GW BGZ2026 Case 2 - How do drugs act on molecular level?

What is the function of the heart and what are the main structures?

The heart is a muscular pump that maintains continuous blood circulation by generating pressure to drive blood through two connected systems:

• Systemic circulation → left heart → body → right heart

• Pulmonary circulation → right heart → lungs → left heart

Its main role is to ensure oxygen and nutrient delivery and waste removal.

The heart consists of:

• Right heart

  • Pumps deoxygenated blood to the lungs

• Left heart

  • Pumps oxygenated blood to the systemic circulation

• Valves (tricuspid, pulmonary, mitral, aortic)

  • Ensure one-way blood flow

  • Prevent backflow during contraction

What are the main types of blood vessels and their functions?

Blood vessels are specialized for different roles:

• Arteries

  • Carry blood away from the heart

  • High pressure, thick muscular walls

• Arterioles

  • Main resistance vessels

  • Major regulators of blood pressure

• Capillaries

  • Site of exchange (O₂, CO₂, nutrients, waste)

  • Very thin walls for diffusion

• Veins

  • Return blood to the heart

  • Low pressure, act as blood reservoir

Blood vessels are not passive tubes:

• They actively regulate blood pressure

• They control regional blood flow distribution

• Especially arterioles determine total peripheral resistance

What are catecholamines?

Catecholamines are stress hormones released during “fight or flight”:

• Adrenaline (epinephrine)

• Noradrenaline (norepinephrine)

They are released from the adrenal medulla in response to stress or sympathetic activation.

How do catecholamines affect the heart?

Mainly via β₁-adrenergic receptors:

• ↑ Heart rate (chronotropy)

• ↑ Contractility (inotropy)

• ↑ Cardiac output

Result:

• The heart pumps faster and stronger

• More oxygenated blood is delivered to tissues

How do catecholamines affect blood vessels?

Effects depend on receptor type:

• α₁ receptors (most vessels)

  • → vasoconstriction

  • → ↑ systemic blood pressure

• β₂ receptors (skeletal muscle, lungs)

  • → vasodilation

  • → increased blood flow to muscles

What is the net effect of catecholamines?

Combined effects lead to:

• Increased blood pressure

• Redistribution of blood flow

  • more to muscles and heart

  • less to digestive system

• Preparation for rapid physical activity

How is blood vessel tone regulated?

By GPCR-mediated signaling pathways in smooth muscle cells:

• Balance between contraction and relaxation signals

• Controlled by intracellular messengers:

  • Ca²⁺ → contraction

  • cAMP → relaxation

How does vasoconstriction and vasodiliation occur?

Vasoconstriction

Mainly via α₁ receptors (Gq pathway):

• Activation → IP₃ increases intracellular Ca²⁺

• Ca²⁺ → smooth muscle contraction

• Vessel diameter decreases

• → increased blood pressure

Vasodilation

Mainly via β₂ receptors (Gs pathway):

• Activation → ↑ cAMP

• cAMP inhibits contraction machinery

• Smooth muscle relaxes

• Vessel diameter increases

• → decreased resistance / BP or redistribution

What is the baroreflex?

A fast neural feedback system that stabilizes blood pressure:

• Sensors in carotid sinus & aortic arch

• Detect changes in pressure

• Adjust:

  • heart rate

  • vascular tone

If BP drops:

• ↑ sympathetic activity

• ↑ heart rate

• ↑ vasoconstriction

What is RAAS?

A slow hormonal system activated by low blood pressure:

• Kidney releases renin

• → angiotensin II formation

• Effects:

  • vasoconstriction

  • stimulates aldosterone

Aldosterone:

• ↑ Na⁺ and water retention

• ↑ blood volume → ↑ BP

What is ADH?

Antidiuretic hormone:

• Increases water reabsorption in kidneys

• Increases blood volume

• → raises blood pressure

What is ANP?

A hormone released when BP is too high:

• Causes vasodilation

• Promotes salt and water excretion

• Opposes RAAS

How do drugs lower blood pressure?

By targeting heart, vessels, or fluid volume:

• β-blockers

  • ↓ heart rate and contractility

• ACE inhibitors

  • ↓ angiotensin II → vasodilation

• Diuretics

  • ↓ blood volume

• Calcium channel blockers

  • relax vascular smooth muscle

How do drugs increase blood pressure?

By increasing vascular tone or cardiac output:

• α₁ agonists

  • vasoconstriction

• Adrenaline (emergency use)

  • ↑ heart rate + vasoconstriction

How does stress affect blood pressure?

Stress activates catecholamines leading to:

• ↑ cardiac output (β₁)

• ↑ vasoconstriction (α₁)

• blood redistribution

Result:

• Rapid increase in blood pressure (“fight or flight response”)

What is log₁₀(x)?

It is the power to which 10 must be raised to obtain x:

• log₁₀(x) = y → 10ʸ = x

Examples:

• log₁₀(1) = 0

• log₁₀(10) = 1

• log₁₀(100) = 2

How do you convert number → log?

• Take log base 10

• Example: log₁₀(50) ≈ 1.7
  → because 10¹·⁷ ≈ 50

How do you convert log → number?

• Raise 10 to the power of the log value

• Example: log₁₀(x) = 3
  → x = 10³ = 1000

What are the 5 main biologic drug target categories?

• 1. Receptors

  • Bind signaling molecules (hormones, neurotransmitters)

  • Example: β-adrenoceptors

• 2. Enzymes

  • Catalyze biochemical reactions

  • Inhibition alters pathways

  • Example drugs:

    • ACE inhibitors

    • Aspirin

    • Statins

• 3. Transporters

  • Move molecules across membranes

  • Example:

    • Fluoxetine blocks SERT

    • → more serotonin in synapse

• 4. Ion channels

  • Control ion flow and excitability

  • Example:

    • Amlodipine blocks Ca²⁺ channels

    • → vasodilation

• 5. Structural proteins / nucleic acids

  • Affect cell structure or DNA function

  • Example:

    • Paclitaxel → tubulin stabilization

What 5 different receptors are there?

1. GPCRs (7TMRs)

• Largest receptor family (>800 genes)

• Span the membrane 7 times

• Activate G proteins

• Produce second messengers such as:

  • cAMP

  • IP₃

  • DAG

• Second messengers activate proteins like protein kinase A (PKA).

2. Ligand-gated ion channels

• The receptor is the ion channel.

• Ligand binding opens the channel within milliseconds.

• Allows ions such as:

  • Na⁺

  • K⁺

  • Cl⁻

  • Ca²⁺

3. Kinase-linked receptors

• Usually activated by:

  • Growth factors

  • Insulin

• Ligand binding causes receptor dimerization.

• Intracellular kinase phosphorylates proteins.

• Leads to changes in cell growth, metabolism, or survival.

4. Nuclear receptors

• Located inside the cell (cytoplasm or nucleus).

• Ligands are lipid-soluble and cross the cell membrane.

• Ligand–receptor complex binds DNA and changes gene expression.

• Slow onset (hours to days), but effects last longer.

5. Cytokine receptors

• Bind cytokines involved in immune regulation.

• Lack intrinsic kinase activity.

• Signal mainly through the JAK–STAT pathway.

• Important in inflammation and immune responses.

What is propranolol, how does it work and what is the effect?

• Non-selective β-adrenoceptor antagonist

• Target: Blocks β₁ and β₂ adrenergic receptors

• Competitively blocks β1 receptors in the heart:

  • Decreases heart rate (negative chronotropy)

  • Decreases force of contraction (negative inotropy)

  • Slows conduction through the AV node

• Blocks β2 receptors in the lungs and blood vessels:

  • Can cause bronchoconstriction

  • May reduce glycogen breakdown and mask signs of low blood sugar

Normal β-receptor signaling

Adrenaline or noradrenaline binds β receptors:

β receptor → Gs protein → adenylyl cyclase → ↑ cAMP → ↑ PKA activity

Results:

• Increased heart rate

• Increased contractility

• Increased renin release

What is amlodipine, how does it work and what is the effect?

• Dihydropyridine calcium channel blocker.

• Blocks L-type calcium channels in smooth muscle

• Reduces calcium entry into cells

• With amlodipine

  • ↓ Ca²⁺ entry → ↓ contraction → smooth muscle relaxation

• Leads to:

  • Vasodilation (especially arteries)

  • Lower peripheral resistance

  • Reduced blood pressure

Normal calcium channel function Calcium enters smooth muscle cells through L-type channels.

Calcium binds calmodulin.

This activates myosin light-chain kinase.

Result:

Smooth muscle contraction.

What is salbutamol, how does it work and what is the effect?

• Salbutamol is a selective β₂-adrenoceptor agonist

• It is a drug mainly used as a bronchodilator in respiratory disease

• Target type: G protein-coupled receptor (GPCR)

• Binds to β₂ receptors on smooth muscle (especially in the lungs)

• Activates the Gs protein pathway

• Leads to:

  • ↑ Adenylyl cyclase activity

  • ↑ cAMP

  • ↑ Protein kinase A (PKA) activation

• This causes:

  • ↓ intracellular calcium

  • Relaxation of smooth muscle

Key idea:

• β₂ activation → smooth muscle relaxation

What blood pressure medications are there and how do they work?

β-blockers (e.g. propranolol, metoprolol)

• Block β₁ receptors (heart + kidney)

• Effects:

  • ↓ heart rate

  • ↓ contractility

  • ↓ renin release

  • ↓ blood pressure

ACE inhibitors (e.g. enalapril, lisinopril)

• Block ACE enzyme

• Effects:

  • ↓ angiotensin II

  • ↑ vasodilation (also ↑ bradykinin)

  • ↓ aldosterone

  • ↓ blood pressure

ARBs (e.g. losartan, valsartan)

• Block AT₁ receptor (angiotensin II receptor)

• Effects:

  • Prevent vasoconstriction

  • ↓ aldosterone release

  • ↓ blood pressure

Renin inhibitors (e.g. aliskiren)

• Block renin

• Effects:

  • ↓ angiotensin I → ↓ angiotensin II

  • ↓ blood pressure

Calcium channel blockers (e.g. amlodipine)

• Block L-type Ca²⁺ channels

• Effects:

  • ↓ vascular smooth muscle contraction

  • Vasodilation

  • ↓ peripheral resistance → ↓ BP

Diuretics (e.g. hydrochlorothiazide, furosemide)

• Increase Na⁺ and water excretion

• Effects:

  • ↓ blood volume

  • ↓ blood pressure

What are affinity, potency, and efficacy?

1. Affinity

• How strongly a drug binds to a receptor

• Measured by KD

• Lower KD = higher affinity

• KD = is the concentration of a drug (ligand) at which 50% of the target receptors are bound by the drug at equilibrium.

• KD= k off/k on

2. Potency

• How much drug is needed for an effect

• Measured by EC50

  • The concentration producing 50% maximal effect.

• Lower EC50 = higher potency

3. Efficacy

• Maximum effect a drug can produce

• Measured by Emax

  • Emax most commonly refers to the maximum drug effect in pharmacology

• Higher Emax = greater effect possible

Is a higher dose always better?

• No

• Dose–response is sigmoidal

• After receptor saturation:

  • No extra benefit

  • More side effects

  • More toxicity

Key idea

• Use lowest effective dose

What is dose margin (therapeutic window)?

• Range between:

  • Effective dose (ED50)

  • Toxic dose (TD50)

Formula:

• Therapeutic index = TD50 / ED50

Interpretation:

• High TI → safer drug

• Low TI → narrow safety margin

What is an agonist and what types are there?

An agonist:

1. Binds receptor

2. Activates receptor

3. Produces response

Full agonist

• Binds to a receptor and produces the maximum possible response (Emax).

• Has high efficacy.

Partial agonist

• Binds to the receptor but produces less than the maximum response, even when all receptors are occupied.

• Has lower efficacy than a full agonist.

• Can act as an antagonist in the presence of a full agonist because it competes for the same receptor.

What is an antagonist and what types are there?

An antagonist:

1. Binds receptor

2. Does not activate receptor

3. Blocks agonist action

Competitive antagonist

• Binds to the same (active) binding site as the agonist.

• Binding is reversible.

• Can be overcome by increasing the agonist concentration.

Effect on dose-response curve

• Emax: unchanged

• EC₅₀: increases (curve shifts to the right)

Non-competitive antagonist

• Binds irreversibly to the active site or binds to an allosteric site.

• Prevents receptor activation even if more agonist is added.

• Cannot be overcome by increasing agonist concentration.

Effect on dose-response curve

• Emax: decreases

• EC₅₀: usually unchanged

Would you prefer an antagonist or an agonist for treating a disease?

Antagonists (usually preferred)

• Block excessive signalling

• Safer

• Less receptor overstimulation

Agonists

• Used when signalling is too low

• Higher risk:

  • tolerance

  • receptor downregulation

Rule

• Too much activity → antagonist

• Too little activity → agonist

Describe what you see in the curves and what information can you get out of it?

This curve shows how much drug is bound to receptors as concentration increases.

What you see

• Sigmoidal (saturable) curve

• At low concentrations → little binding

• At higher concentrations → binding increases

• Eventually reaches a plateau = Bmax

Key information you get

• KD (affinity)

  • Concentration where 50% of receptors are occupied

  • Low KD → high affinity (left shift)

• Bmax

  • Maximum binding capacity

  • Reflects total number of receptors, not drug strength

Main concept

• This is about binding, not effect

Describe what you see in the curves and what information can you get out of it?

This shows drug concentration vs biological response.

What you see

• Sigmoidal curve (usually plotted on log scale)

• Low dose → small effect

• Middle range → steep increase

• High dose → plateau (Emax)

Why log scale is used

• Expands the middle (clinically relevant) part

• Makes EC50 easier to compare between drugs

Key information you get

• EC50 (potency)

  • Concentration that gives 50% of max effect

  • Low EC50 → high potency

• Emax (efficacy)

  • Maximum achievable effect

  • Independent of dose once saturation is reached

Key concept

• Effect ≠ binding

  • Full receptor binding does not always equal full effect (receptor reserve, signaling efficiency)

Describe what you see in the curves and what information can you get out of it?

This shows what happens when an antagonist competes with an agonist at the same receptor.

What you see

• Multiple dose–response curves

• With increasing antagonist:

  • Curve shifts to the right

  • Shape stays the same

  • Maximum height stays the same

What changes

• EC50 increases → potency decreases

  • Need more agonist to get same effect

What does NOT change

• Emax stays the same

  • Because high agonist concentration can outcompete antagonist

Mechanism

• Reversible binding at the same receptor site

• Competition depends on concentration

Key conclusion

Competitive antagonists reduce potency but do not reduce efficacy.