TOPIC C: Autonomic control of energy and metabolism Flashcards
Which type of receptors do NA and A target?
- GPCR (G protein coupled receptors)
What is the main role of NA in context of metabolism and energy?
- Provide energy, alertness, concentration (focus)
Is NA a neurotransmitter or hormone?
- Neurotransmitter
Is A a neurotransmitter or hormone?
- Hormone
What does the speed of the response depend on in cells?
- The receptor type (class)
What do receptors respond to?
- Endogenous substances in boy (activated receptors)
What two roles can drugs have on receptors?
- ADD to level of receptor activation (enhanced level of activation)
- PREVENT receptor activation (repressed level of receptor activation)
What is the main NT for the sympathetic ns?
- NA
Which two types of receptors can be affected with NA?-
- Alpha adrenoceptros
- Beta adrenoceptors
How is NA synthesied and where?
- Synthesised in nerve endings
- enzymes are transported down TO nerve endings
Does NA have to be stored in vesicles?
- YES! Otherwise it will break down.
What are the steps of NA synthesis?
- Tyrosine enters nerve ending via PRECURSOR TRANSPORTER
- Tyrosine —-> DOPA via TYROSINE HYDROXYLASE
- DOPA— Dopamine via DOPA DECARBOXYLASE
- Dopamine transported into synaptic storage vesicle via VMAT (Vesicular Monoamine transport)
- Dopamine–> NA via DOPAMINE BETA HYDROXYLASE
- Action potential opens Ca2+ channels to allow synaptic vesicles to move to nerve terminal and NA is exported.
Which two ways is NA terminated (Action)?
- REUPTAKE into nerves (MOST IMPORTANT FACTOR) -Like to reuse NA
- Enzymatic breakdown (via MAO)–> MAO found in mito.
Which well known drug blocks reuptake of NA?
- Cocaine (increased and prolonged effects of SNS)
Where is Adrenaline synthesised and released into?
- Synthesized in the adrenal medulla and released into bloodstream where it is circulating hormone
What is the precursor for adrenaline and enzyme that converts it?
- NA is precursor for A
- PNMT is enzyme that converts NA–> A in adrenal medulla
Which adrenoceptor increases force and HR, Slows/relaxes gut activityand relaxes/dilates smooth muscle to INCREASE BLOOD FLOW?
-BETA adrenergic receptors
Why can our tissues have different effects despite the same beta adenoceptors?
-It depends on the type of enzymes that are coupled to G protein receptor -different enzymes coupling to receptor will cause different effects
For beta receptors, which protein is phosphorylated and what is the response in the LIVER?
- Glyogen phosphorylase is protein (enzyme) —> glycogenolysis—-> increased glucose—> energy (glycolysis)
For beta receptors, which protein is phosphorylated and what is the response in the CARDIAC MUSCLE (HEART)?
- Troponin/phosphoholamban is protein
- Leads to INCREASED HR and INCREASED force of contraction
For beta receptors, which protein is phosphorylated and what is the response in the SMOOTH MUSCLE?
- Myosin light chain is protein
- Leads to relaxation
Are there multiple Beta receptors?
- YES!
Where are Beta1 receptors found?
- In cardiac muscle (increased force of contraction and HR)
- Liver
- Skeletal muscle (blood vessels)
Where are Beta 2 receptors found?
- Lungs (bronchiole smooth muscle)
- Blood vessel beds in skeletal muscle
- Leads to relaxation
Where are Beta 3 receptors found?
- Fat (adipose)
What are 4 things the sympathetic nervous system does in exercsie?
- Liver releases glucose
- Heart pumps faster
- Breathing fast
- Oxygen needed for muscles
In exercise; i. what effect, ii: which receptor iii. Does an increase or decrease result from beta adrenoreceptors in:
LIVER?
i. Glycogenolysis effect
ii. Via Beta 1 receptor
iii. Leads to an INCREASE in activity of adrenoceptors
In exercise; i. what effect, ii: which receptor iii. Does an increase or decrease result from beta adrenoreceptors in:
SKELETAL MUSCLE?
i. Glycogenolysis effect via Beta 1
Glucose uptake via beta2
thermogenesis via beta 3
- acts to INCREASE activity
In exercise; i. what effect, ii: which receptor iii. Does an increase or decrease result from beta adrenoreceptors in:
WAT (white adipose tissue)?
- Lipolysis effect
- Via beta 3 receptors
- Acts to INCREASE response
What does BAT do (Brown Adipose tissue)?
- Thermogenesis (non shivering)
- Via B3 receptors to increase activity
What do Adrenaline and NA encourage (metabolism terms)
- Encourages glycogen and fat to form glucose and FAs–> GNG–> energy
What is the Beta `1 receptors effect on metabolism? (which tissues is it in and what does it cause)
- LIVER-> stimulates glycogenolysis
- Glycogen phosphorylase ACTIVATED and glycogen synthase INHIBITED
- SKELETAL MUSCLE: Stimulates glycogenolysis
- Stimulates glucose uptake into muscle cells INCDEPENDENT of insulin
Do adrenoceptors affect BOTH brown and white adipose tissue?
- YES
What are WATs mainly used for?
- Energy storage
What are BATs mainly used for?
- Specialised for heat production
Are FAs from WAT or BAT released during fasting?
- WAT
What are the characteristics of WAT?
- Single large lipid droplet
- FEW mitochondria
- Excess energy stored as triglycerides
- FAs released during fasting
- Activated by circulating adrenaline
- Innervation..not sure
What are the characteristics of BAT?
- MULTIPLE small lipid droplets
- LOTS of mitochondria
- Densly vascularised
- Innnervated by sympathetic nerves
Where is white fat found?
- Where fat people have it
Where is brown fat found?
- Suprarenal
- Paravertebral
- Paraaortic
- Supraclavicular
What activates brown adipose tissue?
- Cold temperature
Typically, does a lean person have more BAT activated than white compared to a fat person?
- YES
What allows for heat generation in brown fat?
- Mitochondria have UCP-1 (uncoupling protein 1)
What is the pathway for Beta3 adrenoceptor activation in BAT?
- Final activation of lipase
- GPCR/Beta3 activation of adenylate cyclase –> cAMP–> PKA + Phosphorylation and activation of lipase –> triglycerides –> free FAs
Which process produces long chain FAs which then upregulate the expression of UCP-1 (in oxidative phosphorylation)?
- The Beta oxidation process
What are possible treatments for obesity based on BAT and Beta 3 adrenoceptors?
- Cold stimulation + NA= best inducer of brown fat
- Possible use of Beta3 agonist in obesity –> increases lipolysis and energy expenditure
Can beta3 agonist secretion turn white fat cells into brown fat cells?
- YES! (sort of more of a beige fat adipose tissue –> produces heat)
What does a Beta1 adrenoceptor antagonist do (betablocker)?
- REDUCES exercise tolerance (not a lot of increased blood flow vessels)
- LOWERS BP and CO (Only affects the active state, not if you are resting)
Is bronchiole smooth muscle innervated by the sympathetic nervous system?
- NONONO!!!
- Beta2 receptors in lungs rely on circulating ADRENALINE (hormone) to activate them
What effect do Beta2 receptors have when stimulated in the lungs?
- In the lungs ) they cause BRONCHODILATION /mediate it
What type of drug would you give to someone with an asthma attack?
- Beta 2 agonist (to dilate the airways)
What will the Beta2 antagonist do in asthmatics?
- Brocnhospasm (worsening of airway) `
Are there Beta2 receptors in muscle (like actual muscle, not blood vessels in muscle) ?
- YES!!
- A or NA affects the speed of twitchign of different faet twitch or slow twitch fibres –> leads to muscle tremor
- Increases the amount of fast twitch fibres.
- Beta2 receptor agonist
e. g. Salbutamol (asthma drug) -> muscle tremor as side effect
What is the effect of beta blockers (beta2 antagonists) in the skeletal muscle?
- Removes the muscle tremor (nervousness) –> sympathetic response
What is the effect of a beta2 agonist in skeletal muscle?
- INCREASES the twitch tension of fast muscle fibres and DECREASES the tension of slow twitch muscle fibres
- INCREASES the INSTABILITY of reflex control of muscle length (temor)
What are 4 general effects of a beta adrenoreceptor antagonist?
- Steadiness of voluntary muscle
- Fatigue (blocking of B1 receptors in heart)
- Cold extremities (blocking Beta2 vasodilator in blood vessels
- Narrowing of bronchi (poor exercise tolerance)
What are 5 general effects of a Beta adrenoreceptor agonist?
- INCREASE in HR and FORCE –> increase in exercise capacity
- Activation of Beta1 receptors in heart –> increase in cardiac function/capacity
- INCREASE in blood flow to voluntary muscles –> activation of vasodilator beta2 receptors on BLOOD VESSELS
- Widening of bronchi–> increases exercise tolerance and O2 delivery (b2 on lung)
- Increases muscle tremor
What type of drug is clenbuterol?
- Beta2 receptor agonist
- Bronchodilator
- Increases oxygen uptake
- Skeletal muscle fast and slow twitch
What is pharmacokinetics and which 4 factors does pharmacokinetics include?
How body INTERACTS with drug Absorption Distribution Metabolism Excretion = ADME
What is pharmacodynamics and which 3 factors does this include?
Binding to target tissue (receptor)
Efficacy (ability of drug to get its job done well)
Affinity
Do drugs have to have a good balance of lipid and water solubility?
- YES!
- Because most of body is WATER BUT also has to get into cells
What do drugs have to get into in order to rapidly spread around body?
into SYSTEMATIC CIRCUIT
What are the 4 main routes of administration of drugs?
- Injections
- Sublingual
- Rectal
- Oral
What are the details of injections for drug routes?
- goes into the SYSTEMIC circuit
- have a RAPID onset , especially IV
What are the details of a drug given sublingually and where does it go directly to, also why is this type of administration good (what does it avoid) ?
- goes directly to VENA CAVA
- Good because it avoids the stomach acids which contains enzymes that can break drug down
e. g drug: Nitroglycerin
What is the pathway for the oral route of drug administration?
- needs to go through stomach/small intestine (absorbed)–> then into SYSTEMIC CIRCULATION (takes longer)
Where are the final targets for drugs?
- SYSTEMIC CIRCULATION and plasma (levels in plasma depend)
- Needs to access all body organs/cells (mostly)
To gain access to all organs and most cells what must the drug be like?
- Must be LIPID SOLUBLE to pass through all cell layers BUT must have some H2O property to be in the SYSTEMIC CIRCULATION
Where will drugs remain if they are inhaled?
- Only in the lungs
What is a key property that drugs must have to leave the body?
- Water soluble (hydrophillic)
What does the liver do to metabolites in terms of excreting them?
- Makes metabolites that are more water soluble for EXCRETION
Do drugs move across ALL body compartments?
- YES! Must be in equilibrium…e..g if drug is removed from plasma drug will come out of cell to equalize
What happens when you are put under a general anaesthetic?
- Have to get injection first –> thiopentone (induction anaethetic SHORT ACTING barbituate (10-20 secs) -has fast access to brain –> unconsciousness
- then a tube is put into trachea and GAS put in that maintains the unconsciousness
Why does thiopentone have fast access to the brain and only lasts for a short amount of time?
- Because it is LIPID SOLUBLE
- Will quickly leave bloood –> BRAIN –> muslce –> fat
IF a drug is already water soluble, does it get metabolsied as much?
- NO
- just excreted –> unchanged
Where are the products formed to be more lipid soluble?-
- In LIVER –> byproducts –> biotransformed –> excreted in urine
Can liver break down drug into toxic metabolites?
- YES
- This is why drugs need to be tested
What does metabolism in the liver occur via?
- Liver microsomal enzymes (also happens in gut and kidney)
Are all drugs active when entering body?
NO! Some are pro-drugs
- Must be activated by metabolism
How are drugs excreted?
- Filtered by KIDNEY (urine)
- Faesces, bile ,lungs(expelled air)
Which 3 ways can drugs be metabolised and excreted in liver?
- Drug–> Phase I–> Phase II–> Excretion
- Drug—————-> Phase II–> Excretion
- Drug ——————————-> Excretion (no change, very polar drug)
What occurs in phase I of liver metabolism of drug and which class of enzymes is contained here?
Oxidation
Reduction
Hydrolysis
- All act to produce a more water soluble metabolite
- Contain CYTOCHROME P450 ENZYMES (liver microsomal enzymes)
What occurs in phase II of liver metabolism of drug?
- Metabolite combined with endogenous molecule e.g. glucuronide acetyl –> produces an EVEN MORE water soluble molecule
- Contains UDP glycuronysl transferase enzyme
What is the role of cytochrome p-450 (CYP) enzymes?
- Can degrade endogenous substances and has role in biosynthesis (steroids lipids vitamins)
- Metabolises xenobiotics
Are there lots of different P-450 family enzymes?
- YES!
Which families are most of the metabolising drug enzymes found in?
- CYP 1, 2, 3 gene families
What is the substrate specificity like for the CYP 1, 2,3 families?
- BROAD substrate specificity (2 or more enzymes can catalyse the same reaction)
What does he CYP3A4 enzyme belong to and where is it?
- Belongs to family 3, subtype A,4
- In GI tract –> poor oral availability of drugs
Which 6 factors can change the level and activity of Cyp enzymes?
- Nutrition
- Smoking
- Alcohol
- DRUGS
- Environment
- Genetic poylmorphisms (e.g. African)
How come you shouldn’t eat grapefruit with some drugs such as statins?
- Grapefruit can block enzyme action in small intestine
- Grapefruit is an INHIBITOR of the enzyme that destroys the drug
- INCREASES amount of medicine absorbed in body and thus a risk of overdose
- BOTH DRUG + GRAPEFRUIT COMPETE AND INTERACT WITH CYP450 ENZYME
What do enzyme inducers cause?
- Enzyme inducers cause the drug to be matabolized quickly and fall below the normal range
Which CYP enzyme do chargrilled food induce?-
CYP1A enzyme
Which enzyme does grapefruit juice inhibit?
- CYP3A
Which enzyme in general does liver diseases such as cirrhosis, cancer, hemochromatosis, fatty liver inhibit?
- P450 activity impaired
- Cardiac disease slows blood flow to liver which decreases metabolism
Can metabolism of drugs lead to toxic metabolites?
- YES e.g. paracetamol
What toxic intermediate can paracetamol metabolism lead to if too much is ingested?
- NAPQ1 (n-acetyl-p-benzoquinoneimine)
- Normally in low levels then CONJUGATED for excretion
How is NAPQ1 normally detoxified?
- By reacting with glutathione
Which two ways can lead to paracetamol toxicity?
- Glutathione is DEPLETED OR normal conjugation is prevented (too much panadol)
Effects of NO GLUTATHIONE (paracetamol toxicity)`
- NAPQ1 reacts with tiol groups on liver cell membrane –> hepatotoxicity–> Liver failure (35% liver failure from paracetamol poisoning)
