NURS2001 - Wk 3 Lec Pharmacodynamics

Pharmodynamics

What the drug does to the body

Where do drugs bind

• Ligand binds to a receptor to initiate an action (eg. opening a channel one macromolecule)

Ionotronic receptors

• Ligand-gated ion channel

• Ligand = drug

• drug binds to receptors

• Then a channel opens which initiates ions to enter the cell

• Process causes hyperpolarisation or depolarisation of cell

Changing the charge of the cell membrane

This process occurs very quickly (milliseconds)

eg. GABA a Receptors

Metabotropic Receptors

• G protein-coupled receptors

• Ligand binds to receptors

• Activates the action of G-proteins

• Causing a cascade of effects eg. multiple enzymes changing etc.

Occurs in seconds

eg. Beta receptors

Kinase-linked receptors

• Receptor is both intracellular and extracellular

• intracellular receptor = enzyme

• Extracellular receptor is bind by a ligand triggering phosphorylation of the interior enzyme within the cell

• causing gene transcription and then protein synthesis

This process takes Hours

eg. Insulin receptors

Nuclear receptors

• Drug (ligand) must go past cell membrane and into nucleus of the cell

• Initiating gene transcription and then protein synthesis

This process takes the longest (more hours)

eg. steroid receptors

IMPORTANT TO NOTE

Fastest to slowest responses to drugs (how fast the effect of a drug takes)

Isotronic receptors, Metabotropic receptors, Kinase-linked receptors, Nuclear receptors

Isotronic > Beta blockers etc. > Insuline/cytokine receptors > Steroids / oestrogen receptors

Ion channels (other places drugs/ligands may bind to)

eg. Local anaesthetics inhibit voltage gated sodium channels

• Essentially, these drugs jam and block the receptor channel to prevent a signal from going through

Carriers (other places drugs/ligands may bind to)

eg. LDL (pts w high cholesterol often have high low-density lipoprotein) bind to LDL receptors which causes metabolism within the cell

Enzymes (other places drugs/ligands may bind to)

NSAIDs (eg ibuprofen) inhibit cyclooxygenase enzymes to trigger the anti-inflammatory effect

Agonist

Bind to receptors to produce a response (mimicking endogenous ligands that naturally produce a response)

Antagonist

Bind to receptors to prevent/inhibit a response by blocking the receptor from natural ligand binding activity

Affinity

• Drug binding to the receptor

• The ability of a drug to bind to a receptor

Efficacy

• Ability of drug to activate the receptor once bound

• Even though a drug can bind, it’s efficacy is dependent on whether it can produce a response

Drug receptor binding curve

Higher affinty = curve will shift to the left since it takes less concentration for drug to reach its max bound capacity

• Bounding quicker

Concentration effect curve

Higher efficacy = higher response

Dose response relationship: efficacy

Max effect = Full agonist

Sub-max effect = Partial agonist

eg. Buprenorphine = partial agonist as although it has a high affinity, its ability to create a max response is limited, thus a partial agonist

Potency

Concentration or amount of drug required for a max response

eg. drug A can reach max (or same) response with a lower conc compared to drug B, thus drug A has a higher potency

• Although they have the same efficacy, their potency is different

Selectivity

• How selective and specific a drug is when binding to a receptor

eg.

Propranolol = non selective Beta blocker

Metoprolol = selective beta blocker

• Therefore, propranolol is more likely to cause adverse effects such as bind to beta 2 receptors in the lungs

—> This in turn can cause bronchial restriction, impacting patients with asthma etc.

Higher dose = more likely to bind to more variety of receptors no matter if selective or non selective

Competitive antagonism

Higher conc of antagonist = higher conc of agonist required to overcome and reach max agonist occupancy

—> this is reversible competitive antagonism as you can still combat the antagonism

Higher conc of antagonist = higher conc of agonist required, however conc of agonist occupancy decreases as antagonist conc increases

—> therefore irreversible competitive antagonism

Drugs

All have some form of side effects (eventually)

Adverse drug event

• Medication errors

• Adverse drug reactions

• Can occur with everything happening well, but still something happens

Adverse drug reaction

• Unintended

Type A = Predictable and dose-dependent (eg. side-effect, toxicity/overdose)

Type B = Hypersensitive reaction, unpredictable and not dose dependent (eg. allergic reaction, intolerance)

Risk of ADR

• Age

• Sex (females)

• Disease

• genetic factors

• history of adverse reactions

How to prevent ADRs?

• Accurate medication history

• Pt interview and reviewing of Pt

• Therapeutic drug monitoring (measuring conc of drugs)

Therapeutic index (range)

• Margin of safety

• The gap between the the drug response and the time it takes to have adverse effects

• Thinner gap = lower margin of safety

Physiochemical interactions

• Physical incompatibility

Eg. drugs may not be compatible to be mixed in IV mixtures (eg crushing and mixing 3 drugs in mixture)

• Can lose activity ability or cause adverse effects

Pharmokinetic

ADME

Absorption = Normal food-interactions

Distribution = Protein binding

Metabolism = Cytochrome P450 (CYP450)

Elimination = ????

Onset —> offset of inhibition interaction of a drug

• Increased dosing = increased other drug conc, decreased enzyme activity (eg. CYP3A4) and HARM

Induction reaction

• Increased dosing = decreased other drug conc and its effect, while increase enzyme metabolic activity (eg. CYP2C9)

Pharmacodynamic interactions

• Drugs with similar mechanisms of action and pharmacological effects

• Antagonist and agonists

Examples of Enzymes

Inducers = Phenytoin

Inhibitor = Clarithromycin