required for prescription-only medicines for kids under 12.
• Standard prescriptions last for 6 months, unless a controlled medicine is prescribed.
• An off-label use of a medicine is when a medicine is licenced in the UK but is being used in a way that is different to that described in the product licence.
• Never Events are serious and avoidable errors where preventative measures should be in place.
• Prescribing unlicensed medicines raises prescriber responsibility; competence and patient info are critical.

Controlled Substance Prescriptions

For Schedule 2 and 3 drugs.

• Patient's name and address
• Drug name
• Dose (avoiding "as directed")
• Formulation
• Strength, if applicable
• Total quantity in both words and numerals
• Prescriber's signature and address
• Date of issue
• Specifics for installment prescriptions
• The words "for dental treatment only" if prescribed by a dentist
• Schedules 2,3, & 4 require appropriate record keeping.

Laws related to Medicines

• The Department of Health and Social Care (DHSC) recommends limiting Schedule 2, 3, and 4 drugs prescriptions to the amount necessary for up to 30 days' treatment.
• Schedule 2, 3, and 4 drugs prescription balances must be dispensed within 28 days.
• The Medicines Act 1968 contains medicine regulations. The Human Medicines Regulations 2012 contains UK drug manufacture, import, etc information.
• In these Regulations (Human Med Regs 2012), “medicinal product" means - (a) any substance or combination of substances presented as having properties of preventing or treating disease in human beings; or (b) any substance or combination of substances that may be used by or administered to human beings with a view to (i) restoring, correcting or modifying a physiological function by exerting a pharmacological, immunological or metabolic action, or (ii) making a medical diagnosis.

Medicines Classifications in the UK:

• General Sale List (GSL) – Available in general retail outlets such as supermarkets. GSLs are a type of medicine that have few legal restrictions. They can be bought almost anywhere. Although these medicines are typically deemed "not dangerous", it doesn't mean that they come with no risk - so you should still be careful when administering them to a person.
• Pharmacy (P), is available under supervision.
• Prescription Only Medicines (POM) are available only with a prescription.
• Controlled Drugs (CD) are under Misuse of Drugs Act 1971.

Misuse of Drugs Act 1971 and Regulations 2001:

Misuse of Drugs Act 1971: -The Misuse of Drugs Act 1971 is the main law to control and classify drugs that are 'dangerous or otherwise harmful' when misused. -Act classifies drugs into Classes based on harm: -A: most harmful -B & C

• Also makes possession, supply, production, import and export illegal. Misuse of Drugs Regulations 2001: -allows legal possession/supply of controlled drugs for approved use via prescription, dispensing; covers storage + disposal.

Other Agencies:

Medicines & Healthcare Products Regulatory Agency (MHRA): -regulates medicines, medical devices & blood components in the UK. Statutory Instruments (SI): -Parliament delegates law alteration via these instruments.

Ethics & Rules

• Professional duty of care arises from law and professional bodies. Balance of Probability
• Criminal Law applies to harming others and Property beyond reasonable doub Equality Act 2010: -legally protests people from discrimination. Human Rights Act 1998: -allows one defend of rights via courts and compels organisations and councils to treat all fairly.
• Patient confidentiality required unless unconscious, best interests of the patient, under Court Order, Statutory duty to disclose, Public Interest, or Police Powers - PACE 1984.

Pharmacology Terms

• AAA - refers to 'apply to affected area' and not abdominal aortic aneurysm in prescribing.
• Active Transport - moves molecules against concentration gradients via proteins; needs energy.
• Adherence - matches patient actions to recommendations of the prescriber. Non-adherence implies fully explain
• The ATC code - assigns medicine code by affected system/organ and usage mode. Active medication levels are classified via 5 tier codes.

Other Pharmacology Terms

• Area Under the Curve (AUC) – total body response to drug concentration over time.
• Bactericidal Antibiotics - kill bacteria.
• Bacteriostatic Antibiotics - blocks the bacterial growth; keeps bacteria in stationary phase
• Bioavailability – fraction of oral medication that reaches systemic circulation.
• British Pharmacopoeia (BP) - authoritative UK medicines' standards.
• C-Max - maximum concentration of a drug in the body.
• Compliance -patient behaviour matches doctor's orders.

More Terminology

• Concentration Gradient - concentration variance facilitates increased molecule spread.
• Concordance - patient and professional medication therapy agreement.
• Dimensional analysis - measurement unit principle to avoid error.
• Drop Rate Denominator (DRD) - drops of liquid equal to one mL.
• Drug - chemical alters body's physiology.
• Drug monograph - generic form, action and side effects relating to allergy and use, sensitivity, effects during pregnancy.
• Enterohepatic Cycling - liver cycles for drug metabolism.

Excretion, Kinetics, and Metabolism Terminology:

• Excretion - permanent & irreversible removal of drug from the body.
• First Order Kinetics - elimination rate directly links to substance concentration.
• First Pass Metabolism (Pre-systemic Metabolism) – specialized cells degrade drug prior to circulation.
• Glucose-6-phosphate dehydrogenase (G ৬PD) - enzyme that helps red blood cells work properly. Lack leads to anaemia.
• Half Life (t1/2) - action duration; body's lowered drug load relative to peak concentration.
• Hydrophilic Drugs - water mix; ADME variations: slower body absorption, not fully consumed.
• Invasiveness pathogen's tissue damage.
• Lipophilic Drugs - fats are readily soluble as medicine passes through body via cell membrane .

More Pharmacology Terms

• Medicine - Drugs/ingredients prepare, and treat, and prevent disease.
• Minimum Inhibitory Concentration (MIC) - concentration of antibacterial expressed in mg/L
• Narrow Therapeutic Index (NTI) – small therapeutic difference (aminoglycosides, ciclosporin, NTI, carbemazapine, digoxin, warfarin).
• Passive Diffusion - medicine passes through the cell membrane due to pressure.
• Pathogenicity - causes diseases.
• Patient Information Leaflet (PIL) – plain language version of the SmPC.
• Pharmacophore - portion with molecular interaction.
• Pharmacopoeia - legal medicines.
• Prodrug - inactive when administered, body turns turns into an active compound.
• SmPC - information on effectively safe use, and effects of medications.
• Steady State - stable ratio of concentration relative concentration for optimal therapy.
• ** Therapeutic Window** - drug dosing for safe effects while lessening hazards.
• Total Clearance - metabolism and release.
• Virulence - microbe's and virus' power and reproduction.
• Volume of Distribution (VD) – required drug for specified plasma concentration.
• Zero Order Kinetics - concentration of metabolized and eliminated - independent of dosage.
• Zoonotic diseases - animals pass infectious disease.

Explore the principles of pharmacodynamics, including drug-receptor interactions, agonists, antagonists, and factors influencing drug action. Learn about drug potency, efficacy, and the impact of allosteric modulators. Master the fundamentals of how drugs affect the body.