Pharmacology Quiz on Prodrugs and Drug Development

Prodrugs

• Prodrugs are inactive forms of drugs that are administered and metabolized to give the active form
• Uses for prodrugs include:
  • Altering drug solubility
  • Improving membrane permeability
  • Slowing release of active agent
  • Masking drug toxicity
  • Masking drug side effects

Lipinski's Rule of 5

• Used for predicting druglikeness of compounds

Core Pharmacology Concepts

• Pharmacokinetics -- refers to the movement of drugs in the body
• Pharmacodynamics -- refers to the effects of drugs on the body

Drug Development Phases

• Discovery
  • Understanding drug target and treatment indication.
  • Finding lead molecule using natural products, ligand-based design, or structure-based design.
  • Understanding disease, drug target, and lead compound.
• Development
  • Testing from cells to animals to humans.
  • Pre-clinical pharmacology (PD + PK).
  • Pre-clinical toxicology.
  • Clinical trials (humans).
• Regulation
  • TGA (Therapeutic Goods Administration) approval
  • PBS (Pharmaceutical Benefits Scheme) approval

Conflict of Interest in Drug Development

• Scientists need to remain independent, even though funding is needed for projects
• Honest, open and transparent scientific practices are necessary
• Disclosure of all interactions with potential sources of conflicts of interest is essential

Regulatory Approval

• All pharmaceuticals must be registered in OECD countries before they can be marketed
• Each country has its own regulatory authority
• Drug companies must apply for market authorization in each jurisdiction

Challenges in Drug Development

• Patentability of drug
• Efficacy and safety testing
• Regulation for new drug products

Sources of Drugs

• Plant-derived sources:
  • Paclitaxel is extracted from the Pacific yew tree
  • Dauno- and Doxorubicin are extracted from bacteria found in Castel del Monte in Italy
• Molds: Penicillin
• Seeds: Ricin from the castor plant
• Viruses: Variola virus

Smallpox

• Edward Jenner developed the first smallpox vaccine in 1796
• WHO successfully eradicated smallpox in 1980

Rabies

• Rabies is a zoonotic viral disease that is spread through bites
• Almost 100% fatal once symptoms appear
• Louis Pasteur and Emile Roux developed the first rabies vaccine in 1885

Vitamin C Deficiency

• Scurvy results from Vitamin C deficiency
• James Lind demonstrated in 1747 that citrus fruit helped prevent scurvy
• The first running clinical trial was conducted by Lind

Development of Clinical Trials

• The first double-blind clinical trial was conducted in 1943 for Patulin
• The first randomized controlled trial of streptomycin for TB was conducted in 1946

LogP

• LogP describes lipophilicity and predicts movement in cell membranes
• LogP = Log10 Partition Coefficient
• LogP = 0 when equal amounts of a compound are distributed in both organic and aqueous phases.
• Positive LogP values indicate increased affinity for the organic phase.

Movement of Drugs Across Cell Membranes

• Passive (simple) diffusion: Movement across the membrane via pores or by dissolving in the cell membrane. This follows concentration gradient
• Facilitated diffusion: Some compounds move across the membrane by combining with solute carrier (SLC) transporter proteins (facilitated diffusion) e.g., glucose
• Active transport: Movement against concentration gradient and requires energy, often mediated by carrier proteins
• Special carriers: Peptides, amino acids, and glucose
• Pinocytosis: E.g., Vit B12 (intrinsic factor essential for absorption)

Fick's Law of Diffusion

• Simple diffusion is governed by the permeability of the membrane and the drug concentration gradient
• When the thickness of the barrier is small and/or the permeability, surface area or the starting concentration are high relative to the receiving compartment then flux across membrane is favored.

Drug Absorption: Role of Drug Ionization

• Many drugs are either weak acids or weak bases, and can be predominantly in ionized or unionized form depending on the pH of the environment
• The unionized forms of weak acids (HA) and weak bases (B) are the lipid soluble forms

Tissue pH and Drug Disposition

• Tissue pH can affect drug disposition

Drug Metabolism

• Phase I reactions: Oxidation, reduction, hydrolysis
• Phase II reactions: Conjugation, build, add, result in more polar, more likely to be excreted
• Glucuronidation: Most common Phase II reaction
• Glutathione: Reactive species detoxification

CYP450 system

• Responsible for metabolism of many drugs
• Located in the smooth endoplasmic reticulum
• Requires NADPH, O2 as cofactors
• Some drugs are metabolized by more than one CYP
• Some drugs are metabolized to active metabolites
• Some drugs are metabolized to toxic metabolites

Codeine

• Converted into morphine by CYP2D6
• Genetic polymorphisms exist:
  • Poor metabolizers -- poor analgesia
  • Rapid metabolisers -- strong opioid effects
  • Ultra-rapid metabolisers (more common in people of Middle Eastern, Mediterranean, sub-Saharan African, Northern European, and Chinese descent)

Excretion and Elimination

• Elimination is achieved through renal and metabolic biotransformation
• Renal: glomerular filtration, active tubular secretion, tubular reabsorption
• Others (minor): pulmonary, sweat, saliva, hair, breast milk

Drug Elimination

• Total clearance (Cltotal) = Cl renal + Cl hepatic (liver) + Cl....

Specificity and Selectivity

• No drug acts with complete specificity -- hence side effects
• Selectivity = ability of given drug concentration to produce one effect over another
• Higher concentrations -- lower selectivity

Affinity

• Ability of a drug to bind to a target
• Quantified as IC50 (Concentration of drug required to occupy 50% of target proteins)

Intrinsic Efficacy

• Ability of a drug to elicit/produce a response
• Maximal effect drug can produce on specific tissue as fraction of maximal effect of a full agonist on that tissue
• Full agonist -- intrinsic efficacy = 1
• Antagonist -- intrinsic efficacy = 0
• Partial agonist -- 0-1

Potency

• Concentration of a drug that causes a specified effect
• More potent -- produce effect at lower concentration

Orthosteric and Allosteric Binding

• Orthosteric binding site: Recognized and bound by the endogenous molecule on the receptor
• Allosteric binding site: A different location on the receptor
• Agonists and antagonists bind to the orthosteric site.
• Modulators bind to the allosteric site.

Enzymes

• Biocatalysts that speed up reactions
• Mostly proteins
• 28% of drug targets are enzymes

Enzyme Structure

• Enzymes provide:
  • Reaction surface (active site)
  • Suitable environment for reaction to occur

How Enzymes Provide Suitable Surface and Environment

• Enzymes are specific for their substrate and have absolute selectivity.

Lowering Activation Energy

• Activation energy is the energy needed to bring reactants to a transition state.
• Enzymes lower activation energy by positioning substrates correctly and facilitating bond re-arrangements.

Binding Energy

• Energy derived from enzyme-substrate interactions.
• This energy lowers the activation energy of the reaction.

Receptor Pharmacology

• A drug may bind to the same receptor to achieve a different effect.
• Acetylcholine will contract bronchial smooth muscle while salbutamol will relax it

Partial Antagonism

• A drug that exhibits partial agonism has an intrinsic efficacy between 0 and 1
• Not 100% response even at 100% receptor occupancy

Chemical Antagonism

• When 2 substances combine to form an inactive compound

Isomers

• Different compounds with the same molecular formula
• Structural Isomers: Structural differences
  • Functional isomers -- differ in functional group
  • Tautomeric isomers -- differ by the displacement of 1 hydrogen atom
  • Positional isomers -- functional group in different arrangement
• Stereoisomers: Same connectivity but differ in arrangement of atoms in space
  • Enantiomers -- non-superimposable mirror images
  • Diastereoisomers -- not mirror images

Enantiomers

• Contain a stereogenic (chiral) centre
• Non-superimposable mirror image
• 50:50 mixture of enantiomers is called a racemic mixture
• Pair of enantiomers have identical physical and chemical properties except for:
  • Ability to rotate plane polarized light
  • Chemical reactions with other molecules containing a stereogenic center