Intro to pharmacology

What are drugs

Chemicals that produce biological effects

Define pharmacodynamics

What the drug does to the body, its mechanism of action

Define pharmacokinetics

What the body does to the drug, how it is absorbed, distributed, metabolised, excreted (ADME)

Describe the pharmacodynamics (mechanism of action) of aspirin. Primary, Secondary and research uses

• Primary

  • analgesic (pain killer)

  • anti-pyretic (reduce fever)

  • anti-inflammatory (reduce immune response)

• Secondary

  • anti-platelet aggregation in low doses (¯ formation of blood clots)

• Research

  • possible actions of reducing cancer of colon and rectum?

  • delays onset of Alzheimer’s disease?

Describe the pharmacodynamics of aspirin

Inhibits an enzyme called cyclooxygenase (COX)

COX catalyses the conversion of arachidonic acid into prostaglandins (PGs) and thromboxanes

List the actions of prostaglandins

Sensitising pain nerve endings

Dilating blood vessels - redness

Increasing blood vessel permeability - swelling

Setting body temperature during fever

Thromboxanes cause platelet aggregation

What are the actions of aspirin

analgesic, anti-inflammatory, anti-pyretic and anti-platelet aggregation

Describe the pharmacokinetics of aspirin

• Routes of administration – oral (other routes IV, IM, SC)

• Readily absorbed from stomach and intestine

• Broken down in liver by esterases, some excreted unchanged – half-life of 4 hours in low doses

• Excreted in urine – need kidney function

• Important in deciding the dose / how often administrated

What are the adverse effects of aspirin

• Gastrointestinal irritation and bleeding,  might be severe in some individuals (side effect)

• Kidney dysfunction

• Tinnitus, vertigo, nausea and vomiting – high doses (side effect)

• Should be avoided in asthmatics – stimulate attack (this is a potential contraindication)

• May cause Reye’s syndrome in children which can be fatal – do not give to young children (contraindication)

What are the properties of drugs

Tissue selective: adrenaline acts on the heart, blood vessels, lungs but not skeletal muscle

Chemical selectivity: small changes in structure greatly alter action of a drug

Amplification of action: drugs work at very low concentrations

What must receptors have for drugs to function

Expressed in selective tissues

Have the correct chemical structure to bind the drug

Linked to amplification of signals

What is a drug receptor

A receptor is a cellular molecule (often a protein) that a drug binds to. Binding of drug to receptor couples to a change in cellular effects

e.g. adrenaline binding to ß-adrenoceptors in the heart leads to an increase in heart rate

List the types of drug targets (receptors) and give examples

Receptors - Adrenaline acting at β-adrenoceptors

Enzymes - Aspirin acting at cycloxygenase

Carrier molecules - Fluoxetine acting at serotonin uptake carrier

Ion channels - Lignocaine acting at Na⁺ channels

What is an agonist

A drug which binds to a receptor to produce a biological cellular response

E.g.  adrenaline increases heart rate

What is an antagonist

A drug which binds to a receptor (same as an agonist) but does not produce a biological effect. Antagonist bind to receptors to prevent agonists producing effects

E.g. Atenolol blocks adrenaline-mediated increases in heart rate

 

define drug affinity

The strength of the interaction between a drug and its target receptor.

It indicates how tightly a drug binds to a receptor, influencing its effectiveness and potency.

define drug efficacy

refers to the ability of a drug to produce the desired therapeutic effect when administered at a specified dose.

(only agonists produce a cellular response)

List the types of weak/reversible drug bondings

Hydrogen bonding

Ionic bonding

Van der Waal’s forces

List the types of strong/irreversible drug bondings

Covalent bonding

What is Reversible binding of an agonist to a receptor is governed by

Law of Mass Action

describe the law of mass action

The rate of a chemical reaction is proportional to the concentrations of the reactants

What determines affinity

Law of mass action

A + R ⇌ AR (Agonist + Receptor ⇌ Agonist Receptor complex)

Low [A] - lots of R_free - few AR interactions

As we increase [A] - more AR interactions - reaction reaches maximum as numbers of receptors is finite

What is equilibrium constant of a drug (KA)

When 50% of receptors are free and 50% are bound to agonist

K_A is the [A] at equilibrium, e.g. K_A of 50 nM means that at this agonist concentration 50% of receptors will be occupied

What does a smaller K_A mean

 

Smaller K_A (e.g. 5 nM) means agonist has a greater AFFINITY for receptor (it binds more) than a drug with a higher K_A value (e.g. 50 nM)

Define affinity and efficacy

Affinity – occupancy, binding of drug to receptor

Efficacy – biological effect, e.g. increase in heart rate

Describe EC₅₀

Effective concentration giving  50% biological response

Describe Partial agonists

E.g. Buprenorphine for opioid addiction

• Present at receptors – high affinity, but less efficacy

• Reduces withdrawal effects

• Reduces additive ‘highs’

• Heroin-induced highs (full agonist) are reduced in presence of partial agonist

 

describe Competitive Antagonism

• Receptors only bind either Agonist (A) or Antagonist (Ant)                

• A and Ant compete for the same binding site

• A and Ant both bind reversibly

• Reaction now dependent on two equilibrium constants, K_A and K_ant

• If K_Ant < K_A, then Ant has greater affinity for Receptor than A

• [A] must increase to overcome Ant binding to Receptor

 

Describe Non-competitive antagonism

Ant binds to a different site to that of the agonist

e.g. ketamine (anaesthetic) blocking glutamate NMDA receptor in brain

 

Describe Irreversible antagonism

Ant binds irreversibly to either agonist- or non-agonist binding sites on the receptor through covalent bonds

Reduces number of receptors the agonist can bind to

e.g. aspirin – acetylates COX enzyme