Pharmacology: Pharmacokinetics and Pharmacodynamics

• Pharmacology is the study of drugs, their effects, and how they work. It comes from the Greek words "pharmakon" (drug, poison, spell) and "logia" (study of, knowledge of).
• Pharmacology explains what drugs do and how they do it.
• Pharmacy deals with preparing and dispensing medications, while pharmacology is the branch of medicine concerned with the uses, effects, and modes of action of drugs.

Pharmacodynamics (PD)

• Explores "What the drug does to the body’
• This involves the biochemical, physiologic, and molecular effects of drugs on the body
• Includes chemical interactions, receptors, and signal transduction.

Pharmacokinetics (PK)

• Explores "What the body does to the drug"
• This involves the movement of a drug into, through, and out of the body
• Includes liberation, absorption, distribution, metabolism, excretion, and toxicity.
• Key concepts: Half-life ($t_{1/2}$), bioavailability, etc.

Definition of a Drug

• A substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease.
• Any substance that brings about a biological change or effect on the body.

Drug Sources

• Plants: Digitalis (foxglove) → digoxin, belladonna ↔ atropine
• Animals: Glandular products, e.g., Pregnant Mare Urine = Premarin (estrogens for menopause)
• Microorganisms: Antibiotics, e.g., penicillin (from penicillium notatum, a mould)
• Minerals: lithium carbonate (an antipsychotic), $MgSO_4$ (a laxative)
• Synthetic: Laboratory produced, e.g., Sulfonamides
• Recombinant proteins: Proteins produced by expression of cloned genes in recombinant cells, e.g., Insulin (human gene in bacteria)

Drug Classes

• By Makeup: Hormone, Carbohydrate
• By Action: Beta blockers, ACE Inhibitors
• By Therapeutic Effect: Antiarrhythmics, Antianginals
• By System/Target: Drugs affecting the CNS, ANS, cardiovascular system, respiratory system, hormones,

Drug Names

• Chemical Name: Identifies the chemical elements and compounds in the drug.
• Generic Name (non-proprietary): Universally accepted name of a drug, e.g., Ibuprofen.
• Brand or Trade Name (proprietary): Copyrighted and trademarked name given by the drug company, e.g., Advil.

Drug Schedules

• A national classification system controls how medicines and poisons are made available.
• Managed by the TGA. Defined in Poisons Standard 2018.
• Schedule Classifications:
  • Schedule 1: (not used)
  • Schedule 2: Pharmacy medicine
  • Schedule 3: Pharmacist only medicine
  • Schedule 4: Prescription only medicine
  • Schedule 5: Caution
  • Schedule 6: Poison
  • Schedule 7: Dangerous poison
  • Schedule 8: Controlled drug
  • Schedule 9: Prohibited substance
  • Schedule 10: Dangerous substances (prohibited)

Drug Interaction with the Body (A Drug's Life Cycle)

• Administration: Getting the drug in
• Absorption: Drug gets into the bloodstream
• Distribution: Blood carries the drug to tissues
• Drug Action: Drug binds & affects cells
• Termination of Effect: Metabolism and/or elimination
• Absorption, Distribution and Elimination are part of Pharmacokinetics
• Drug Action is part of Pharmacodynamics

Route of Administration

• The path by which a drug, fluid, poison, or other substance is taken into the body

Routes of Administration - Systemic

• Enteral:
  • e.g. Oral, Buccal, Rectal
  • Drug reaches the target via the GI tract.
  • Oral: majority of drugs, but least reliable
  • First-pass metabolism (gut & liver)
• Parenteral:
  • e.g. Intravenous, Intramuscular, Subcutaneous, Intradermal, Transdermal, Inhalational, Transtracheal
  • Does not involve the GI tract; direct delivery to plasma.
  • Rapid effect
  • Avoids first-pass metabolism
  • Pain, infection, etc

Routes of Administration - Local

• Topical:
  • e.g. Skin, Eyes, Ears, Intranasal, Vaginal, Urethral
  • Direct local effect (mainly) local systemic.

Factors Determining Route of Administration

• Physical & Chemical Properties: Solid, liquid, gas; solubility, pH, stability, etc.
• Therapeutic Objectives: Site of action, need for rapid onset, long-term treatment, restricted delivery to target site.
• Effect of Digestion & Metabolism: Impact of digestive juices, first-pass metabolism.
• Condition of the Patient: Consciousness, ability to swallow, etc.

The Enteral Route – First Pass Metabolism

• Most drugs absorbed from the GI tract enter the portal (liver) circulation before they reach systemic circulation.

First Pass Effect

• Drugs are often metabolized in the liver before reaching their target organs.
• This process can decrease the drug's effectiveness.
• Example: Nitroglycerin is 90% cleared during its first passage through the liver, which is why it is administered sublingually instead of orally.
• The oral dose is typically higher than other routes of administration.
• ensures sufficient drug reaches circulation and the target.

'Rights' of Safe Administration

• Designed to reduce medication errors and prevent harm.
• Core Five Rights:
• Right patient
• Right drug
• Right dose
• Right time
• Right route
• Additional rights:
• Right documentation
• Right to refuse
• Right education
• Right assessment/reason
• Right evaluation/response

How Drugs Work

• Transport Systems: e.g., ion channels, carriers. Example: Xylocaine (lidocaine) blocks voltage-gated sodium channels.
• Enzymes: e.g., block or prevent enzyme activity. Example: Viagra (sildenafil) blocks phosphodiesterase type 5 (PDE5).
• Non-specific Actions: e.g., chelation, antacids, osmotics. Example: Desirox (deferasirox) reduces chronic iron overload.
• Receptors: A receptor is a biological molecule that receives chemical signals and transduces them into cellular responses.
• For a drug to be effective, it must bind to the correct receptor.

Factors Altering Drug Response

• Drugs do not work the same every time, or equally in every person
• Drug responses can vary among individuals due to: Age, body mass, gender, time of administration, pathologic state, genetic factors, psychological factors

Variability in Drug Response - Examples

• Geriatric Patients:
• Decreased cardiac output, renal function, brain mass, total body water, body fat, serum albumin, and respiratory capacity
• Pregnant Patients:
• Increased cardiac output, heart rate, and blood volume (up to 45%)
• Decreased protein binding
• Altered hepatic metabolism and blood pressure
• Placental barrier permeability/lactation effects on the child

Pharmacokinetics

• The study of the basic processes that determine the duration and intensity of a drug's effect.
• Describes "what the body does to the drug."
• Key principles: Absorption, Distribution, Metabolism, Elimination
• Different routes of administration affect how drugs are absorbed, distributed, metabolized, and eliminated.

Absorption

• Refers to how medicines enter the bloodstream (plasma).
• Influenced by fast and slow absorption speeds
• Enteral (slow):
• Orally (swallowed)
• Rectally (suppository)
• Through mucus membranes
• oral mucosa (e.g. sublingual)
• Nasal mucosa (e.g. insufflated)
• Transdermal: slow; parental; through the skin
• Topical: slow; through the skin
• Parenteral (fast):
• Injection
• Intravenous (IV)
• Intramuscular (IM)
• Subcutaneous (SC)
• Intraperitoneal (IP)
• Inhaled (through lungs)

Absorption & Drug Solubility

• Water-soluble drugs are ionized (have an electrical charge), cross capillary pores but not cell membranes.
• Lipid-soluble drugs are non-ionized (no electrical charge), cross cell membranes and blood-brain barrier.

Bioavailability

• The fraction of an administered dose that reaches systemic circulation as intact drug, taking into account both absorption and local metabolic degradation (first-pass).
• Following IV administration, bioavailability = 1 (or 100%).
• High bioavailability: same dose for IV and oral routes (e.g., metronidazole, fluconazole, amoxicillin).
• Low bioavailability: lower dose for parenteral than oral routes (e.g., morphine: 10 mg s/c or IM = 30 mg po ).

Distribution

• The reversible transfer of a drug from the bloodstream to tissues.
• Drug moves between different body compartments and reaches the site of action (receptors).
• Depends on the drug's physical and chemical properties.
• Drugs must distribute into interstitial and intracellular fluids to reach their target.

Distribution & Effect of Protein Binding

• Drugs bind to plasma proteins, forming drug-protein complexes.
• Protein-bound drugs are pharmacologically inactive.
• Only free drugs can bind to their receptors.

Body Fluid Compartments & Volume of Distribution

• Drugs distribute into plasma, interstitial, and intracellular compartments.
• The volume of distribution (Vd) is a theoretical measurement that shows how widely a drug spreads throughout your body compared to its concentration in the blood.
• The magnitude of Vd indicates the extent of drug distribution in the body, but not the location.
• Large Vd (>42 L): drug distributes outside blood and body fluids into tissues.
• Small Vd (≤42 L): drug has limited distribution, typically restricted to blood or physiological fluids.

Metabolism

• The irreversible conversion of one chemical compound into another.
• Most metabolism occurs in the liver, but also in the gut, lungs, and blood plasma.
• The first-pass effect allows the liver to metabolize or deactivate medicines and potentially harmful drugs before they enter systemic circulation.
• Liver hepatocytes contain the necessary enzymes for metabolism (cytochrome P450 group).

Excretion

• Refers to how the body eliminates a drug or its metabolites.
• Main routes:
• Kidneys: Transform drugs into compounds for excretion in urine.
• Faeces: Metabolized drugs secreted by the liver in bile and enters the small intestine where it is either resorbed into the bloodstream or eliminated in faeces.

Clearance

• Reflects the elimination of the drug from the body; related to the plasma concentration ($C_p$) and dose rate.
• Collection of processes by which the body removes the drug
• Occurs via metabolism and elimination.
• Defines how much drug should be administered and how frequently.

Clearance & Kinetic Order

• Two types of kinetics describe the rate at which a drug leaves the body:
• Zero-order kinetics: Constant rate of elimination, independent of drug concentration, constant amount eliminated per unit of time (e.g., alcohol).
• First-order kinetics: A constant fraction of the drug is eliminated per unit of time. When the drug concentration is high, the rate of disappearance is also high.

Drug Concentration and Half-Life

• Half-life ($t_{1/2}$) is the time it takes to remove half the current concentration of the drug from the body.
• The higher the volume of distribution (Vd), the less a drug is contained in the plasma, resulting in a longer half-life.

First Order Kinetics

• Concentration decreases exponentially over time.
• Rate of elimination is proportional to concentration.
• Plots of $\log[\text{conc.}]$ or $\ln[\text{conc.}]$ vs. time are linear.
• Half-life ($t_{1/2}$) is constant regardless of concentration.

Zero Order Kinetics

• Concentration decreases linearly with time.
• Rate of elimination is constant.
• Rate of elimination is independent of concentration.
• There is no true half-life as it changes.

What is Pharmacodynamics?

• The study of how specific drug dosages produce biochemical or physiological changes in the body.
• Often described as "what the drug does to the body."

How do Drugs Work?

• Transport systems: e.g., ion channels, carriers
• Enzymes: e.g., block/prevent enzyme activity
• Non-specific actions: e.g., chelation, antacids, osmotics
• Receptors: key players in drug action

What are Receptors?

• Macromolecules that mediate biological changes after ligand (drug) binding.
• Most receptors are proteins with:
• Primary ($1^\circ$) amino acid sequence
• Secondary ($2^\circ$) regular sub-structures
• Tertiary ($3^\circ$) 3-D structure
• Sometimes quaternary ($4^\circ$) multi-protein complexes
• Located on the surface or within cells.

The drug + receptor complex

• The drug acts as a key, and the receptor as a lock; their combination yields a response.
• Ligands are molecules that bind to receptors (drugs are ligands).
• The interaction is dynamic and flexible.

Receptor Types & Action

• Four families/classes of receptors mediate different effects and have varying response times.
• Most receptors have naturally occurring (endogenous) molecules that bind to them.
• Exogenous (foreign) molecules can be designed to bind to the same receptor (rational drug design).
• Example: Endorphins (endogenous) bind to opiate receptors; Morphine (exogenous) also binds to these receptors.

Drugs as Agonists or Antagonists

• Agonists:
• Have affinity for the receptor (bind to it).
• Have intrinsic activity (binding elicits a response).
• Antagonists (receptor blockers):
• Have affinity (bind the receptor).
• Lack intrinsic activity (no response).
• Agonists can be endogenous (e.g., estradiol) or exogenous (e.g., Tamoxifen as an antagonist).

Important Implications for Drug-Receptor Interaction

• Drugs act on receptors already present in cells.
• drugs can potentially alter the rate of any bodily/brain function.
• Drugs do not create effects, only modify ongoing ones.
• Drugs cannot impart entirely new functions to cells.
• Drugs can allow effects outside of the normal physiological range.

Drug Effectiveness

• Related to pharmacodynamics and kinetics.
• Important measures include affinity, potency, efficacy, dose-response, $EC_{50}$ & $ED_{50}$, and therapeutic index (TI).

Affinity, Potency & Efficacy

• Affinity: Ability of a drug to bind to its receptor.
• Potency: The ability to produce a tissue response; a lower concentration needed indicates higher potency.
• Efficacy: Ability to activate the receptor and initiate cellular signaling.

Dose Response & Effective Concentration ($EC_{50}$)

• Depicts the relationship between drug dose and effect magnitude.
• $EC_{50}$: Concentration inducing a response halfway between baseline and maximum.
• drug effectiveness varies due to different sites of action, and different affinity, potency, and efficacy.
• The effectiveness of a drug is relative to its safety (therapeutic index)

Therapeutic Index (TI)

• TI is the ratio of the dose that produces toxicity to the dose that produces an effective response:

Arithmetic Dose-Response Curve

• Graded response measured on a continuous (linear) scale.
• The rate of change is rapid at first and becomes progressively smaller as the dose increased
• Rapid initial change that plateaus at maximal effect.

Log Dose-Response Curve

• Graded response on a continuous (log) scale.
• Transforms hyperbolic curve to a sigmoid shape for easier analysis.
• Compresses dose scale
• Proportionate doses occur at equal intervals

Frequency Distribution Dose-Response Curve

• Shows the fraction of a population showing a specific response at progressively increasing doses.
• Response is an either/or event
• Also known as quantal dose-effect plots.

Therapeutic Index (TI)

• Formula: $TI = \frac{TD_{50}}{ED_{50}}$
• Important: Indicates drug safety; a higher TI is better.
• Drugs with a narrow TI may have their dosage adjusted according to measurements of the actual blood level (therapeutic drug monitoring, TDM).
• Narrow TI Drugs: Warfarin, Lithium, Digoxin, Phenytoin, Gentamicin

Receptor-Mediated Action of Drugs

• Receptor: Molecules receive and transduce chemical signals into intracellular responses.
• Binding to a receptor initiates an intracellular signal, resulting in a response/effect.
• For a drug to have an effect, it must bind to the appropriate receptor.

Important Implications for Drug+Receptor Interaction

• Drugs are a ligand and act on receptors already expressed and present in a cell.
• Drugs can potentially alter the rate of any bodily/brain function.
• Drugs cannot impart entirely new functions to cells.
• Drugs do not create effects, only modify ongoing ones.
• Drugs can allow for effects outside of the normal physiological range.

Overview of Pharmacodynamics & Dose Response

• Pharmacodynamics studies how drugs affect the body.
• Key concepts include intracellular signal transduction pathways and receptor actions.

Receptor Binding Initiates a Cascade

• Ligand binding alters receptor shape, leads to activation, and initiates a cascade of signaling events leading to a biological response.

Signal Transduction is a Cascade of Steps

• Key steps: reception, transduction, response
• Each component of a signaling cascade classified according to its role:
• Ligands are first messengers
• Receptors are signal transducers
• Primary effectors may be linked to second messengers, which can activate secondary effectors, and so on.

Families/Classes of Receptor

• Mediate different effects and have different response times
• Ligand-gated ion channel: Rapid
• Kinase (enzyme) linked: Multiple actions
• G protein-coupled: Amplifier
• Nuclear: Long-lasting

Ligand-Gated Ion Channels (Ionotropic Receptors)

• Protein pores in the cell membrane
• Examples: GABA, Glycine, Aspartate, Glutamate, Acetylcholine, Serotonin

G Protein-Coupled Receptors

• Single polypeptide chain threaded back and forth resulting in 7 transmembrane  helices
• Examples: Adrenocorticotropic hormone, Acetylcholine, Angiotensin, Catecholamines, Chorionic gonadotropin, Follicle stimulating hormone, Glucagon, Histamine, Luteinising Hormone, Vasopressin, Serotonin

Kinase-Linked Receptors

• Receptors exist as individual polypeptides
• Each has an extracellular signal-binding site and an intracellular tail with a number of tyrosines and a single a helix spanning the membrane
• Examples: Insulin, Epidermal growth factor (EGF), Platelet-derived growth factor (PDGF), Arterial natriuretic factor (ANF), Transforming growth factor B (TGF-B), Growth hormone

Intracellular (Nuclear) Receptor Signaling

• Some receptors are located in the cytoplasm or nucleus (i.e, not in the plasma membrane)
• The signal molecule must be able to pass through the plasma membrane. Examples: Nitric oxide (NO), Steroids (e.g. estradiol, progesterone, testosterone)

Endogenous Ligands

• Naturally occurring substances that bind to receptors (e.g., endorphins).

Exogenous Ligands

• Designed substances that bind to the same receptors (e.g., morphine).

Properties of Receptor/Ligand Binding

• Affinity: The strength of the interaction between a drug and its receptor.
• Potency: The amount of drug needed to produce a specific effect (measured as $EC_{50}$).
• Efficacy: The ability of a drug to activate a receptor and produce a response.

Ligands (Drugs) as Agonists or Antagonists

• Agonists:
• Have affinity and intrinsic activity.
• Types:
• Full agonists: Maximal efficacy.
• Partial agonists: Less than maximal efficacy.
• Inverse agonists: Induce opposite effects.
• Antagonists:
• Have affinity but lack intrinsic activity.
• Types:
• Competitive antagonists: Compete with agonists for binding.
• Non-competitive antagonists: Bind to receptors and prevent activation.

Types of Agonists & Antagonists

• Multiple types of agonists and antagonists exist for a single receptor.
• Example: Estradiol is endogenous, PPT is exogenous estrogen receptor agonist
• Tamoxifen is an exogenous estrogen receptor competitive antagonist.
• Antagonists have an efficacy of 0

Full vs Partial Agonists

• Agonists are ligands that interact with and activate receptors. Possess both affinity and efficacy
• Full agonists activate receptors maximally
• Partial agonists activate less than maximal efficacy.
• Buprenorphine (Subutex) is an opioid partial agonist & has significant analgesic effects, yet has a much lower risk for producing life-threatening respiratory depression as compared to a full opioid agonist such as morphine

Inverse Agonists

• Bind to the same receptor as agonists but produce opposite effects.
• The receptor must have constitutive activity in the absence of any ligand. An agonist increases activity of a receptor above its basal level
• An inverse agonist decreases the activity below the basal level
• An antagonist will block activity of an agonist and an inverse agonist
• Example: GABAA receptor agonists create sedation, while inverse agonists can cause anxiety or convulsions.

Competitive Antagonists

• Compete with agonists for receptor binding.
• Increase the $EC_{50}$ for the agonist as antagonist concentration increases.
• Can be overcome with increasing agonist concentration.
• Heroin = opioid receptor agonist
• Naloxone is used in heroin overdose as a competitive opioid receptor antagonist.

Non-Competitive Antagonists

• Bind to receptors and remain bound, preventing agonists from eliciting a maximal effect.
• Causes a shift in the agonist drug Curve to the right
• As more receptors are bound, the agonist becomes incapable of eliciting a maximal effect.

Allosteric Modulation

• Receptors can have additional binding sites (allosteric sites).
• Ligands at these sites can be:
• Positive allosteric modulators: Enhance receptor function.
• Negative allosteric modulators: Decrease receptor function.
• Examples:
• Glycine at NMDA Receptors
• Benzodiazepines at GABAA Receptors

Other factors determining response

• Tachyphylaxis & desensitization (tolerance)
• Sensitization
• Drug/drug interactions

Tachyphylaxis & Desensitisation (Tolerance)

• Tachyphylaxis is a rapid decrease in response to a drug after administration
• It can occur after an initial dose or a series of small doses.
• Increasing the dose may restore the original response
• Desensitisation: Reduced response to a drug.
• Tolerance: Decreased effect of a drug over time.
• Refractoriness: Temporary unresponsiveness.
• Drug resistance: Reduced effectiveness of a drug.
• Results in a right-ward shift in the dose-response (DR) curve.
• Decreased receptor number Homologous desensitization
• Decreased signal transduction Heterologous desensitization
• Common with drugs acting on the nervous system.

How does it happen?

• Changes in the receptor.
• Loss of the receptor.
• Exhaustion of mediators.
• Increased metabolic degradation.
• Physiological adaptation.
• Active extrusion of the drug from cells.

Sensitisation

• Increased response to the same dose with repeated exposure.
• Less drug may be needed to achieve the same effect.
• Results in a left-ward shift in the DR curve.
• People can develop tolerance to some side effects and sensitization to others.

Other mechanisms of Tolerance & Sensitisation

• Psychological: Users learn to counteract effects.
• Set and setting: Expectations and environment influence response.
• Motivational: Habituation and conditioning affect drug response.
• Metabolic: Faster breakdown/excretion of the drug with repeated exposure.

Drug-Drug Interactions

• Pharmacokinetic: One drug affects the absorption, distribution, metabolism, or excretion of another.
• Pharmacodynamic: Two drugs have interactive effects.
• Both types can lead to adverse effects.

Types of interactions between drugs:

• Additive: Effects sum up (1 + 1 = 2).
• Synergistic: Combined effect greater than sum (1 + 1 > 2).
• Antagonistic: Combined effect less than sum (1 - 1 = 0).
• Modification of drug action without changing serum concentration due to pharmacokinetic factors.

Addictive effects:

• When the effect of two drugs is equal to the sum of the effect when taken separately; also referred to as ‘summation’
• Example: Paracetamol + Codeine.

Synergistic Effects

• When the effect of two drugs taken together is greater than the sum of their separate effect at the same doses; also referred to as ‘potentiation’
• Example: Paracetamol + Ibuprofen.

Antagonistic Effects

• When the effect of two drugs together is less than the sum of their separate effect at the same doses.
• Example: Acetylsalicylic acid + Ibuprofen.