1. Pharmacokinetics (PK)
1.1. What the body does to the drug once it is administered
1.2. A
1.2.1. Absorption
1.2.1.1. How the drug goes into the bloodstream
1.2.1.2. Gastrointestinal tract (GIT)
1.3. D
1.3.1. Distribution
1.3.1.1. Movement of the drug around the body
1.3.1.2. Blood
1.4. M
1.4.1. Metabolism
1.4.1.1. Breakdown of the molecule to its metabolites
1.4.1.2. Liver
1.5. E
1.5.1. Excretion
1.5.1.1. Removal of the drug from the body
1.5.1.2. Kidneys
1.6. Graph of administration of drug to the body, sudden increase and then a gentle fall back to 0
1.6.1. C(max)
1.6.1.1. Maximum concentration of the drug in bloodplasma
1.6.2. t(max)
1.6.2.1. After what time C(max) is reached
1.6.3. C(50)
1.6.3.1. Half the concentration of C(max)
1.6.3.2. Elimination half-life
1.6.4. T(1/2)
1.6.4.1. Time from T(max) until C(50) is reached
1.6.4.2. Drug half-life
1.6.5. AUC (area under the curve)
1.6.5.1. Total exposure of body to the drug
1.7. Absorption into the cell
1.7.1. Passive diffusion
1.7.1.1. No energy required
1.7.1.2. Small hydrophobic drugs
1.7.2. Facilitated diffusion
1.7.2.1. Requires specialised proteins in the cell wall
1.7.2.2. Larger hydrophobic drugs
1.7.3. Active transport
1.7.3.1. Requires energy
1.7.3.2. Larger hydrophilic drugs
1.7.4. Fisk's law: Rate of diffusion = (Surface area of the cell * Concentration gradient)/Diffusion distance
1.8. Bioavailability
1.8.1. Amount of drugs that reaches the systemic circulation
1.8.1.1. Intravenous injection = Rapid absorption into the systemic circulation
1.8.1.1.1. Fast
1.8.1.1.2. Requires less initial drug
1.8.1.2. Oral administration = Slower absorption into the systemic circulation
1.8.1.2.1. Slow
1.8.1.2.2. Requires more initial drug
1.8.2. Bioavailability = Drug present in the bloodstream/ Drug given
1.8.2.1. Always 100% in case of IV
1.9. Distribution
1.9.1. Movement of the drug from plasma to the rest of the body (molecular target)
1.9.1.1. Circulation
1.9.1.1.1. Movement around the rest of the body
1.9.1.2. Partition
1.9.1.2.1. Movement from the circulation into the tissues and between the tissues of the body
1.9.1.2.2. Plasma protein binding
1.9.1.2.3. Barriers
1.10. Volume of distribution (Vd)
1.10.1. Body compartments
1.10.1.1. The fluid compartments of the body as well as the fat compartment
1.10.1.2. Vascular compartment. Plasma. 5% of body weight
1.10.1.3. Interstitial fluids, lymph. 15% of body weight
1.10.1.4. Intracellular fluids, muscle cells. 35% of body weight
1.10.1.4.1. Elderly people have less muscle mass, the drug uptake is lower, so less watersoluble drugs are needed to achieve the same pharmaceutical effect
1.10.1.5. Transcellular fluids, cereberal spional fluid (CSF), peritoneal fluids (within peritoneal cavities), synovial fluids (within joints). 2% of body weight
1.10.1.6. Fat. 20% of body weight
1.10.1.6.1. Overweight people have more fat, so more fatsoluble drugs are needed to achieve the same pharmaceutical effect
1.10.2. Volume of distribution = Dose of drug administered / Concentration of drug in plasma
1.10.3. Plasma, (3 litres)
1.10.4. Other compartments (38 litres)
1.10.4.1. Interstitial
1.10.4.2. Intracellular
1.10.4.3. Transcellular
1.10.4.4. Fat
1.11. Metabolism
1.11.1. First-pass metabolism
1.11.1.1. Administered drugs that are chemically modified by the body (e.g. liver)
1.11.2. Most drugs need to be metabolised before the body can excrete them
1.11.3. Also know as bio-transformation
1.11.4. Drug -> Metabolites
1.11.4.1. Active drug -> Inactive metabolites
1.11.4.2. Prodrug -> Active metabolites
1.11.5. Phase 1 and 2 reactions (liver)
1.11.5.1. Number is functional, not sequential classification. (e.g. phase 2 reactions can happen on their own)
1.11.5.2. Phase 1 reactions
1.11.5.2.1. Catabolic reactions (breakdown)
1.11.5.3. Phase 2 reactions
1.11.5.3.1. Anabolic reactions (synthesis)
1.11.5.4. Example
1.11.5.4.1. Metabolism of aspirin (salicyclic acid) in the liver.
1.12. Excretion
1.12.1. Ways for the body to excrete
1.12.1.1. Fecal
1.12.1.2. Bile
1.12.1.3. Lungs
1.12.1.4. Urine
1.12.1.4.1. Renal excretion
1.12.2. Clearance
1.12.2.1. The measure of the volume of plasma cleared of a drug in a unit of time and is determined by the rates of metabolism and excretion
1.12.2.2. Total body clearance is sum of clearance routes
1.12.2.2.1. Renal clearance (kidneys)
1.12.2.2.2. Hepatic clearance (liver)
1.12.2.2.3. Other clearances
1.12.2.3. Clearance (ml/min) = Rate of elimination (mg/min) / plasma drug conc (mg/ml)
1.12.2.3.1. Rate of elimination = metabolism + excretion
1.12.2.4. First- and zero-order kinetics
1.12.2.4.1. First-order kinetics
1.12.2.4.2. Zero-order kinetics
1.13. Dosing
1.13.1. Toxic window
1.13.1.1. Concentration of drug in plasma is too high
1.13.2. Therapeutic window
1.13.2.1. Concentration of drug in plasma to maintain a therapeutic effect
1.13.3. Subtherapeutic window
1.13.3.1. Concentration of drug in plasma is too low
1.13.4. Giving repeatedly small doses, faster than rate of elimination to maintain a dose within the therapeutic window.
1.13.4.1. A loading dose would be an initial large amount of drug to immediately have enough drug in the plasma for a therapeutic effect. After this is achieved, smaller & more infrequent doses are given
1.13.5. Frequent small doses
1.13.5.1. Oral
1.13.5.2. Bothersome for the patient
1.13.6. Infrequent large doses
1.13.6.1. Intramuscular
1.13.6.2. After each dosing, the concentration of the drug in the plasma is above the therapeutic windows, but for such a small time that there will be little to no toxic effects
1.13.7. Mainly based on body weight and function of the kidneys
1.13.7.1. Lean body weight if the patient is obese and the drug is non-fat soluble
1.13.7.2. If the patient has kidney problems, less metabolites are excreted from the blood and thus keeping the overall concentration in the blood higher for longer
2. Targets for Drug Action
2.1. Agonist
2.1.1. Drugs that activate receptors
2.2. Antagonist
2.2.1. Drugs that inhibit receptors
2.3. Ligand
2.3.1. A molecule or substance that binds to a biological molecule and produces or initiates a biological response
2.3.1.1. Endogenous ligand
2.3.1.1.1. Naturally produced in the body
2.3.1.2. Exogenous ligand
2.3.1.2.1. Not naturally produced by the body, e.g. certain drugs. They can be designed to mimic an endogenous ligand to have the same pathway in the body
2.4. Therapeutic approaches
2.4.1. Classical
2.4.1.1. Usual for small molecule drugs
2.4.1.2. Drug/therapeutic -> Molecular Target -> Therapeutic effect
2.4.1.2.1. Receptors
2.4.1.2.2. Enzymes
2.4.1.2.3. Ion channels
2.4.1.2.4. Transporters
2.4.2. Novel
2.4.2.1. Drug/therapeutic -> Modify biological function -> Therapeutic effect
2.4.2.1.1. Gene-based
2.4.2.1.2. Protein-based
2.4.2.1.3. Cell-based
2.5. Receptor superfamilies
2.5.1. Groups of receptors that are structurally related
2.5.2. Ligand-gated ion channels (aka ionotropic receptors)
2.5.2.1. Location: Membrane
2.5.2.2. Effect time: Milliseconds
2.5.2.3. Drugs on market: <10%
2.5.2.4. Example: Nicotinic acetylcholine receptor
2.5.2.4.1. Drug: Nicotine (activator)
2.5.3. G protein-coupled receptors (aka metatropic receptors)
2.5.3.1. Location: Membrane
2.5.3.2. Effect time: Seconds
2.5.3.2.1. Has to wait on secondary processes
2.5.3.3. Drugs on market: >40 %
2.5.3.4. Example: β-adrenergic receptor
2.5.3.4.1. Drug: Atenolol (Inhibitor)
2.5.4. Kinase-linked receptors (aka enzyme-linked receptors)
2.5.4.1. Location: Membrane
2.5.4.2. Effect time: Hours
2.5.4.2.1. Much more complex cellular reactions
2.5.4.2.2. Many intracellular steps
2.5.4.3. Drugs on market: <5 %
2.5.4.4. Example: Cytokine receptor
2.5.4.4.1. Drug: Basiliximab (inhibitor)
2.5.5. Nuclear receptors (aka cytoplasmic receptors)
2.5.5.1. Location: Intracellular
2.5.5.1.1. Can enter the nucleus of the cell
2.5.5.1.2. Interact with DNA
2.5.5.2. Effect time: Hours
2.5.5.3. Drugs on market: ~10 %
2.5.5.4. Example: Estrogen receptor
2.5.5.4.1. Tamoxifen (Inhibitor)
2.6. Drug action at receptors
2.6.1. No drug
2.6.1.1. Basal activity (aka constitutive activity)
2.6.2. Full agonist
2.6.2.1. Maximum response
2.6.2.2. Example
2.6.2.2.1. Drug: Phenylephrine
2.6.2.2.2. Receptor: α-adrenergic
2.6.3. Partial agonist
2.6.3.1. Sub-maximal response
2.6.3.2. Example
2.6.3.2.1. Drug: Buprenorphine
2.6.3.2.2. Receptor: µ/K opiod
2.6.4. Inverse agonist
2.6.4.1. Stops the ligand from binding to the receptor and stops all basal activity
2.6.4.2. No activity
2.6.4.3. Example
2.6.4.3.1. Drug: Pimavanserin
2.6.4.3.2. Receptor: 5-HT2A
2.6.5. Competitive antagonist
2.6.5.1. Blocks a ligand from binding to the receptor
2.6.5.2. Basal activity (aka constitutive activity)
2.6.5.3. Example
2.6.5.3.1. Drug: Atenolol
2.6.5.3.2. Receptor: ß-adrenergic
2.6.6. Non-Competetitive antagonist
2.6.6.1. Blocks receptor from being activated by the ligand
2.6.6.2. Basal activity (aka constitutive activity)
2.6.6.3. Example
2.6.6.3.1. Drug: Phencyclidine (PCP)
2.6.6.3.2. Receptor: NMDA-glutamate
2.6.7. A drug can act as agonist in one tissue, and antagonist in another
2.7. Other protein targets
2.7.1. Enzymes
2.7.1.1. Location: Intracellular
2.7.1.2. Drugs on the market: >25 %
2.7.1.3. Example: HMG-CoA reductase
2.7.1.3.1. Drug: Atorvastatin (inhibitor)
2.7.2. Transporters
2.7.2.1. Location: Membrane
2.7.2.2. Drugs on the market: ~15 %
2.7.2.3. Example: Serotonin transporter
2.7.2.3.1. Drug: Paroxetine (inhibitor)
2.7.3. Ion channels
2.7.3.1. Examples: Ligand-gated, voltage-gated or second messenger-regulated
2.7.3.2. Location: Cell membrane
2.7.3.3. Drugs on the market: ~5% (voltage-gated)
2.7.3.4. Example: L-type calcium channel
2.7.3.4.1. Drug: Nisoldipine (inhibitor)
2.8. Novel Therapeutic Approaches
2.8.1. Gene-based therapies
2.8.1.1. Example: Voretigine Neparvovec-RZYL
2.8.1.2. Modify RNA virus for delivery of genes into cells
2.8.2. Protein-based therapies
2.8.2.1. Example: Hepatitis B vaccine
2.8.2.2. Insert of antigens so the body's antibodies will bind to it
2.8.3. Cell-based therapies
2.8.3.1. Example: Bone marrow transplant
2.8.3.2. Insert healthy cells from hip bone into the patient
2.8.4. Combination of therapies is also possible
2.8.4.1. Example: CAR T cell therapy
2.8.4.1.1. Extract cells from healthy donor, genetically modify these cells and modify a virus to insert into the patient
2.9. Clinical Linkage - CAR T Cell Therapy
2.9.1. Chimeric antigen receptor T cells
2.9.2. Multiple myeloma
2.9.2.1. Cancer of plasma cells
2.9.2.1.1. Plasma cells are a type of white blood cell that are found in the bone marrow and that produce antibodies, making them an important part of the immune system.
2.9.2.2. Overgrowth of abnormal plasma cells in the bone marrow can thicken the blood
2.9.2.3. Myeloma cells also activate signalling pathways that weaken bones, making them prone to fractures.
2.9.3. Serious side-effects
2.9.3.1. Cytokine release syndrome
3. Drug modality
3.1. Size of drug
3.1.1. Small
3.1.1.1. ≤ 900 Daltons
3.1.1.2. Simple chemical structures
3.1.1.3. Chemically synthesised / natural sources
3.1.1.4. Cheap
3.1.1.5. Convenient in use
3.1.1.6. Usual method of administration orally
3.1.2. Biologics
3.1.2.1. > 900 Daltons
3.1.2.2. Complex chemical structures
3.1.2.3. Natural sources
3.1.2.4. Novel therapeutic opportunity
3.1.2.5. Usual method of administration injection/infusion
4. Route of administration
4.1. Enteral
4.1.1. Simplest route of administration
4.1.1.1. Mouth
4.1.1.1.1. Medication through GI tract
4.1.1.1.2. May be metabolised by the liver before entering the systemic circulation
4.1.1.2. Rectal
4.1.1.2.1. For patients who are unable to swallow (e.g. vomiting)
4.1.1.2.2. May be metabolised by the liver before entering the systemic circulation
4.1.1.3. Sublingual (under tongue)
4.1.1.3.1. Large bloodsupply under tongue
4.1.1.3.2. Bypasses liver
4.1.2. Self-administered
4.1.3. Slow on-set of activation
4.2. Inhalation
4.2.1. Aerosol
4.2.1.1. Direct-to-target (lungs)
4.2.2. Small-molecule drugs
4.3. Transdermal
4.3.1. Directly to the skin
4.3.1.1. Top-layer of skin epidermis
4.3.1.1.1. Lotion
4.3.1.1.2. Patchform
4.3.1.2. Middle-layer dermis
4.3.1.3. Bottom-layer subcutaneous (fat)
4.3.1.4. Muscle
4.3.2. Systemic effect
4.4. Topical
4.4.1. Application to epithelial surface of the affected part
4.4.1.1. Ocular
4.4.1.2. Nasal
4.5. Parenteral
4.5.1. Subcutaneous
4.5.1.1. Into the fatty third layer of the skin
4.5.2. Intramuscular
4.5.3. Intravenously
4.5.3.1. Much faster-action than other routes
4.5.4. Intrathecal
4.5.4.1. Into the spine
4.5.5. Intracardiac
4.5.5.1. Into the heart
4.5.6. Intra-arterial
4.5.6.1. Into a artery
4.5.7. Intra-articular
4.5.7.1. Into the joints
4.5.8. Intraperitoneal
4.5.8.1. Into the peritoneal cavity
4.5.9. Intravitreal
4.5.9.1. Into the eye
5. Miscellaneous
5.1. Subcutaneous injection for slow delivery to the blood
5.2. Insulin
5.2.1. If ingested orally, it is denatured in the stomach so it is not able to enter the blood stream from the intestines
5.2.1.1. This broken down insulin however holds its pharmaceutical effect, it just can't reach the bloodstream
6. Pharmacodynamics
6.1. Dose-response curve
6.1.1. Dose of drug vs response to drug
6.1.2. Efficacy
6.1.2.1. Emax
6.1.2.1.1. Maximum response of the drug
6.1.2.1.2. Maximum inhibition of the drug
6.1.3. Potency
6.1.3.1. EC50
6.1.3.1.1. Concentration of drug that produces half of the maximal response
6.1.3.2. IC50
6.1.3.2.1. Concentration of drug that inhibits half of the maximal response
6.2. Pharmacodynamic representations
6.2.1. Concentration of drug vs % receptor occupancy
6.2.1.1. Binding curve
6.2.1.2. X-axis linear
6.2.2. Concentration of drug vs % molecular response
6.2.2.1. Dose-response curve
6.2.2.2. X-axis linear
6.2.3. Dose of drug administered vs % physiological response OR % people responding
6.2.3.1. Dose-response curve
6.2.3.2. X-axis linear
6.2.4. Dose of drug administered vs % physiological response OR % people responding
6.2.4.1. Dose-response curve
6.2.4.2. X-axis logaritmic
6.3. Drug-receptor binding
6.3.1. Unbound drug
6.3.1.1. D
6.3.2. Unbound recepter
6.3.2.1. R
6.3.3. Bound drug to receptor
6.3.3.1. DR
6.3.3.2. Reversible
6.3.4. Affinity
6.3.4.1. Kd
6.3.4.1.1. Equilibrium dissociation constant
6.3.4.1.2. Lower Kd means higher affinity of drug to receptor
6.3.4.2. Ki
6.3.4.2.1. Inhibitory constant
6.3.4.2.2. Concentration of drug required to bind 50% of receptors
6.3.5. Selectivity
6.3.5.1. Drug going to intended target receptor
6.3.5.2. Intended vs unintended site
6.3.5.3. Low affinity, binds more to unintended recptors
6.3.5.3.1. Low selectivity
6.3.5.3.2. Dosage needs to be higher
6.4. Individual variation
6.4.1. Pharmacodynamic
6.4.1.1. Age
6.4.1.1.1. Example: Albuterol
6.4.2. Pharmacokinetic
6.4.2.1. Genetics
6.4.2.1.1. Example: HMG-CoA reductase inhibitors
6.4.3. Other factors
6.4.3.1. Sex
6.4.3.2. Weight
6.4.3.3. Disease or health status
6.4.3.4. Pregnancy
7. Drug Toxicity
7.1. Drug toxicity is any harmful or toxic effect caused by a drug in a patient.
7.1.1. On-target site
7.1.1.1. The place in the body where the drug needs to go to achieve its intended effect
7.1.2. Off-target sites
7.1.2.1. When the drug is bound to another place in the body which usually can cause side-effects which can range from mild to severe symptoms
7.2. Adverse drug effects
7.2.1. Predictable effects
7.2.1.1. Bleeding (anticoagulants)
7.2.1.2. Sedation (anxiolytics)
7.2.2. Organ toxicity
7.2.2.1. Hepatotoxicity
7.2.2.2. Nephrotoxicity
7.2.2.3. Neurotoxicity
7.2.2.4. GI toxicity
7.2.3. GI effects
7.2.3.1. Upset stomach
7.2.3.2. Nausea and/or vomiting
7.2.3.3. Loss of appetite
7.2.4. Carcinogenesis
7.2.4.1. Cancer-causing (carcinogens)
7.2.5. Teratogenesis
7.2.5.1. Foetal abnormalities (teratogens)
7.2.6. Immunological reactions
7.2.6.1. Hypersensitivity (allergic)
7.2.6.2. Autoimmune
7.3. Mechanisms of drug toxicity
7.3.1. Therapeutic effect
7.3.1.1. Receptor: Intended
7.3.1.2. Tissue: Intended
7.3.2. On-target toxicity
7.3.2.1. Receptor: Intended
7.3.2.2. Tissue: Unintended
7.3.3. Off-target toxicity
7.3.3.1. Receptor: Unintended
7.3.3.2. Tissue: Intended / unintended
7.4. Toxic dosing
7.4.1. ED50
7.4.1.1. Effective dose
7.4.2. TD50
7.4.2.1. Toxic dose
7.4.3. LD50
7.4.3.1. Lethal dose
7.4.4. Therapeutic index (TI)
7.4.4.1. TI = TD50 / ED50
8. Drug Discovery, Design, and Development
8.1. Compound-centered
8.1.1. Compound identified (natural or synthetic)
8.1.2. Characterisation (biological and chemical)
8.1.3. Molecular target and mechanism of action determined
8.1.4. Drug candidate
8.2. Target-centered
8.2.1. Target identified (e.g. protein)
8.2.2. Screening (possible compounds)
8.2.3. Hit
8.2.4. Characterisation
8.2.5. Lead compound
8.2.6. Optimisation (modification)
8.2.7. Drug candidate
8.3. Preclinical drug development
8.3.1. Pharmacodynamic
8.3.1.1. Discovery biology
8.3.1.2. Dose-response curve
8.3.1.3. Emax
8.3.1.4. EC50
8.3.1.5. Kd
8.3.1.6. Selectivity
8.3.2. Pharmacokinetic
8.3.2.1. ADME studies
8.3.2.1.1. Plasma concentration over time graph
8.3.2.1.2. Cmax
8.3.2.1.3. Tmax
8.3.2.1.4. T1/2
8.3.2.1.5. Vd
8.3.3. Toxicity
8.3.3.1. Safety pharmacology
8.3.3.1.1. Dose-response curve individual
8.3.3.1.2. TD50 and LD50
8.3.3.1.3. Adverse drug effects
8.3.4. Manufacturing
8.3.4.1. Pharmaceutical development
8.3.4.1.1. Formulation
8.3.4.1.2. Route of administration
8.3.5. Clinical drug development
8.3.5.1. Phase 1
8.3.5.1.1. Subjects
8.3.5.1.2. # Subjects
8.3.5.1.3. Time
8.3.5.1.4. Goals
8.3.5.1.5. Pharm. concepts
8.3.5.1.6. Design
8.3.5.2. Phase 2
8.3.5.2.1. Subjects
8.3.5.2.2. # Subjects
8.3.5.2.3. Time
8.3.5.2.4. Goals
8.3.5.2.5. Pharm. concepts
8.3.5.2.6. Design
8.3.5.3. Phase 3
8.3.5.3.1. Subjects
8.3.5.3.2. # Subjects
8.3.5.3.3. Time
8.3.5.3.4. Goals
8.3.5.3.5. Pharm. concepts
8.3.5.3.6. Design
8.3.5.4. Phase 4
8.3.5.4.1. Subjects
8.3.5.4.2. # Subjects
8.3.5.4.3. Time
8.3.5.4.4. Goals
8.3.5.4.5. Pharm. concepts
8.3.5.4.6. Design
8.4. CAR T Cell Therapy
8.4.1. 80 patients
8.4.2. Phase 2