Pharmaceutical Vertical Theme - Cardiology

Hypothalamus pituitary axis

* Hypothalamus is the base of the brain which has modified neurosecretory cells which can secret hormones into the blood.
* Hormones are transported to anterior pituitary, which causes the release of pituitary hormones.
* Also in the hypothalamus you have modified neurosecretory cells which act on target organs - they release hormones directly from posterior pituitary into blood- primary hormones

2 Primary hormones in posterior pituitary

1) Vasopressin- anti-diuretic hormones- regulates urine volume and composition.

2) Oxytocin- Bonding hormone, typically released after birth, and in mother and baby skin to skin contact.

5 hormones from anterior pituitary

These 5 other hormones from the anterior pituitary from the hypothalamus act on the pituitary to cause the release of pituitary trophic (stimulating) hormones, which then go on to act on target organs and tissues.

Release of trophic stimulating hormone pathway

Hypophysiotropic releasing/ inhibiting hormones → Pituitary trophic stimulating hormones → Target organ/ tissue.

Acromegaly and its treatment

Excess growth hormone

Treatment: Aims to reduce GH production

* Octreotide and Lanreotide
* Regvistomat - growth hormone receptor antagonist
* Bromocriptine - Dopamine agonist
* Radiation therapy
* Removal of tumour

Hyperprolactinaemia

This is often caused by a Benign Pituitary Tumour, these tumours are not cancerous. Prolactin is the milk hormone. Common presentation of this is-

* Galactorrhoea- milk secretion from breast
* Amenorrhoea- female absence of periods
* Hypogonadism- diminished production of sex hormones in males or females

Dopamine agonists used to treat prolactinoma

* Prolactin inhibiting factor (PIF) is dopamine
* Dopamine act of receptors in the pituitary gland to inhibit prolactin release
* Cabergoline and bromocriptine are dopamine agonists that inhibit prolactin production
* ANTIPRYCHOTICS -D2 receptor antagonist, and can cause hyperprolactemia - causes leakage of milk from breasts

Panhypopituitarism

A deficiency in all anterior pituitary hormones- often caused by a tumour, or as a result of autoimmune suppression. Management of this is by hormone replacement therapy.

Regulation of thyroid gland

* Thyroid is regulated by the production of hormones from the hypothalamus.
* The thyroid gland is responsible for producing Thyroxin (T4), which is then converted to Triiodothyronine (T3)
* T3 gets inside cells producing physiological effects of the thyroid hormone, which are on basal metabolic rate and cellular metabolism.
* The hypothalamus releases trophin releasing hormone (TRH), which acts on the pituitary producing thyroid stimulating hormone

Thyroid hormone synthesis by follicle cells

* Thyroid stimulating hormones act on follicle cells to stimulate the synthesis of NaI transporters, these accumulate iodine inside follicle cells
* Thyroid hormones come from tyrosine residues and tyrosine residues are stored inside follicle cells as thyroglobulin- a bunch of tyrosine together
* Tyrosine globulin and iodine are transported outside the cell to the other side where they meet enzymes TO and TPO (Thyroid Oxidase and Thyroid Peroxidase)

Role or TO and TPO

These enzymes are required to iodinate the tyrosine residues- the tyrosine residues are then stored as thyroglobulin , which is now iodinated- you can get noniodinated (MIT) or diiodinated (DIT). (DIT + DIT = T4) and (DIT + MIT= T3)

T3 and T4 and then released.

Thyroid peroxidase is a target for 2 drugs

These drugs interfere with hormone synthesis.

1) Carbimazole - Prodrug for methimazole which interferes with TPO

2) Propythiouracil - A drug which interferes with TPO

Hypothyroidism

* Most common endocrine disorder
* Most common form is atrophic (autoimmune) hypothyroidism- anti-thyroid antibodies

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Hashimoto thyroiditis

More common in women, this is thyroid gland enlargement, and can either be hyper- or hypo-

Hypothyroidism diagnosis and management

* Serum TSH (thyroid stimulating hormones)- increased levels indicate hypothyroidism- because it means its underactive and not producing enough thyroid hormone. Also suggests not enough TSH to stimulate negative feedback mechanism
* Low free T4

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Treatment of hypothyroidism

Replacement therapy with Levothyroxine

Typically daily maintenance dose 100-150ug

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Hyperthyroidism

Graves disease (stimulating TSH receptor antibodies)-

* Autoimmune disease stimulating TSH receptor antibodies
* Usually accompanied by thyroid eye disease
* Majority exhibit pattern of relapse and remission

Drugs used for hyperthyroidism

* Carbimazole - clinical benefits take 10-20 days but has long half life. Rapid/ partial symptomatic relief can be achieved if co-administered with B-blockers. Between 30-50% of patients complete remission after a single course. FIRST LINE DRUG - 20-40mg daily
* Propythiouracil- 100-200mg 8 hourly- blocks conversion of T3 and T4- so reduces thyroid synthesis, but also inhibits diondinase, so reduces ability to convert to active form.
* Radiodine - contraindicated during pregnancy and breast feeding
* Surgery

Diagnosis of hyperthyroidism

Serum TSH decreased

A raise in T3 or T4 confirms diagnosis

Beta- blockers can be used for symptomatic control in hyperthyroidism

* Propranolol- 40-80mg every 6-8hours- avoid in asthma - used to block cardiovascular symptoms

Major side effects of Carbimazole and propythiouracil

* Carbimazole - jaundice- only occurs in 0.1% of patients
* Propythiouracil- Granulocytosis (deficiency of granulocytes in the blood causing increased vulnerability to infection) only 1 in 1000.

Goitre (thyroid enlargment)

* Present in both hyper and hypo

Effects of glucose of pancreatic cells

* Beta cells → Increase in glucose → Increased insulin secretion → Stores glucose as glycogen in the liver
* Alpha cells → Decrease in glucose → Increased glucagon secretion → Metabolises glycogen to increase glucose levels in the blood.

Type 1 diabetes

* Autoimmune disease, characterised by immune medicated destruction of insulin secreting beta cells of the pancreas
* T cell mediated autoimmune disease, with circulating antibodies to various islet antigens
* Auto-antibodies to insulin (IAA), glutamic acid decarboxylase (GADA), islet cell cytoplasm, zinc transporters and protein tyrosine phosphatase have all been identified

Insulin

* Anabolic hormone
* Insulin activates receptor tyrosine kinase
* Cells are able to carry out a certain amount of glucose metabolism
* Insulin binds to tyrosine kinase, tyrosine residues then become phosphorylated when insulin binds, this activates cellular signalling cascade which activates PI3 kinase, which accounts for the metabolic effects of activating insulin receptors such as - Increase glucose uptake and utilisation, glycogen synthesis and increased glucose formation.

Primary effect of insulin

* One of the primary effects of insulin is to stimulate the expression of glucose transporters in the cell membrane to allow glucose to enter cells

Consequences of insulin resistance

* Fatigue
* Thirst and urination
* Inflammation of the liver
* Hypertension

Nervous system

* Central nervous system- Brain and spinal cord
* Peripheral nervous system- Cranial nerves and spinal nerves (the peripheral nervous system conveys signals between the brain and the tissues)

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Cardiovascular regulation by the ANS

* Control HR
* Contraction and relaxation of smooth muscles in the blood vessels and organ
* Regulation of glandular secretion- exocrine and some endocrine
* Metabolism

Sympathetic and parasympathetic systems

Normally two neuron systems pre and post ganglionic

Pre ganglionic neuron

* Small cell body in CNS
* Small diameter and myelinated
* Synapses at autonomic ganglion
* Preganglionic fibres release ACH
* ACH acts on nicotinic receptors on post ganglionic neruon

Post ganglionic neuron

* Cell body in autonomic ganglion
* Small diameter but unmyelinated
* Synapses are close to the target organ

Adrenal medulla exception

The adrenal medulla is the exception and has a specialised ganglion and the chromaffin cells as specialised post synaptic neurons.

Autonomic ganglion

* Interface between pre and post ganglionic neurons of the autonomic nervous system- in both sympathetic and parasympathetic.
* ACH is the primary transmitter
* Conducts Na+ in and K+ out.
* Generates fast excitatory post synaptic potential

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Physiological consequences of ganglionic nicotinic receptor stimulation.

Sympathetic and parasympathetic post synaptic nerve activation secretes adrenaline from the adrenal medulla. Sympathetic responses effects are complex due to stimulation of the peripheral ganglia- Tachycardia, increase in BP, increased secretions.

Ganglionic blocking drugs

1) Hexamethonium - Non depolarising nicotinic antagonists, no clinical use, historically used as an antihypertensive

2) Local anaesthetics- Sympathetic and ganglionic block, blocks sympathetic mediated pain pathways eg Lidocaine. Co-administered with adrenergic agonists.

What do post synaptic sympathetic fibres release

NORADRENALINE

Exceptions are:

* Renal vessels- Dopamine
* Sweat glands - sympathetic cholinergic

Sympathetic nervous system at target organs

* Most post synaptic sympathetic nerves release noradrenaline
* Cell bodies are in sympathetic ganglion and send axons ending in varicosities.
* Varicosities is where noradrenaline is produced and synthesised- so noradrenaline is synthesised and stored and released at varicosities.

Synthesis of noradrenaline

* Multienzyme synthetic pathway- initial stages are in cytoplasm, final stages of synthesis are on the membrane of the synaptic vesicle
* Precursor molecule is the amino acid L-tyrosine (also precursor molecule for dopamine)
* Final product is noradrenaline, regulates the synthesis via negative feedback process on initial step of synthesis.
* L-Tyrosine (tyrosine hydroxylase)→ DOPA (DOPA carboxylase) → Dopamine (Dopamine B-Hydroxylase) →Noradrenaline (Phenylethanolamine N-methyl transferase) → Adrenaline

Drugs affecting the synthesis of noradrenaline

* Metirosing- Inhibitor of tyrosine hydroxylase - can be used in the treatment of of pheochromocytoma (catecholamine secreting tumours)- can be used prior surgery as you dont want to bring a patient into surgery with a high amount of catecholamines as this will mean an unstable heart rate- so this will stabilise the patient.
* Carbidopa- Inhibits dopa decarboxylase- Used in parkinsons disease to prevent peripheral effects of L-DOPA (high BP and HR).

Regulation of noradrenergic release

1) Depolarisation of nerve endings opens calcium channels

2) Leads to vesicle exocytosis

3) NA is released

4) Release of NA activates presynaptic alpha- 2 receptors that inhibit adenyl cyclase

5) This prevents Ca2+ channels from opening and limits further release of NA- negative feedback mechanism

2 Mechanisms to remove noradrenaline from synaptic cleft

* 70% of noradrenaline will be retaken into the presynaptic neuron, this is achieved by neural epinephrine transporters (NET). Located on presynaptic nerve terminal, actively transports NA back into varicosities- recycles
* Uptake into vesicles via vesicular monoamine transporters (VMAT) - stored into vesicles along with ATP, ATP has opposite drug charge to NA . ATP is co-released with NA as it is a co-transmitter.

NA is not in the cytoplasm as it is very unstable - monoamine oxidase (MAO) will degrade NA- it is a way of protecting it.

* Second way to remove noradrenaline is they can enter into effector cells eg- muscle cells, this is achieved by a transporter known as EMT- extracellular monaime transporter -mechanism transports catecholamines into postsynaptic cell.

What inactivates metabolites in the post synaptic cell

Catechol o-methyl transferase (COMT)

Termination of noradrenergic transmission metabolism

NA is metabolised by either -

* Monamine oxidase
* Found in maninly in neurons, liver and GI
* NA → DOMA

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Drugs inhibiting the release of NA

* Methyldopa (aldomet)- Metabolised to Methyl-NA, false precursor molecule, alpha-2 agonist, peripheral and central effects on blood pressure, sometimes used to treat pregnancy induced hypotension. Also inhibits DOPA decarboxylase . So methyldopa is a medication used for high blood pressure, and one of the preferred treatments for high blood pressure in pregnancy.
* Guanethidine- Substrate for NET (neural epinephrine transporters), and substrate for VMAT (vesicular monoamine transporters)- accumulates in vesicles- stabilising the vesicles, displacing noradrenaline slowly, and the free noradrenaline is metabolised by MAO. Too high of a dose destroys neurons. Overall effect is that it blocks adrenergic neuron.
* Reserpine- Prevents transport of noradrenaline into vesicles, cytoplasmic NA is metabolised by MAO, so vesicular levels fall, this drug is used as an antihypertensive.

Unwanted effects of inhibiting NA synthesis

In general will cause sympathetic effects-

* Hypotension
* Bradycardia
* Digestive disorders
* Nasal congestion
* Sexual dysfunction
* Sedation
* Mood disturbances

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Two receptors for noradrenaline

Alpha- 1 and 2- alpha-2 has negative effects

Beta- 1, 2 and 3- these have positive effects and are coupled with Gs proteins. Gs will stimulate adenyl cyclase.

Alpha-1 is coupled to Gq which will produce activation of phospholipase C

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Selectivity of adrenoreceptors

Adrenoreceptors are relatively unselective and have similar affinity for both adrenaline and NA. However Adrenaline is more potent at B2 and Alpha-2. Whereas NA is more potent at B1 and alpha-1

4 types of receptors and their roles

* Alpha-1= In blood vessels- stimulation causes contraction of blood vessels and so increased blood pressure.
* Alpha-2= Will no produce the release of noradrenaline, so will cause blood vessels to dilate.
* B1- in heart- increased heart contraction
* B2- Highly expressed in bronchioles and trachea- cause dilation.
* B1 and B2 have OPPOSITE effects

Action of B-adrenoreceptors in the heart

If you stimulate NA it will bind to B1, and will increase cyclic AMP, which will activate Ca2+ channels, allowing Ca2+ to enter the cells- causing contraction of cardiac myocyte- this increases contraction, increasing SAN action.

B2 has the opposite effect- causes relaxation.

Agonists of adrenoreceptors

These may be termed sympathetic agonists, adrenergic agonists or sympathomimetic agonists.

Examples are- Adrenaline, noradrenaline, phenylephrine and clodine

Indirectly acting sympathomimetics

* Amphetamines- Substrate for NET and VMAT, prevents NA accumulation in vesicles, inhibits MAO this causes the release of NA from vesicles, increasing cystol NA, increasing NA outflow into synapses.
* Ephedrine and Pseudoephedrine- Increases the amount of NA in synaptic cleft
* Cocaine- Inhibits NET, increases NA in synaptic cleft be inhibiting reuptake

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General antagonists for alpha and beta receptors

* Alpha = Prazosin - in general alpha antagonists cause hypotension, postural hypertension (block of alpha-1), increase cardiac output and cause tachycardia (block of alpha-2- leads to increased sympathetic output)
* Beta= Propanolol - ‘olol’ is a beta blocker

Examples of Alpha antagonists

* Phenoxybenzamine- long lasting covalent binding, also blocks off receptors eg, ACH and histamine.
* Phentolamine- more selective but short acting
* Labetalol and carvediol- mixed alpha and beta agonist

Selective alpha-1 and alpha-2 antagonists

* Alpha-1- cause vasodilation and fall in BP- Examples are **Prazosin,** and **Doxazosin** ( end in ‘azosin’). Relax bladder kneck and prostate capsule- clinically used to treat urinary retention with enlarged prostate.
* Alpha-2 = Yanimbine and synthetic analogue idazokah are experiments. Yanimbine has vascular stimulant effects used to treat male impotence, and reduce BP and many increase fat burn when combined with exercise.

Actions of B-antagonists

* Unexpected anti-hypertensive effects
* In hypertensive arterial pressure drops over several days- reduction in cardiac output, reduction in renin release (important in BP) and in the CNS there is a reduction in sympathetic output. Prevent tremor in skeletal muscle B-receptor (band in target sports).

Unwanted effects of B- antagonists

* Bronchoconstriction ( via B2 antagonists)
* Cardiac failure- but overall generally useful in cardiac failure
* Hypoglycaemia - Glucagon release and glycogenolysis normally stimulated by circulating adrenaline.
* Fatigue due to reduced cardiac output and muscle perfusion during exercise
* Cold extremities- loss of B2- induced dilation of subcutaneous blood vessels
* Erectile dysfunction
* Lucid dreams

Clinical uses of B- antagonists

* cardiovascular- hypertension, angina and cardiac dysthymia
* Other uses- Glaucoma, hyperthyroid disorders, anxiety, tremor, migraine.

3 beta blockers to know

* Propranolol- used in angina, hypertension, cardiac dysthymia, tremor, glaucoma.
* Atenolol - used in angina, hypertension, and dysthymia
* Timolol- Glaucoma- topical

Mixed beta and alpha antagonists

* Labetalol- Hypertension in pregnancy - doesnt cross placenta
* Carvedilol- Heart failure

Calculation for blood pressure

BP = Cardiac output (HR x Stroke vol) X Total peripheral resistance

Blood vessels are composed of 3 things

* Tunica intima- inner surface of smooth endothelium
* Tunica media- middle portion of vessel wall
* Tunica adventitia- outer layer of the blood vessel wall

2 Main pathways in vascular smooth muscle contraction

* Agonist mediated pathway- The stimulus is an agonist which acts for GPCRs (G-Protein coupled receptors). A whole range are expressed in the smooth muscle - they are all coupled to these receptors and result in an increased calcium concentration in smooth muscle, leading to contraction.
* Another pathway is Gai/o receptors- Noradrenaline= alpha 2. Alpha 2 are generally presynaptic and sits on the nerve presynaptic membrane of adrenergic synapses and parasympathetic membrane of adrenergic synapses- negative feedback loop. So stimulation reduces amount of mediator released.
* Another pathway is depolarisation induced pathway- which is controlled by changes in the membrane. This stimulus is activated by L-type voltage gated Ca2+ channels. Electromechanical driven by voltage leading to contraction.

What happens when calcium enters the cell

Calcium interacts with calmodulin, which is a calcium binding molecule, and this stimulates the activation of myosin light chain kinase (MLCK). Due to the activation of this enzyme it will then phosphorylate myosin light chain- the phosphorylation will cause contraction

Phosphorylase dephosphorylates this process leading to relaxation

How does calcium levels increase in the cell initially in agonist induced activation

GPCR activates Gq/11 protein which goes onto activate phospholipase C, which breaks down PIP2 into DAG and IP3.

IP3 will act on own channels sitting in the membrane of sarcoplasmic reticulum within muscle cell leading to Ca2+ entering cell, leading to contraction.

Alternative depolarisation will stimulate calcium influx through L-type VACC

3 factors which determine the contraction of blood vessels

* Increase in cystolic calcium via two parallel pathways via agonist inducted or depolarisation.
* Determined by phosphorylated state of myosin light chain kinase- Phosphorylate MLC causes contraction, dephosphorylation causes relaxation.
* Calcium sensitisation- agonist phosphorylation of CPI-17 an endogenous inhibitor of MLCP

What things cause vasodilation

* Agonists → GPCR
* Adrenaline/ NA → B2
* Prostaglandin I2 → IP
* Adenosine → A2
* Histamine → H2

Hyperpolarisation

Activation of K+ channels- relaxation of blood vessels

Two main vasodilators

* Nitric oxide is an endothelial derived relaxing factor, prostaglandins (PGI2 or prostacyclin) are also endothelial derived relaxing factors.
* Nitric oxide isoforms- neuronal nitric oxide synthase are calcium dependent . Inducible nitric oxide synthase are calcium independent. Endothelial NOS is constiutivly expressed calcium dependent- Vasodilation of blood vessels, reduces platelet aggregation and adhesion.

Two main prostanoids

* IP (receptor)- Ligands are I2 or D2- abundant in cardiovascular system, platelet and neurons- general inhibitory actions in smooth muscle contraction and platelet aggregation.
* TP-Thromboxane A2- abundant in cardiovascular system, platelet and immune cells, general excitatory action- smooth muscle contraction and platelet aggregation.

Overall vasodilating mechanism of action (eNOS)

* Stimuli increases calcium concentration inside the cells.
* Triggers pathway activating nitric oxide synthase- which synthesises nitric oxide.
* Nitric oxide is a gas, and is released towards smooth muscle cells, it then binds and activates guanylyl cyclase.
* This causes vasorelaxation of smooth muscles

Agonist (ACH or bradykinin) → increases Ca2+ levels → Binds to calmodulin → Activates NOS → converts arginine into citrulline + NO → activates guanylyl cyclase → converts GTP into CGMP leading to RELAXATION.

Drugs targeting eNOS and NO signalling pathway

* Competitive NOS inhibitor (endogenous)- similar to arginine, negative regulator of nitric oxide activity. Asymmetric dimethylarginine (ADMA)
* ADMA is an inhibitor of endothelial nitric oxide synthase by competing with substrate L-Arginine, thus impairing nitric oxide production

Prostacyclin and prostanoids

* Cyclo-oxygenase- COX-1 - constitutive, COX-2 -inducible (except in kidney)
* Synthesis of eicosanoids - cyclo-oxygenase and prostanoids- use arachidonate acid as substrate for synthesis or various prostanoids.
* Prostaglandin I2- Vasodilators, stop platelet aggregation
* Prostaglandin E2- Vasodilators, hyperalgesics
* Prostaglandin F2a- Inhibits platelet aggregation
* Thromboxane A2- In platelet and important vasoconstrictor .
* PROSTANOIDS REGULATE INFLAMMATORY RESPONSE!

Synthesis of prostanoids

Membrane phospholipids (Ca2+ Cyst) → Arachidonic acid (COX-1) → PGG2 → PGH2 → either PGI2 (in endothelial cells) OR TXA2 (in platelets).

Syndrome

A group of symptoms which consistently occur together or a condition characterised by a set of symptoms.

Metabolic syndrome

A group of conditions that together raise your risk of coronary heart disease, diabetes and stroke. The association of metabolic syndrome and diabetes is very high

Symptoms that will be characterised by metabolic syndrome

* Insulin resistance
* Elevated fasting blood glucose
* Hypertension
* Dyslipidaemia - elevated serum triglycerides, reduced high density lipoprotein cholesterol, elevated small density particles.

Other symptoms of metabolic syndrome

* Elevated serum fibrinogen and plasminogen activator inhibitor (PAI)- increased procoagulant.
* Endothelial dysfunction- impaired vessel relaxation, thrombosis.
* Systemic inflammation- elevated c- reactive proteins.
* Oxidant stress
* Inflamed adipose tissue- monocyte infiltration
* Albuminuria- sign of kidney disease, means you have too much albumin in your urine.
* Decreased adiponectin- protein hormone which is involved in the regulation of glucose levels as well as fatty acid breakdown.
* Hyperpigmentation of skin folds

Risk factors to metabolic syndrome

* Visceral obesity- waist measurement correlates with insulin resistance
* Older age increases chance
* Weight
* Race
* Non- alcoholic fatty liver
* History of gestational diabetes
* Polycystic ovary syndrome

Where you fat accumulates effects the risk of metabolic syndrome

* Subcutaneous fat = Doesn’t induce metabolic syndrome.
* Stomach fat= Increases chance of metabolic syndrome
* Deposit of fat around liver, heart and muscles cause metabolic syndrome
* Smoking, genes and stress can induce metabolic syndrome.

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How does smoking increase chance of metabolic syndrome

Nicotine activates the sympathetic system (nicotine will activate nicotinic receptors in sympathetic ganglia and adrenal medulla).

Nicotine will cause constriction of blood vessels and so will increase BP

Insulin resistance

Decreased HDL (good cholesterol), increased triglycerides.

Elevated cortisol

Diagnosis of metabolic syndrome

* Waste >94cm men, >80cm women
* Elevated triglycerides in serum
* Reduced density of HDL
* Hypertension >140/90mmHg
* Elevated fasting blood glucose
* Thrombosis
* Inflammation

ANY OF THESE 3 AND YOU HAVE METABOLIC SYNDROME!

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2 Main risk factors of metabolic syndrome

* Cardiovascular disease
* Type 2 diabetes

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Adipocytes

Major energy storage site in your body and have endocrine functions- essential part in understanding metabolic homeostasis:

* Brown fat: Key role in thermogenesis, levels fall dramatically with age, energy expenditure.
* White fat: Energy storage
* ‘Brite’ : Mix of white and brown fat, potentially important for balancing storage, and expenditure, energy homeostasis.

Adipocytes secrete adipokines (hormones)

* Leptin
* Adiponectin
* TNF
* IL-6
* Resistin

Leptin

A hormone secreted from the adipose tissue.

* High levels of leptin- body stops eating as is satisfied
* Increased in obesity, but resistance to its action
* Increased ratio of CSF to serum leptin in obesity
* Metraleptin- synthetic analogue to lectin, this will reduce a persons weight and they will stop eating as much.

Adiponectin

* Secreted by adipose tissue- but decreased in obesity
* Low plasma adiponectin is a risk factor for metabolic syndrome - as low levels will stop fat in adipose tissue from being used- so reduction in breakdown of fats.
* Decrease hepatic glucose production
* Increased insulin sensitivity- increased glucose uptake by energy requiring cells. Increased energy expenditure.

HOWEVER IF A PATIENT HAS REDUCED LEVELS OF ADIPONECTIN THIS WILL NOT OCCUR

Thiazolidinediones (Glitizone drugs)

Drugs used to enhance insulin sensitivity

Vascular dysfunction in metabolic syndrome

* Decreased nitric oxide signalling- nitric oxide is a vasodilator and acts on muscle cells of your blood vessels.
* Also when you have metabolic syndrome you produce oxidative stress, oxidative stress with nitric oxide can produce damage.
* Increase of triglyceridaemia- This will start to accumulate inside the blood vessels- this will make a passage through vessels and will increase blood pressure, and you are more at risk to have a stroke.

Nitric oxide is very important in regulating the blood pressure

It is a vasodilator produced by endothelial cells and some nerve cells by nitric oxide synthase (NOS).

Produced from L-arginine

When you have metabolic syndrome you have increased arginase, producing ornithine and urea, so reduced nitric oxide and increased urea.

Conversion of arginine into nitric oxide

* L-arginine (NOS) → L-citrulline → Nitric oxide (Vasodilator)
* L-arginine (arginase) → Ornithine and urea

What happens in metabolic syndrome with oxidative stress

In metabolic syndrome you have more oxidative stress, and with more oxidative stress your mitochondria is not working how it should be, and so they start to produce O2. (free radical).

NO. + O2. → DONO. (peroxynitrile - doesn’t produce muscle relaxation).

When you have high fat and high fructose you are more likely to produce oxidative stress, which will produce peroxynitrile.

Key points: Metabolic syndrome is associated with-

* Insulin resistance
* Oxidative stress
* Lipid peroxidation
* Decreased nitric oxide
* Decreased vasorelaxation

Metabolic syndrome therapies

* Exercise- helps weight loss, releases hormone irisin which helps the body to respond to insulin
* Bariatric surgery (gastric bypass) - fastest way to loose weight
* Diet- microbiota interaction drives obesity and so metabolic syndrome.
* Smoking stopping
* Pharmacology- cholesterol lowering drugs and antihypertensive

Functions of the kidney

* Regulation of extracellular (bodily) fluids.
* Maintenance of ion balance and pH
* Excretion of foreign substances
* Renin secretion and activation of the RAAS- Renin angiotensin aldosterone system- critical regulator of blood volume, electrolyte balance and systemic vascular resistance. While baroreceptors respond to short term decrease in arterial pressure the RAAS is responsible for acute and chronic alterations.