What are the different branches of pharmacology?
- Clinical pharmacology
- Veterinary pharmacology
- Pharmaceutical sciences
- Medicinal Chemistry
What is pharmacodynamics?
The physical effect of a drug or its mechanism of action
What the drug does to you!
What is pharmacokinetics?
The disposition of a drug by the body, its metabolism and removal from the system.
What you do to the drug!
What is a drug?
A molecule/chemical that will do something to the physiological system that addresses an imbalance in physiology
Must be a chemical that is not part of a diet
Is herbal medicine a drug? Why?
Herbal medicine is not a drug as thousands of molecules in the solution derived from the plant
Therefore, lots of chemicals present that may help but nobody knows why due to the presence of so many chemicals
Specific drugs can sometimes be identified e.g. Willow Bark contains aspirin which takes away a headache
What are the 2 ways a drug act on the body?
What is a therapy? Example.
A drug which treats causes of a condition but does not rectify the underlying physiological cause.
E.g. Atenolol treatment for hypertension
E.g. Cetirizine hydrochloride as an antihistamine
What is a cure? Example.
A drug which removes the underlying physiological cause of a condition.
E.g. antibiotic treats bacterial infections
E.g. antifungal treats fungal infections
Importance between therapy and cure medication?
Important in production of drugs:
Cures = less profitable as you only use it once
Therapies = people will continue to use it as it does not take the condition away
What are the methods in which drugs can be named?
E.g. 2-(4-(2-methylpropyl)phenyl)propanoic acid
2. Generic (no capital)
3. Brand name
E.g. nurofen, Calprofen
What name should you use when talking about drugs?
Generic name with NO CAPITAL LETTER
How do we make drugs?
1. Identify the condition
2. Indentify the pathophysiology that is causing the condition
3. Identify receptors involved in the pathophysiology, that can be bound to to effect change
4. Using a compound library, trial-and-error different compounds and observe the effect on the receptor
Where do drugs come from?
1. Assessment of target expression - determine target localisation, determine target quantification
2. Lead compound optimization - characterization of disease phenotypes, efficacy of compound
3. Pre-phase I studies - microdosing, pharmacokinetics
Used to check if the compound has nasty side effects, using animal subjects
4. Clinical Phases I-III
5. FDA approval
What are the features of clinical trials?
Phase 1 :
- assess the safety of a drug or device - effects including how it is absorbed, metabolized, and excreted, side effects
- small number of healthy volunteers (20 to 100)
- test the efficacy of a drug - elative safety and effectiveness of the new drug
- involves up to several hundred patients
- randomized trials where one group of patients receives the experimental drug, while a second "control" group receives a standard treatment or placebo.
- "blinded trials"
- studies involve randomized and blind testing
- several hundred to several thousand patients.
- effectiveness of the drug or device, the benefits and the range of possible adverse reactions
How do drugs have their effects?
Bind to biological molecules
What are the biological molecules that drugs can bind to?
2. Nucleic acids
3. Proteins: receptors, enzymes, ion channels, protein carriers (transporters)
Examples of drugs and the biological molecules that they bind to?
Lipids - potential lipoprotein targets in viral infections
Nucleic acids - anti-cancer agents
Receptors - Beta-adrenoceptors antagonists
Enzymes - angiotensin converting enzyme inhibitors
Protein carriers - selective serotonin reuptake inhibitors
What are the protein biological molecules that drugs effect?
2. Ion Channels
4. Protein carriers (transporters)
Types of drugs that effect receptors? How do they have their effect?
1. Agonist - drug which binds to receptor and activates it
This has an effect on:
- direct effect - ion channel opning/closing
- transduction mechanisms - enzyme activation/inhibition, ion channel modulation, DNA transcription
2. Antagonist - drug which binds to receptor but does not activate it, endogenous mediators blocked
This has an effect on:
- no effect, endogenous mediators blocked
Types of drugs that effect ion channels? How do they have their effect? Example.
1. Blockers - prevents ions passing through channel
Has an effect on: permeation blocked
2. Modulators - binds to protein of receptor and changes the function
Has an effect on: increased of decreased opening probability
Types of drugs that effect enzymes? How do they have their effect? Example.
1. Inhibitor - binds to enzyme and inhibits it
Has an effect on: normal reaction inhibited
E.g. Captopril - reversible ACE inhibitor
E.g. Aspirin - irreversible COX inhibitor
2. False Substrate - acts as a substrate which competes with endogenous substrate
Has an effect on: abnormal metabolite produced
E.g. Fluorouracil - replaces uracil (anticancer)
3. Prodrug - chemical which is not yet a drug, relies on an enzyme to convert the chemical into the drug of choice
Has an effect on: active drug produced
E.g. L-DOPA - once it has crossed the blood brain barrier, converted to dopamine (cannot cross blood brain barrier on its own, affects the peripheral nervous system not the CNS)
Types of drugs that effect transporters? How do they have their effect? Example.
1. Inhibitor - binds to transporter protein and prevents endogenous substrates passing through
Has an effect on: transport blocked
2. False substrate - binds to transporter protein and prevents endogenous substrates passing through
Has an effect on: abnormal compound accumulated
E.g. almost all drugs bind to transporter proteins
Features of drug binding for agonists?
hydrophobic interaction/hydrogen bond (transient association) between agonist drug and receptor which forms drug-receptor complex and activates receptor
Features of drug binding for antagonists?
Antagonist binds to receptor, forms a drug-receptor complex and eventually dissociates
Stops other things having effect on receptor
What are the 4 types of receptor?
1. Ion channel receptors
2. G protein coupled receptors
3. Enzyme linked receptors
4. Nuclear receptors
What are ion channels receptors? Examples?
Molecule binds to receptor, changes conformation and ions flow through
Nifedipine - calcium channel blocker for hypertension
Nitrazepan - benzodiazopine GABA receptor modulator
What are G protein coupled receptors? Examples?
7 transmembrane domain receptor, can bind to agonist which leads to conformational change of receptor which leads to activation of G-protein within the cell, this activates target enzyme which creates a secondary messenger
Phenylephrine - alpha1 adrenoceptor agonist - decongestant localized vasodilation
Propranolol - beta adrenoreceptor antagonist - tratment of hypertension
What are enzyme linked receptors? Examples?
Agonist binds to receptor, causing two subunits to combine which can lead to phosphorylation cascade (tyrosine kinase linked or tyrosine kinase associated)
Insulin and cytokines as therapy for conditions
What are nuclear receptors? Examples?
Receptor that normally exists in the cytoplasm, bound to a chaperone protein.
When bound to the agonist, it dissociates from the chaperone proteins and moves into the nucleus.
Within the nucleus, it can either activate/suppress protein synthesis.
E.g. steroid hormones and glitazone drugs, e.g. rosiglitazone
Summary of the biological molecules that drugs bind to in order to have their effects?
Important terms in drug binding?
Bmax = binding capacity or total receptor binding - all receptors are bound
Disocciation constant (Kd) = concentration of ligand at 50% of receptor occupany
Kd = [drug][receptor]
What are drug binding curves?
What do drug binding curves tell us?
Affinity of drug to the tissue
What do dose-response curves tell us?
Efficacy of drug
Features of dose response curve?
What is efficacy?
The ability of a drug to elicit a physiological response in the target tissue
How is efficacy measured?
Measured using effective concentration 50 (EC50) = the concentration of drug required to elicit half a maximal response
Lower EC50 = higher efficacy
Sometimes effective dose concentration (ED50) = the dose of the drug required to elicit half a maximal response
What is the difference between concentration and dose?
Concentration = fixed concentration of drug
Dose = total amount per weight of subject
Define selectivity? How is it measured?
A measure of the ability of a drug to bind at different sites
Measured typically using Kd
smaller Kd = greater selectivity
Define affinity? how is measured?
A measure of the ability of a drug to bind to a specific receptor
Measured using Kd at a specific receptor
What is an agonist?
A drug which has both affinity for the target and efficacy at the target
What is an antagonist?
A drug which has affinity for the target but no efficacy at the target
Will switch off the effect of the agonst
What is a reversible drug?
A drug which binds to the target and changes the function of the target but will also dissociate
What is an irreversible drug?
A drug which binds permantly to the target and changes the function of the target
Features of antagonist binding?
How do antagonist reduce efficacy on a dose response curve?
Features of irreversible competitive antagonists on a dose-response curve?
What is a partial agonist?
A drug which has both affinity and efficacy at the target, but which is incapabe of generating maximum response compared to a full agonist
What is an inverse agonist?
An agent that binds to the same receptor as the agonist but induces a pharmalogical response opposite to that agonist
A neutral antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either
inverse agonist on a concentration-response curve?