Alles fysio ADME

Wat is het verschil tussen agonist, partieel agonist en antagonist, en hoe vertaalt dit zich naar de dosis-responsrelatie?

• agonist; bindt receptor en activeert volledig → maximale respons → EEmax hoog

• partieel agonist; bindt receptor maar geeft lagere maximale respons → lagere Emax zelfs bij hoge dosis 

• Antagonist; bindt receptor maar activeert niet → blokkeert effect van agonist 

Dosis-respons:

• agonist → volledige curve 

• Partieel agonist → lagere Emax 

• Antagonist → verschuift curve (rechts bij competitief), geen eigen effect

Wat is het verschil tussen potentie en intrinsieke activiteit?

• Potentie = hoeveel drug nodig is voor effect (EC50)

  • lagere EC50 = hogere potentie 

• Intrinsieke activiteit (efficacy); maximale effect dat een drug kan bereiken (Emax)

Aan welke receptoren bindt angiotensine II? Welke intracellulaire cascades volgen?

Het bindt vooral aan AT-1 receptor (soms AT2) 

AT1 cascade;

• Gq-eiwit → fosfolipase C (PLC)

• → IP3 + DAG 

• → ↑ Ca²⁺ + PKC activatie

Effect; 

• Vasoconstrictie

• ↑ bloeddruk

• ↑ aldosteron

Wat zijn spanning gemedieerde (ionotrope) Ca2+-kanalen en hoe verschillen ze van ligand gemedieerde (metabotrope) ionkanalen?

• spanningsgemedieerd (ionotroop) 

  • openen door verandering in membraanpotentiaal 

  • snel 

  • bv. Ca2+ kanalen in hart/spier 

• ligandgemedieerde (metabotroop) 

  • via receptor + second messenger 

  • trager

  • indirecte opening van kanalen

Wat zijn de bèta-1- en bèta-2-adrenerge receptoren? Via welke intracellulaire route werken ze en wat is het fysiologisch effect op hart en vaten?

• B1 (hart) 

  • Gs → ↑ adenylyl cyclase → ↑ cAMP → ↑ PKA

  • Effect; ↑ hartfrequentie + ↑ contractiliteit

• B2 (vaten en longen) 

  • ook Gs → ↑ cAMP

  • Effect; vasodilatatie + bronchodilatatie

Via welke receptoren beïnvloedt het autonoom zenuwstelsel hartfrequentie, contractiliteit en vaattonus?

• sympatisch 

  • B1 → ↑ hartfrequentie & contractiliteit

  • B2 → vasodilatatie 

  • a1 → vasoconstrictie 

• Parasympatisch 

  • M2 (muscarine receptor) → ↓ hartfrequentie

Welke stappen doorloopt het RAAS van reninesecretie tot aldosteronwerking? (5)

• Nier → renine

• Angiotensinogeen → angiotensine I

• ACE → angiotensine II

• Angiotensine II:

  • Vasoconstrictie

  • ↑ aldosteron (bijnier)

• Aldosteron → Na⁺/water retentie → ↑ bloeddruk

Wat is bradykinine, via welk enzym wordt het afgebroken, en welke receptoren medieert het?

• Functie: vasodilatatie + ↑ vaatpermeabiliteit

• Afbraak: door ACE

• Receptoren: B1 en B2

Wat is het verdelingsvolume (Vd)? En wat zegt een hoge vs. lage Vd? Welke patiënt specifieke factoren kunnen een invloed hebben op het Vd?

• definitie: verdeling van geneesmiddel in lichaam

• Hoog Vd; veel in weefsel (lipofiel)

• Laag Vd: blijft in bloed (hydrofiel)

Invloed factoren;

• leeftijd

• vetpercentage

• oedeem

• Plasma-eiwitten

Wat is het first-pass effect? Via welke enzymen worden geneesmiddelen gemetaboliseerd?

• Definitie: afbraak in lever vóór systemische circulatie

• Enzymen: vooral Cytochrome P450 (CYP)

Hoe beïnvloedt lipofiliciteit (log P) de absorptie, weefselverdeling, plasma-eiwitbinding en metabolisme?

↑ lipofiliciteit:

• ↑ absorptie

• ↑ weefselverdeling (hoog Vd)

• ↑ eiwitbinding

• ↑ levermetabolisme

Wat bepaalt de biologische beschikbaarheid (F) van een oraal geneesmiddel? 4

• Lipofiliciteit

• Oplosbaarheid

• First-pass effect

• Transporters (zoals P-gp)

Hoe beïnvloeden lever- en nierfunctiestoornissen metabolisme en excretie?

• Leverstoornis:

  • ↓ metabolisme → ↑ concentratie

• Nierstoornis:

  • ↓ excretie → accumulatie

Wat is het verschil tussen COX-1 en COX-2, en hoe verklaart dit de therapeutische effecten van ibuprofen?

• COX-1

  • constitutief (altijd actief)

  • beschermt maag, nierfunctie, bloedplaatjes

• COX-2

  • geinduceerd bij ontsteking

  • Zorgt voor pijn, koorts, onsteking

• Ibuprofen remt beide →

  • therapeutisch; ↓ pijn, ↓ koorts, ↓ ontsteking

Via welk mechanisme beschermen prostaglandinen het maagslijmvlies, en wat gebeurt er wanneer dit wordt geremd?

• stimuleren;

  • slijmproductie

  • bicarbonaat

  • doorbloeding

• remming →

  • minder bescherming

  • grotere kans op ulcera en bloedingen

Waarom heeft ibuprofen zowel analgetische, antipyretische als anti-inflammatoire effecten en paracetamol niet alle drie?

Omdat paracetamol vooral centraal werkt (CNS) → waardoor het nauwelijks anti-inflammatoir effect heeft

Hoe wordt ibuprofen geabsorbeerd vanuit het maagdarmkanaal, en welke eigenschappen van het molecuul bepalen dit?

• snel uit maag/darm (passieve diffusie)

• belangrijke eigenschappen

  • lipofiliciteit

  • klein molecuul

  • zwak zuur

Wat is plasma-eiwitbinding, en hoe beïnvloedt een verminderde albumineconcentratie (zoals bij nierziekte) de vrije fractie van ibuprofen?

• het bindt aan albumine

• alleen een vrije fractie = actief

Als albumine verlaagt door bijvoorbeeld een nierziekte dan →

• ↑ vrije fractie

• ↑ effect + ↑ kans op toxiciteit

Wat is de pH-partitiehypothese, en hoe verklaart dit de absorptie van ibuprofen als zwak zuur in verschillende compartimenten?

• zwakke zuren

  • niet-geioniseerd in zuur milieu → betere opname

• Ibuprofen:

  • goed opname in maag (zuur)

  • minder in basisch milieu

Wat is het verschil tussen fase I- en fase II-metabolisme, en welke enzymen zijn betrokken bij de afbraak van ibuprofen?

• Fase I:

  • Oxidatie/reductie

  • Enzymen: CYP450 (vooral CYP2C9)

• Fase II:

  • Conjugatie (glucuronidering)

  • Maakt stof wateroplosbaar

Welke factoren bepalen de renale excretie van geneesmiddelen, en waarom worden ibuprofen-metabolieten bij deze patiënt minder goed uitgescheiden?

• Bepaald door:

  • Filtratie

  • Secretie

  • Reabsorptie

Bij nierfunctie ↓:

• Minder uitscheiding metabolieten

• Accumulatie → ↑ bijwerkingen

How to attack bacteria

tegen te gaan door cell walls van bacteria te targetten

Beta-lactams

• largest class targeting bacterial cell wall

• Contain a beta-lactam ring → needed for their antibacterial activity (bactericidal)

• (inhibit pencillin-binding proteins (PBPs) → these are needed for peptidoglycan cross-linking)

How do beta-lactamase inhibitors bind?

they bind irreversibly to beta-lactamases

How do glycopeptides work?

• antibiotica → celwand

• prevents transglycosylation and transpeptidation from inhibiting cell wall cross linking

Aminoglycosides wat is het en wat doet het

• bind reversibly (with high affinity) to the 16s ribosomal RNA on the 30S ribosome

• Antibiotica die bacterien doodt door het verstoren van eiwit synthese

Antiviral therapy

• drugs need to target virus and not the host cell

• virus specific drugs → protease inhibitors

• ineffective → many cycles of viral replication occur during the incubation period (no symptoms)

• Some viruses become latent → CMV; impossible to treat when latent

• Drug-resistant viral mutants → ineffective/regimen change needed

Basis of HIV therapy

Antiretroviral therapy (ART)

ART initiation regardless of CD4 count → after entry to a cell, single-strand RNA is reverse transcribed into HIV DNA, which is then integrated into the host DNA → this fact makes the virus exceedingly difficult to eradicate with current therapies → HIV has a HIGH mutation rate

Combination of 3 medications – 1 pill

Monitoring therapy

• Viral loads

• CD4 cell count

What kind of virus is hepatitits C

Hepatitis C is an RNA virus and replicates via RNA-dependent RNA polymerase (NS5B)

What drug is used in hepatitis C and how does it work?

• Sofosbuvir is a nucleotide analogue prodrug → activated intracellularly (see acyclovir)

• Incorporates into viral RNA chain → chain termination → viral replication stops

• Human cells do not have RNAdependent RNA polymerase → highly selective (minimal toxicity)

What kind of inhibitor is Oseltamivir and for what disease does it work

neuraminidase inhibitor and oseltamivir for influenza

How does oseltamivir for influenza work?

• Inhibits viral neuraminidase enzyme on influenza surface

• Neuraminidase normally cleaves sialic acid → releases new virus particles from infected cell → allows viral particle spread

• Oseltamivir blocks neuraminidase → virus particles remain stuck to cell surface → cannot spread to new cells

• Reduces duration of illness by ~1 day if started within 48 hours of symptoms

What is the MoA of echinocandins

• MoA: Inhibition of 1,3 - β -D glucan synthesis → a critical structural polysaccharide in the fungal cell wall

• β-1,3-glucan forms a scaffold-like mesh that maintains the integrity, rigidity, and shape of the fungal cell wall → progressive weakening of the cell wall, cell lysis, and fungal cell death

• Can cause hepatotoxicity

What is the MoA of azoles

Remt de synthese van het membraan van door inhibition of 14 -α sterol demethylase waardoor ergosterol synthese niet kan plaats vinden

MoA: inhibition of 14 -α sterol demethylase (needed for ergosterol synthesis)

Ergosterol is the primary sterol in the fungal cell membrane, maintains membrane integrity, and the function of proteins.

Azoles block the oxidative demethylation of lanosterol to ergosterol → disrupting membrane structure and function → increased membrane permeability, impaired nutrient transport, and inhibition of fungal growth

Where is insulin produced?

Insulin is a peptide hormone produced by B cells in the islets of Langerhans in the pancreas

Insulin release is stimulated by;

- ↑ Blood glucose (main stimulus, responds to both absolute level and rate of rise)

- Amino acids (arginine, leucine)

- Fatty acids

- Parasympathetic nervous system - Incretins — GLP-1 and GIP (gut hormones released after eating)

- Sulfonylurea drugs (pharmacological stimulus)

Insulin release is inhibited by;

• Sympathetic nervous system — adrenaline via α₂ receptors on β cells

• Somatostatin, galanin, amylin

How does insulin decrease blood glucose?

• increasing glucose uptake into muscle and fat via Glut-4

• increasing glycogen synthesis

• decreasing gluconeogenesis

• decreasing glycogen breakdown

When and why is glucagon released?

Glucagon is released in response to low blood glucose levels, insulin lowers blood sugar, glucagon raises it

What does glucagon do?

It is a fuel-mobilising hormone (produced in the pancreas), stimulating gluconeogenesis (synthesizing new glucose from non-carbohydrate precursors like amino acids and fatty acids) and glycogenolysis (breaking down stored glycogen into glucose, which is released into the bloodstream), also lipolysis and proteolysis.

What are type 1 and type 2 diabetes

• type 1 = an absolute deficiency of insulin

• type 2 = a relative deficiency of insulin associated with reduced sensitivity to its action (insulin resistance)

How does a GLP-1 receptor agonist work?

• Mimic GLP-1 (incretin hormone released from gut after eating)

• Bind GLP-1 receptor → ↑ insulin secretion (glucose-dependent) → ↓ blood glucose/↓ glucagon → ↓ blood glucose, ↓ gastric emptying → ↓ appetite

• Glucose-dependent → low hypoglycaemia risk

• Significant weight loss, use in OBESITY (semaglutide)

What are the two types of thyroid hormones?

• T4 (thyroxine is the main secreted hormone

• T3 is the more active form (more potent) → T4 is converted to T3 in tissues

• Calcitonin controls plasma Ca2+ → involved in bone metabolism

What are the actions of T3 and T4

• stimulation of metabolism, causing increased oxygen consumption and increased metbolic rate

• regulation of growth and development

What do abnormalities of thyroid (schildklier) function include;

• hyperthyroidism → either diffuse toxic goitre or toxic nodular groitre

• hypothyroidism; in adults this cause myxoedema; in infants → gross restriction of growth and intellectual disability

• simple non-toxic goitre caused by dietary iodine deficiency, usually with normal thyroid function

Levothyroxine

• what is it used for

• which form

• how does it work

• levothyroxine = the synthetic form of thyroxine T4 and is the standard replacement therapy for hypothyroidism

• After PO admin: in peripheral tissues (liver, kidney, muscle) → deiodinase enzymes convert T4 → T3 (active form)

• T3 is 3 –5x more potent than T4

• T3 is lipid soluble → crosses cell membrane freely

• Binds to thyroid hormone receptors (THR) in the nucleus (nuclear receptor!)

• T3 -THR complex binds thyroid response elements (TREs) on DNA where activates or represses specific gene transcription

• → ↑ Production of proteins controlling metabolism, growth and development

Thionamides

• what is it used for

• which form

• how does it work

Antithyroid drugs (thionamides):

• Carbimazole, propylthiouracil (PTU)

• Inhibit thyroid peroxidase (TPO) → ↓ oxidation of iodide → ↓ iodination of thyroglobulin → ↓ T3/T4 synthesis

• PTU also blocks peripheral conversion of T4 → T3

Radioiodine

• what is it used for

• which form

• how does it work

• Radioactive iodine taken orally → concentrated in thyroid (thyroid naturally takes up iodine)

• Emits β radiation → destroys thyroid tissue → ↓ hormone production

• Often results in hypothyroidism → lifelong levothyroxine needed

OEstrogens and antioestrogens

• Oestrogen is a lipid-soluble steroid hormone → can passively diffuse across cell membrane and directly into the cytoplasm or nucleus

• Binds to receptors (ER) → gene transcription → synthesis of new proteins that mediate oestrogens physiological effects

• Such as proliferation of uterine and breast epithelium, bone maintenance, and cardiovascular protection.

• Slow onset (hours to days)

Antioestrogens are competitive antagonists or partial agonists.

Progestogens

• The mechanism of action: intracellular receptor (progesterone receptors PR-A or PR-B) → altered gene expression → progesterone physiological effects (relaxes smooth muscle, luteal phase, maintaining pregnancy etc..) Oestrogen stimulates synthesis of progesterone receptors, whereas progesterone inhibits synthesis of oestrogen receptors.

• Clinically: contraception, endometriosis,

• Combined with oestrogen for oestrogen replacement therapy in women with an intact uterus, to prevent endometrial hyperplasia and carcinoma.

Antiprogestogens

• Medical termination of pregnancy: mifepristone (partial agonist) combined with a PG (e.g. gemeprost).

• Emergency contraception (morning-after pill): ulipristal (selective progesterone receptor modulator), also used to reduce the size of uterine fibroids pre-operatively.

Androgens

• The main endogenous hormone is testosterone; intramuscular depot injections of testosterone esters are used for replacement therapy.

• Mechanism of action is via intracellular receptors/altered gene expression.

• Clinical uses of androgens and anti-androgens Androgens (testosterone preparations) as hormone replacement in:

• male hypogonadism due to pituitary or testicular disease.

Anti-androgens

Anti-androgens (e.g. flutamide, cyproterone) are used as part of the treatment of prostatic cancer.

• 5α-Reductase inhibitors (e.g. finasteride) are used in benign prostatic hyperplasia

What is the mechanism of NSAIDs

Goal; to block prostaglandins which is responsible for pain, fever, inflammation

• Mechanism: inhibit COX (cyclooxygenase) enzymes → ↓ prostaglandin synthesis

• COX converts arachidonic acid → PGH₂ → downstream prostaglandins

What is the MoA of opioids?

MoA; agonist for mu-opioid receptor (GPCRs on neuronal cells in the brain stem and thalamus

How does the mechanism of opioids work? pre and post synaptic side

On pre-synaptic side ↓ cAMP intracellular concentration and ↓ Ca2+ ion influx and ↓ release of excitatory neurotransmitters

Post-synaptic invoke hyperpolarization of the neuronal membrane → ↓ probability of action potential, ↓ neuronal excitability

What are immunosuppressants?

• drugs that reduce or suppress the activity of the immune system

• used when the immune system is overactive or misdirected

• Three main clinical settings;

  • transplantation to prevent organ rejection

  • autoimmune disease

  • inflammatory conditions

Glycocorticosteroids

they simultaneously turn on anti-inflammatory genes and turn off pro-inflammatory genes

Antiproliferative agents in immunosuppression

• The immune response requires rapid multiplication of lymphocytes (T and B cells) to mount an attack

• Antiproliferative drugs interfere with this multiplication at different points (the signal, the building blocks, or the DNA itself)

• Fewer lymphocytes available → weaker immune response → less rejection or autoimmune damage

• These drugs are not lymphocyte-specific → they affect all rapidly dividing cells

Lymphocyte depleting agents

• do not block lymphocyte activation → physically remove them

• fewer lymphocytes in circulation → less immune activity

Biologics

• Designed to be more precise → theoretically fewer side effects than broad immunosuppression

• Biologics are large protein molecules (antibodies or receptor decoys) that neutralise a specific cytokine or block a specific receptor

IV JAK inhibitors what are they and how do they work

• JAK inhibitors are small molecules that block the intracellular signalling pathway used by many cytokines simultaneously

• Rather than neutralising one cytokine outside the cell they block the common internal pathway many cytokines share

• One drug interrupts signals from IL-2, IL-6, IFN-γ and many others at once

• Despite being "targeted" still carry infection risk and other side effects because the pathways they target also have normal physiological roles

What do antihistamines block?

They block histamine receptors, primarily H1 receptors

What is the nromal function of histamine

• H1 is a GPCR, specifically coupled to Gq protein

• ↑ intracellular Ca²⁺:

• Smooth muscle contraction (bronchoconstriction), oedema, itch and pain, runny nose (mucus), vasodilation (flushing and redness)

How do antihistamines work?

Antihistamines: competitive antagonists at H1 receptors (GPCRs)

• Block histamine binding → ↓ Gq signalling → ↓ IP₃ → ↓ intracellular Ca²⁺ → ↓ inflammatory effects

cytotoxic drugs

• drugs that directly kill cells or prevent cell division

• target rapidly diving cells → both cancer cells and normal rapidly dividing cells

• often used in combination to target multiple mechanisms simultaneously

HOrmones and hormone antagonists

• some cancers are driven by hormones thus blocking hormonal signalling slows or stops growth

• examples; breast and prostate cancer

• generally better tolerated than cytotoxic drugs

• used as adjuvant therapy, after surgery, or as long-term maintancence

• resistance can develop over time as tumour can become more hormone-independent

Protein kinase inhibitors

• Cancer cells often have overactive kinases driving uncontrolled proliferation

• These drugs block specific kinases → ↓ growth factor receptor signalling → ↓ proliferation

• More selective than cytotoxic drugs → generally better tolerated

• Resistance develops frequently due to mutations in kinase domain

What are monoclonal antibodies?

large protein molecules targeting specific antigens on cancer cells or tumour vasculature

• more targeted than cytotoxic drugs because they act on specific surface markers

What are the three mechanisms of monoclonal antibodies?

• direct cell killing

• immune-mediated destruction

• blocking growth factor receptors or tumour vasculature

Facts about viruses

• accellular

• require a host cell to replicate

• have genetic material (a genome)

  • composed of single-stranded DNA

  • or single stranded or double stranded RNA

  • never both

• Resistance

• non motile

Which neurotransmitter influence the heart

• acetylcholine → rest and digest → slow heartbeat

• adrenalin, noradrenalin → fight or flight → increase heartbeat

What is arrhythmia

hartritmestoornis waarbij je hart niet in een normaal ritme klopt

• te snel

• te langzaam

• onregelmatig

Antiarrhythmic drugs welke classes 5

• Class I → Na+ channel blockers (Ia t'/m Ic)

• Class II → B-blockers

• Class III → K+ channel blockers

• Class IV → Ca2+ channel blockers

• Class V → miscellaneous

What are the four electrical phases of the heart

• phase 4 - pacemaker potential

  • the heart slowly builds up electrical cahrge

  • this determines your heart rate

• phase 0 - rapid depolarisation

  • a fast spike → triggers contraction

  • mainly driven by sodium (na+) influx

• Phase 2 - plateau

  • the signal is sustained

  • balance of calcium (Ca2+) entering and potassium (K+) leaving

• Phase 3 - repolarisaiton

  • the heart resets electrically

  • mainly potassium (K=) leaving the cell

On which phase do class I drugs work?

Sodium channel nlockers act on phase 0 (rapid depolarisation)

• slow down the sharp spike

• reduce stimulation from adrenaline

On which phase do class III drugs work?

Potassium channel blockers act on phase 3 (repolarisation)

• prolong the reset phase

• make it harder for abnormal rhythms to restart

• they stretch the heartbeat cycle

On which phase do class IV drugs work?

Calcium channel blockers act on phase 2 (plateau)

• reduce calcium entry

• slow conduction, especially in Av node

• help control heart rate

How can B-agonists help the heart?

They are the opposite of beta-blockers

• increase heart rate

• speed up pacemaker activity in phase 4

What are B-adrenoreceptors and how do they work?

• Beta-adrenoceptors are GPCRs (G-protein coupled receptors) which activate adenylyl cyclase

• the receptor responds to hormones like adrenaline en noradrenaline

• When activated they usually increase heart rate and force of contraction

How do beta-blockers work on B-adrenoceptor

• antagonist for B-adrenoreceptor

• competitive binding with adrenaline and noradrenaline

• so they block that receptor and therefore decrease the heart rate

Where can you find B1 receptors and where can you find B2 receptors?

B1 - mainly in heart → rate, contractility, conduction

B2 - lungs, blood vessels, liver

How does the heart rate go up by activation of beta-adrenoceptors

• activation of b-adrenoceptors increases cAMP

• → which activates a cAMP dependent protein kinase PK-A

• → which phosphorylates L-type calcium channels

• → causes increased calcium entry into the cell

• → which leads to enhanced release of calcium by the sarcoplasmic reticulum in the heart

• → contractility increases → heart rate goes up

Beta-blockers reduce these effects by blocking these processes

What are non selective blockers

Non-selective blockers (e.g. propanolol) block both B1 en B2 → risk of bronchospasm, peripheral vasoconstriction

What are cardioselective blockers?

Metoprolol, atenolol, bisprolol

• preferentially block B1

• safer in respiratory disease

What does selectivity say about beta-blockers

it is relative, not absolute.

• At high doses cardioselective drugs still block B2

Lots of points about beta-blockers in hypertension

• what do they do

• How do they do it

• along side what are they used

• when are they useful

• reduce cardiac output → lower blood pressure

• decrease renin release from kidneys → less angiotensin II → less vasoconstriction

• often used alongside diuretics or ACE inhibitors

• particularly useful in patients with coexisting heart failure or post MI

• less preferred as first-line in uncomplicated hypertension (vs ACE inhibitors/CCBs)

Beta blockers in arrhythmia what do they do and when are they useful?

• slow conduction through the AV node → controls ventricular rate

• useful in atrial fibrillation & atrial flutter (rate control)

• reduce sympathetic drive, which is a major trigger for arrhythmias

Side effects of Beta-blockers

BAD FISH

• Bradycardia/Bronchospasm → (bronchospasm avoid in asthma)

• AV block/ arrhuthmias

• Dizziness/Depresion

• Fatigue

• Impotence

• Sings of hypoglycemia masked

• Hypothension

To what does calcium influx lead

Calcium influx into heart and vascular smooth muscles leads to casoconstriction and contraction of these muslces

More calcium = constriction and contraction

How do calcium channel blockers work?

Calcium channel blockers inhibit L-type calcium channels leading to vasodilation, decreased contractility, and a reduction in heart rate

What is a reduced ejection fraction

The heart can’t pump or squeeze enough blood out to the body

What is a preserved ejection fraction?

the heart can’t fill with enough blood

HOw does digoxine work for heart failure?

• drug class

• MoA

• drug class; cardiac glycoside

• MoA; antagonist for the Na+/K+ ATPase in the myocardium (on cardiac cells)

What are nitrates used for and what is the effect for a higher and lower dose?

• NO → smooth muscle relaxation → vasodilation

• Veins (low dose) ↓ preload → heart works less → ↓ O₂ demand

• Arteries (higher dose): ↓ afterload + coronary dilation → more blood to heart

Organic nitrates (e.g. glyceryl trinitrate);

Does act directly

• ↑ cGMP cascade leads to smooth muscle relaxation

• Relaxation = vasodilation → reduced preload/afterload → less cardiac workload

What is hypertension?

Increased cardiac output

• stress

• renal disease

• pregnancy

Increased vascular resistance

• atheroscelerosis

• diabetes

• stress

How do RAAS en sympathetic nervous system work together?

Ang II directly increases noradrenaline release from sympathetic nerve terminals, versterking vasoconstriction

What are the function of the RAAS system?

1. restore BP and blood volume when they fall

2. control Na+ excretion and fluid balance

3. regulate vascular tone

What is the function of renin in RAAS system?

Renin released from kidney in response to ↓ BP, ↓ Na ⁺, or ↑ sympathetic activity

• Renin cleaves angiotensinogen (liver) → Angiotensin I (inactive)

• ACE (mainly in lung) converts Ang I → Angiotensin II (active vasoconstrictor)