Pharmacology Flashcards
What is the hypothalamo-pituitary axis?
The hypothalamus is part of the brain that monitors many aspects of the state of the body systems, integrating a large amount of information from many sensory pathways.
With regards to the endocrine system it is recognised as being closely linked with the pituitary gland, a small gland hanging from underneath the hypothalamus.
There are two parts to the pituitary gland, an anterior part (the adenohypophysis) and a posterior part (the neurohypophysis).
What can pituitary disease cause?
- Over- or underactivity of each of the hypothalamic-pituitary-end-organ axes
- Benign pituitary tumours (adenomas) are the most common cause (90%)
- Vision loss due to compression of the optic chiasm is a common comorbidity
What is Hypopituitarism?
- Diminished hormone secretion by the pituitary gland, causing dwarfism in children and premature ageing in adults
- Rare
- Managed by replacement therapy with the appropriate hormone
Explain different types of thyroid hormones
- Triiodothyroxine (T3) and Thyroxine (T4: 90% of total)
- T4 regarded as a prohormone for T3
: has a lower affinity
: T4 is convereted to T3 in peripheral tissues by Type I and Type II deiodinases
: Half-life of T3 (1day) is shorter than T4 (6days) - Thyroid hormones circulate bound to plasma proteins (>99%)
: thyroxine-binding globulin (TBG), transthyretin (TTR) and thyroxine binding prealbumin - Thyroid hormones regulate BMR and enhance actions of cathecholamines
What is Pendrin and how does it contribute to thyroid hormone synthesis?
- Pendrin is a sodium-independent chloride/iodide transporter and acts as an antiporter anion exchanger protein
- Pendrin presents at the apical (luminal) membrane of follicular cells in the thyroid gland, where it transports iodide from cytoplasm to follicle lumen. Its activity is necessary for production of thyroid hormone
What are Thyroid Oxidase (TO) and Thyroid peroxidase (TPO) responble of?
- iodination of tyrosyl residues in TG (thyroglobulin) and coupling reactions
What are the physiological effects of thyroid hormone in the following targets?
- Cardiovascular system
- Bone
- Respiratory system
- GI system
- Blood
- Neuromuscular function
- Carbohydrate metabolism
- Lipid metabolism
- Sympathetic nervous system
- Cardiovascular system
- Increases HR and Cardiac Output - Bone
- Increases bone turnover and resorption - Respiratory system
- Maintains normal hypoxic and hypercapnic drive in respiratory centre - GI system
- Increases gut motility - Blood
- Increases RBC 2, 3-BPG faciliating oxygen release to tissues - Neuromuscular function
- Increases speed of muscle contraction and relaxation and muscle protein turnover - Carbohydrate metabolism
- Increases hepatic gluconeogenesis/ glycolysis and intestinal glucose absorption - Lipid metabolism
- Increases lipolysis and cholesterol synthesis and degradation - Sympathetic nervous system
- Increases catecholamine sensitivity and b-adrenergic receptor numbers in heart, skeletal muscle, adpose cells and lymphocytes
- Decreases cardiac a-adrenergic receptors
What is Hypothyroidism?
- Abnormally low activity of the thyroid gland, resulting in retardation of growth and mental development in children and adults.
- One of the most common endocrine disorders
- Usually primary (disease of thyroid) but can be secondary (decreased TSH)
- Most common form is atrophic (autoimmune) hypothyrodism
What are clinical features of hypothyroidism?
- Tiredness
- Weight gain
- Cold intolerance
- Goitre (swelling in neck)
- Mental Slowness
- Dry skin and hair
- Bradycardia
- Slow-relaxing reflexes
What is diagnosis and management of Hypothyroidism
Diagnosis
- Serum TSH ( increased level confirms primary hypothyroidism): low free T4 confirms the diagnosis and excludes TSH deficiency (secondary hypothyroidism)
Management- Replacement therapy with levothyroxine (lifelong)
What is Hyperthyroidism?
- Over-activity of the thyroid gland, resulting in a rapid heartbeat and an increased rate of metabolism
What is diagnosis and management of Hyperthyroidism
Diagnosis
- Serum TSH (↓< 0.05 mU/L): raised T3 (more sensitive) or T4 confirms the diagnosis
- TSHR-Ab usually present (80%) but not routinely measured
- Thyroid peroxidate (TPO) and thyroglobulin antibodies usually present
Management
- Antithyroid drugs e.g Carbimazole
- Radioiodine
- Surgery
What are the hormones secreted by endocrine pancreas?
Beta cells
- produce and release insulin
- stimulates glucose utilisation and uptake
Alpha-cells
- produce and release glucagon
- increases breakdown of glycogen and glucose release
What features does insulin have regarding plasma levels?
- Decrease glucose
- Decrease amino acids
- Decrease FFAs
- is Anabolic
What features does glucagon have regarding plasma levels?
- Increases glucose
- Increase ketones
- is Catabolic
What are the issues associated with untreated high BP.
Atherosclerosis (Endothelial damage)
Internal organ damage (Kidney, eyes and nerves..)
Strain on heart Pulmonary oedema (left ventricular hypertrophy) Peripheral oedema (congestive heart failure)
Give the cardiovascular risk factors.
Smoking
High salt intake
Systemic hypertension
Alcohol (greater than 21 units in men, and greater than 14 in women)
Lack of exercise
Obesity
Dyslipidaemia
Diabetes
Genetics
Age
Lifestyle
What are some causes of systemic hypertension.
Majority of the time, there is no apparent cause…
Endocrine gland disorders
Kidney disease
Drug induced
White-coat hypertension
Describe when stage 1, 2, and 3 hypertension is diagnosed.
Stage 1 = greater or equal to 140/90mmHg in the clinic, and greater than 135/85mmHg when measured at home
Stage 2 = greater or equal to 160/100mmHg in the clinic, and greater than 150/95mmH when measured at home
Stage 3 = greater or equal to 180/110
When is hypertension treated?
Stage 1 hypertension = lifestyle changes
Stage 1 + one of the following... Target organ damage Established CVD Renal disease Diabetes 10-year CV risk greater or equal to 20%
Stages 2 and 3
What are the different types of anti-hypertensives available.
Drugs that act on RAAS (Renin angiotensin aldosterone system)
- ACEi
- ARBs
- Renin inhibitors
- Aldosterone antagonists
Kidneys
-Diuretics
Directly acting vasodilators
- CCB
- Potassium channel openers
- others..
Drugs that act on the sympathetic nervous system
- Beta blockers
- Alpha 1 adrenoceptor antagonists (targets blood vessels)
What is the first line treatment of hypertension.
Under the age of 55
-ACEi or angiotensin II receptor blocker (ARB)
Over aged 55 or black person of african or caribbean family origin (any age)
-CCB
How is the secretion of renin regulated. What is the purpose of it.
Drop in blood pressure Sympathetic stimulation of beta 1 adrenaline receptors Low blood volume Increases in PGE2/PGI2 Loss of NA+
Renin is released from the juxtaglomerular cells in the kidney and rapidly enters the bloodstream
Cleaves angiotensinogen (inactive) which is produced in the liver and is constantly circulating the blood –> Angiotensin I (inactive)
Angiotensin converting enzyme is abundantly present on endothelial cells surfaces to produce angiotensin II,
Describe how angiotensin II elicits its effects.
Angiotensin II binds to AT1 receptors (Angiotensin II type 1 receptors)
This causes 3 main things..
Vascular growth
- Hyperplasia (increase in number of cells)
- Hypertrophy (increase in size of cells)
Vasoconstriction
-Directly acts on blood vessels and causes sympathetic NA release
Salt retention
- Increases aldosterone
- Increases Na+ reabsorption
How do ACEi work?
What is a common side effect?
ACEi prevent angiotensin II from being produced from angiotensin I – via inhibition of the angiotensin converting enzyme.
This reduces vasoconstriction and reduce the amount of aldosterone produced – less salt is retained, and so there is less water entering the blood to increase the blood pressure via osmosis.
ACE breaks down bradykinin. The inhibition of it therefore results in increased bradykinin levels.
Increased bradykinin increases the vasodilating effects, but also causes a cough.
–pril drugs
How do ARBs work?
Angiotensin receptor blockers prevent angiotensin II from binding to AT1 receptors. This, like ACEi, reduce the levels of aldosterone and vasoconstriction.
–> reduced blood pressure
However, because ARBs are specific to AT1 receptors, this does not block the breakdown of bradykinin from ACE.
Hence, angioedema and coughs are prevented
–sartan drugs
What is the triple whammy effect with respect to the use of NSAIDs, ACEi and diuretic.
Dangerously low GFR and potential for renal failure.
The blood volume is decreased due to the diuretic. This causes the GFR to decrease. RAAS is stimulated in order to increase the blood volume and hence increase the GFR.
However, ACEi impairs the function of RAAS. This prevents effective constriction of the efferent arterioles resulting in a greater reduction of the GFR.
The afferent arteriole cannot relax more due to the NSAID blocking COX-2. Further reducing GFR.
–>Renal failure?
What are the common side effects of ACEi
- Hypotension
- Taste disturbances (Captopril)
- Dry cough
- Angioedema
- Hyperkalaemia (reduced excretion of potassium due to aldosterone reduction)
- Reversible renal failure in patients (reversed if ACEi is stopped)
What is Type 1 diabetes mellitus?
- Body unable to produce any insulin
- Usually appears in childhood and before the age of 40
- Sudden onset
- Accounts for between 5-15% of all people with diabetes
What are the symptoms of T1DM?
- Increased thirst
- Increased urination
- Weight loss
- Fatigue
- Nausea, Vomitting
- Coma
- Patients often diagnosed in an emergency setting as symptoms develop over a short period of time
What type of disease is T1DM?
- Autoimmune disease
- Characterised by immune-mediated destruction of the insulin-secreting beta-cells of the pancreas
- Auto-antibodies to insulin (IAA), glutamic acid decarboxylase (GADA), islet cell cytoplasm, zinc transporter and protein tyrosine phosphate have all been identified
What causes T1DM?
- Genetic risk factors (HLA)
- Environmental factors
e. g viral infection
What are the risk and benefits of the islet cell transplantation for T1DM?
Risk
- Transplantation surgery risk
- Immunosuppresants drugs side effects
- Need 2-3x transplants
Benefits
- Live without insulin injections
- Improved blood glucose control
What is Type 2 Diabetes Mellitus?
- Body cannot produce enough insulin OR the body cannot respond to insulin = ‘insulin resistance’
- Used to appear in people >40yrs of age but younger poeple are increasingly diagnosed
- Can go undiagnosed for a long time
- Accounts for between 85-95% of all patients with diabetes
What are the symptoms of T2DM?
- Increased thirst
- Increased urination
- Increased appetite
- Fatigue
- Blurred vision
- Slow-healing infections
- Slower onset than T1DM, symptoms develop over a long period of time and may go unnoticed
What are the risk factors of T2DM?
- Parent, brother, sister with diabetes
- Obesity
- Age greater than 45 yrs
- Some ethnic groups
- Gestational diabetes or delivery a baby >9lbs
- High blood pressure
- High cholesterol level
what is Gestational diabetes?
- Associated with pregnancy and usually transient
- Body cannot product enough insulin
- Serious risk to mother and baby
What testings are there for diabetes?
- Glycosylated haemoglobin (HbA1c)
- when glucose attaches to proteins they become glycated
- measures glycated haemogloblin - Fasting plasma glucose test (FPG)
- Fast for 8h, blood sample taken - Oral glucose tolerance test (OGTT)
- Fast for 8h, blood sample taken, drink sugary drink, 2h later blood sample taken - Urine analysis
- Glycosuria
- Ketone bodies
What are the metabolic complications of diabetes?
- Hypoglycaemia/Hyperglycaemia
- Diabetic ketoacidosis (DKA)
- Hyperosmolar hyperglycaemic state (HHS)
What are the microvasuclar complications of diabetes?
- Damage to small blood vessels (arterioles, capillaries, venules)
: retina (retinopathy)
: kidney (nephropathy)
: nerves (neuropathy)
What are the macrovascular complications of diabetes?
- Damage to larger arteries
: brain (stroke)
: heart (coronary heart disease)
: legs & feet (peripheral vascular disease)
How are hypoglycaemia and hyperglycaemia induced?
Hypoglycaemia
- not eating enough carbohydrates
- taking too much insulin
- exercising too much
Hyperglycaemia
- eating too much sugary food
- drinking alcohol
- not taking medication
- not exercising
How is diabetic ketoacidosis in T1DM induced?
- when glucose not available for energy generation
- body uses fat where ketones are a by-product of fat metabolism, lowers plasma pH
How is hyperosmolar hyperglycaemic state (HSS) induced?
- High blood sugar results in high osmolarity without significant ketoacidosis
How does diabetic retinopathy occur? What are the stages?
Background retinopathy
- Tiny bulges develop in the blood vessels, which may bleed slightly but don’t usually affect vision
Pre-proliferative retinopathy
- More severe and widespread changes affect the blood vessels, including more significant bleeding in the eye
Proliferative retinopathy
- Scar tissue and new blood vessels, which are weak and bleed easily, develop on the retina
How does diabetic nephropathy occur?
- Damage to the capillaries in the glomerulus leads to breakdown of filtration barrier and more protein collected in the urine
- Exacerbated by hypertension, a common prioblem in DM
- Develops very slowly and over time, decline in kidney function leads to chronic kidney failure
How does diabetic neuropathy occur?
- Peripheral nerve dysfunction
- Capillary damage can lead to nerve damage and loss of sensation
- Loss of sensation and circulation problems leads to increased risk of infection, ulcer and gangrene
What is the major mechanism underlying macrovascular complications in diabetes mellitus?
Atherosclerosis
- results from chronic inflammation and injury to the arterial wall in the peripheral or coronary vascular system
Give examples of cardiovascular regulation by the ANS
- Control of heart rate
- Contraction & relaxation of smooth muscle in blood vessels & organs
- Regulation of glandular secretion
- Metabolism
Why are drugs that affect RAAS not used in specific patient groups.
Elderly patients’ RAAS system is less effective. (55 yrs+)
Patients of african/caribbean origin have a lower activity of RAAS
There is potential for teratogenic effects in pregnant women.
How are CCB effective in treatment of hypertension.
They block L-type voltage gated ion channels – reduces calcium entering the smooth muscle cells.
- > Causing arterial dilation and venodilation
- > Decrease in TPR & cardiac after load and reduces venous pressure and cardiac preload respectively.
Good alternate treatment in the elderly, pregnant and caribbean/african population.
-dipine drugs
What are the common side effects associated with CCB
Postural hypotension Tachycardia Hypotension Ankle oedema Headaches and flushes Myocardial ischaemia Constipation AV block, bradycarida Negative inotropic effect -- do not use the drug in heart failure
How can potassium channel activators be used in the treatment of hypertension.
ATP-sensitive potassium channels are activated in the vascular smooth muscles.
This causes membrane hyperpolarisation
L-type voltage gated calcium channels are closed
There is less calcium influx
Vasodilation occurs
Give an example of a potassium channel activator, and name some common side effects.
Minoxidil
Reflex tachycardia
Fluid retention
Diabetes mellites (by inhibiting insulin release from beta pancreatic cells
Hisutism (hair growth)
What is hydralazine? In what patient groups is it indicated for? What are the side effects?
A direct actin vasodilator
Causes systemic dilation of arteries and arterioles
Decreases TPR & cardiac afterload
Indicated for severe hypertension in pregnancy (with diuretic and beta blockers)
Heart failure in those of african-caribbean origin. (with nitrates)
Side effects:
- Lupus syndrome
- Tachycardia & palpitations
- Hypotension and peripheral oedema
Give examples of drug classes for hypertension that act on the sympathetic NS.
Beta blockers Alpha 1 receptor antagonists Alpha 2 receptor agonists Imidazoline receptor agonists Ganglion blockers Adrenergic neuron blockers
How do beta-blockers work?
Block beta-1 receptors in the heart – responsible for increasing of heart rate.
Reduces reflex tachycardia
Reduces renin release and activation of RAAS
Reduces central sympathetic activity
-olol drugs
When are beta-blockers used? What are the side effects commonly associated with drug
Resistant hypertension
Severe hypertension in pregnancy (only labetalol)
Bronchoconstriction (asthma???) Hypoglycaemia and reduced awareness of it Bradycardia Negative inotropic effect Fatigue Cold extremities Erectile dysfunction
Receptors in noradrenergic transmission
: alpha and beta can be further subdivided into
alpha - alpha1, alpha 2
beta- beta1, beta2, beta3
What does this subdivision induce?
- Receptor subtypes mediate different responses by coupling to different second messenger systems
When would alpha 1 adrencoceptor antagonists be used.
What are the side effects of the drug.
Severe hypertension in addition to first line treatment drugs & diuretics
First dose hypotension
Dizziness
Fatigue
What are the therapeutic applications of:
- ) Moxonidine
- ) Alpha Methyldopa
- ) Clonidine
Moxonidine = resistant hypertension
Alpha methyldopa = severe hypertension in pregnancy
Clonidine is usually used in migraine, insomnia and opioid detoxification – rarely used as a antihypertensive.
Give the adverse effects of central acting drugs
Rebound hypertension upon withdrawal Dry mouth Sedation and drowsiness Respiratory depression Immune haemolytic reactions Liver toxicity
How does trimetaphan work.
Competitive nicotinic acetylcholine receptor antagonist at the autonomic ganglia
Acts on both sympathetic and parasympathetic ganglia
Give 2 examples of ganglion blocking drugs
- Hexamethonium
- Non depolarising nicotinic antagonist
- No clinical use
- Local anaesthetics
- Sympathetic ganglion block
- Blocks sympathetically-mediated pain pathways
How is a transmitter synthesised?
- Postganglionic fibres send axons to target organ
- Enzymes involved in transmitter synthesis made in cell body
- Synthetic enzymes transported to nerve terminus
- Transmitters made at terminal varicosities
Describe synthesis of noradrenaline at nerve terminal
- L-tyrosine, under influence of Tyrosine hydroxylase, forms DOPA
- DOPA, under influence of DOPA decarboxylase, forms Dopamine
- Dopamine, under influence of dopamine beta-hydroxylase, forms Noradrenaline
Drugs affecting synthesis of noradrenaline
- The initial enzyme in formation of NA (L-tyrosine to DOPA) is tyrosine hydroxylase
- inhibited by alpha-methy-p-tyrosine (Metirosine) - Second stage of synthesis (DOPA to Dopamine) by DOPA decarboxylase
- inhibited by Carbidopa - Dopamine beta-hydroxylase inhibited by Nepicastat but is not clinically useful
How is nor-adrenergic release regulated?
- Depolarisation of nerve ending opens calcium channel
- Leads to vesicle exocytosis
- NA released
- Released NA activates presynaptic receptors that inhibit adenylyl cyclase
- This prevents calcium channel opening and limits further release of NA
Describe termination of Noradrenergic transmission
- NA rapidly removed from synaptic cleft by Neuronal Epinephrine Transporter (NET) - Uptake 1
- Uptake into vesicles by Vesicular Monoamine Transporter (VMAT)
- Free concentration of NA low in neuron cytoplasm due to monoamine oxidase (MAO) activity
- Extraneuronal Monoamine Transporter (EMT) - Uptake 2
Which drugs inhibit release of noradrenaline?
- Methyldopa
- metabolised to methyl-NA
- false precursor molecule
- alpha2 agonist
- Peripheral and central effects on BP
- Also inhibits DOPA decarboxylase - Guanethidine
- substrate for NET
- blocks depolarisation at nerve terminal
- also substrate for VMAT
- overall effect: block of adrenergic neurons - Reserpine
- inhibits VMAT
- prevents transport of NA into vesicles
- vesicular level falls
- antihypertensive
What are the unwanted effects of inhibiting NA synthesis/release?
1. General anti-sympathetic effects \: hypotension \: bradycardia \: digestive disorder \: nasal congestion \: sexual dysfunction
- Central effects common
: sedation
: mood disturbance
Which enzymes metabolise Noradrenaline?
- Monoamine oxidase (MAO)
- found mainly in neurones, also liver & GI tract
- NA → DOMA - Catechol-o-methyl transferase
- neuronal and non-neuronal tissue
- also metabolises DOMA produced from MAO
Receptors in noradrenergic transmission
: alpha and beta can be further subdivided into
alpha - alpha1, alpha 2
beta- beta1, beta2, beta3
What does this subdivision induce?
- Receptor subtypes mediate different responses by coupling to different second messenger systems
What is atherosclerosis
A progressive disease of large and medium sized muscular arteries.
It is characterised by inflammation and dysfunction of the lining of the blood vessel, and results in the build up of cholesterol, lipids and cellular debris.
This forms an atheroma that obstructs good blood flow, and results in poorer oxygen supply to target organs.
Largely asymptomatic
What are the complications relating to atherosclerosis
CHD
Leading angina
ACS & MI
Cerebrovascular atherosclerotic disease
What are the risk factors associated with atherosclerosis
Hypertension Uncontrolled diabetes mellitus Smoking Excessive alcohol consumption High fat diet Lack of exercise Obesity
Gender
Age
Genetics
What are some of the plasma markers that can indicate atherosclerosis
CRP
Homocysteine
Coagulation factors
Lipoprotein(a)
Describe the 2 types of cholesterol
LDL
- Single apolipoprotein – B-100 – important for recognition of the lipoprotein by the receptors
- Small size
- Low protein to cholesterol ratio
HDL
- Recycles unused cholesterol back to the hepatocytes to be reused.
- Main lipoproteins are A-I and A-II
- Small size
- High protein to cholesterol ratio
What are some ways in which cholesterol and lipoproteins are transported
Chylomicrons: They transport triglycerides and esterified cholesterol into the bloodstream from the intestines. (EXOGENOUS CHOLESTEROL)
VLDL (very low density lipoprotein): Cholesterol esters and newly synthesised triglycerides (ENDOGENOUS CHOLESTEROL)
IDL (Intermediate density lipoprotein): Cholesterol
Describe the movement of dietary cholesterol.
10 marks
Dietary cholesterol is transported into intestinal cells via the Niemann-Pick C1-Like 1 transporter alongside with triglycerides.
The cholesterol is then modified and transported into a vesicle with fatty acids (triglycerides) and produces a chylomicron vesicle using MTTP.
This is then absorbed into the intestine lumen and is enriched with other apolipoproteins.
The chylomicron can then enter the bloodstream via hepatic and lymphatic pathways.
The lipoprotein lipase on the surface of endothelial cells can remove triglycerides from the chylomicron to produce chylomicron remnants - uptake by hepatocytes possible via LDL receptors (recognises apolipoprotein B) or by LRP1.
Adipocytes can take up the cleaved triglycerides and convert it into fat reserves.
The uptaken chylomicron remnants can then be repacked with newly synthesised triglycerides to form VLDL. The product can then be secreted into the bloodstream.
Surface lipoprotein lipases on cells can then cleave off the fatty acid on the VLDL to produce IDL and energy.
Hepatic lipases can then strip off the other proteins on IDL to produce LDL.
This can then be taken up again into hepatocytes
via LDL receptors. Hepatocytes recycle the cholesterol. Cells can also take up the cholesterol to restructure the cell membrane, or produce lipid metabolising mediators.
Unused non-esterified cholesterol can be transported out of the cell via ABCA1 and ABCG1 into the plasma back to the liver in the form of HDL. It is then taken up by the hepatocytes via SRB1
The cholesterol can also be esterified using LCAT. The esterified cholesterol can be transferred into LDL/VLDL using CETP
Describe selectivity of adrenoceptors
- Adrenoceptors are relatively unselective (similar affinity) for two neurotransmitters
: Adrenaline (A)
: Noradrenaline (NA) - Both NA and A activate alpha and beta adrenoceptors
: A more potent at alpha 2 & beta 2
: NA more potent at alpha 1 & beta 2
What are adrenoceptors agonists?
- Agents that bind to a receptor and elicit a response
- Agonists of sympathetic alpha and beta receptors (adrenoceptors) may be termed
: sympathetic agonist
: adrenergic agonist
: sympathomimetic agonist - Agonists can act either directly/indirectly on the receptor
Give examples of direct sympathomimetics and their effects & uses
- Phenylephrine
- selective alpha 1
- vasoconstrictor
- can treat acute hypotension, glaucoma, adjunct to local anaesthetic - Clonidine
- selective alpha 2
- prevent NA release and reduce BP
- primary action in medulla to inhibit sympathetic outflow - Beta-agonists
- increase cardiac output
- adrenaline in analphylactic shock
- dobutamine used to treat cardiogenic shock
Give examples of indirectly acting sympathomimetics
Structures similar to NA but do not activate receptors
- Amphetamines
- substate for NET and VMAT
- prevent NA accumulation in vesicle
- inhibit MAO
- promotes NA export via NET
- increase cytosol NA
- increase NA outflow into synapse - Ephedrine, Pseudoephedrine
- reverse NET - Cocaine
- inhibits NET
- increase NA in synapse by inhibiting reuptake
What are the receptors and indications for the following direct-acting sympathetic agonists?
- Isoprenaline
- Dobutamine
- Salbutamol
- Phenylephrine
- Clonidine
- Isoprenaline
- beta
- Asthma (obsolete) - Dobutamine
- beta1
- Cardiogenic shock - Salbutamol
- beta2
- Asthma - Phenylephrine
- alpha1
- Acute hypotension
- Nasal decongestant - Clonidine
- alpha2
- hypertension
What are the actions and uses for the following indirect-acting sympathetic agonists?
- Tyramine
- Amphetamine
- Ephedrine
- Cocaine
- Tyramine
- NA release
- No clinical use - Amphetamine
- NA release from vesicles
- CNS stimulant - Ephedrine
- NA release
- Decongestant - Cocaine
- Blocks NET: synaptic NA increased
- Abuse
Describe functions of different adrenoceptors
alpha1 agonists
- constrict most smooth muscle
- except GI where they relax
alpha2 agonists
- mediate presynaptic inhibition of neurotransmitter release
- sympathetic and parasympathetic
beta1 agonists
- increase heart rate and force of contraction
beta2 agonists
- dilate/relax smooth muscle
beta3 agonists
- stimulate thermogenesis in skeletal muscle
Describe action of beta-adrenoceptor receptor activation in the heart
Heart
- increase in cardiac myocyte Ca2+
- increase in pacemaker activity in SA node
- increase rate and force
Describe actions of adrenoceptors antagonists
- Bind to receptor but elicit no response
: prevents binding of an agonist - Can be selective for alpha or beta receptors
- NA activity can also be indirectly antagonised by interfering with its synthesis
What does alpha-adrenoceptor antagonists(non-selective) do?
- Cause hypotension, postural hypotension
: alpha1 blockade - Increase cardiac output and cause tachycardia
: reflex due to hypotension
: alpha2 blockade leads to increased sympathetic output
What does alpha1-antagonist (selective) ‘-azosin’ do ?
- Block direct action of NA ana A on vascular smooth muscle
- Cause vasodilation and fall in arterial pressure
: hypertensive drugs - Relax bladder neck smooth muscle and prostate capsule
What does alpha2-antagonists (selective) do?
- Limited clinical use
- Yohimbine mainly experimental
- Yohimbine has vasodilator and stimulants effects
What is action of the beta-antagonists (beta-blockers)?
- Most important desired effects on cardiovascular system
- Decreases arterial pressure
: reduction of cardiac output (CO)
: reduction of renin release
: CNS - reduce sympathetic output - Prevent tremor
: skeletal muscle beta-receptor
What are the unwanted effects of beta-antagonists?
- Bronchoconstriction
- Cardiac failure
- Bradycardia (low HR)
- Hypoglycaemia
- Fatigue
- Cold extremities
What is the clinical use of beta-antagonists?
Cardiovascular
- hypertension
- angina
- cardiac dysrhythmias
Other uses include
- glaucoma
- Hyperthyroid disease
- anxiety
- tremor
- migraine
GIve 2 examples of Mixed alpha/beta antagonists and their Actions & Uses
- Labetalol
- alpha/beta antagonist
- Hypertension in pregnancy - Carvedilol
- alpha/beta antagonist
- Heart failure
Clues in the name
Drugs name ending in ‘azocin’ are alpha1-antagonists
Drugs name ending in ‘-olol’ are beta-antagonists
ga yau ga yau
What is metabolic syndrome and what are the constituent conditions?
- Abnormal carbohydrate and lipid metabolism
- It puts you at greater risk of getting coronary heart disease, stroke and other conditions that affect the blood vessels
Combination of
- insulin resistance
- elevated fasting blood glucose
- hypertension
- Dyslipidaemia
What are the risk factors of metabolic syndrome?
- Visceral obesity
- Age
- Weight
- Race (higher in afro-carribean, asian)
- Non-alcoholic fatty liver
- History of gestational diabetes
- polycystic ovary syndrome
What does lipid overflow-ectopic fat represent?
- Increased muscle fat (intracellular lipid)
- Increased epicardial fat
- Increased liver fat and altered function
How is Metabolic syndrome diagnosed?
3 or more of
- Waist >94cm men, >80cm women (or BMI >30)
- Elevated serum triglyceride ( >1.7mM)
- Reduced HDL ( <1mM men, <1.3mM women)
- Hypertension ( >140/90mmHg)
- Elevated fasting blood glucose ( >5.6mM)
- Thrombosis
- Inflammation
What are the sources & utilisation of glucose?
Sources
- Dietary intake of carbohydrate
- Gluconeogenesis
- Glycogenolysis
- Fatty acid catabolism
Utilisation
- Glycogenesis
- Glycolysis
- Fatty acid synthesis
How are LDL taken up by cells.
They bind to the LDL receptor, and are both taken up by endocytosis.
This produces an endosome.
The cholesterol is released into the cell.
The LDL receptor is then recycled back into the membrane
How are LDL receptors controlled.
Expression of LDL receptors is controlled by the protein PCSK9.
When the levels increase sufficiently, it will interact with the LDL receptor.
The LDL receptor is then taken up via endocytosis to produce an endosome.
The endosome is converted into a lyzosome to degrade the receptor.
–> reduces the number of LDL receptors
Describe how an atheromatous plaque forms.
- ) Endothelial cell dysfunction (initiaton):
- Weakened endothelium due to risk factors
- ->Hypertension and uncontrolled diabetes in particular
- The bioavailability of nitrous oxide is reduced, this leads to an upregulation of endothelial adhesion receptors.
- The endothelial permeability to LDL increases
- Chemokines and cytokines are released.
- ) Lipid accumulation and oxidation:
- LDL accumulates in the sub-endothelial space.
- Increase of adhesion receptors promote binding of LDL particles to the surface -> results in further penetration of the LDL into the cell
- LDL is oxidised by ROS or enzymes (that were released by macrophages/other inflammatory cells).into oxy-LDL particles.
–> FORMATION OF OXIDISED LDL PARTICLES & NON-ESTERIFIED CHOLESTEROL CRYSTALS
- ) Immune cell accumulation (occurs at the same time as lipid accumulation):
- Adhesion and infiltration of monocytes into arterial wall
- Monocyte –> macrophage via M-CSF (macrophage colony stimulating factor)
- Macrophages then engulf the oxidised LDL
- ->FORMATION OF FOAM CELLS AND FATTY STREAKS
- ->INCREASES THE PROINFLAMMATORY CYTOKINE IL-BETA 1
- ) SM cell recruitment:
- Proliferation and migration of smooth muscle cells into the sub endothelial space
- There is increased matrix protein synthesis and deposition
–>FORMATION OF A STABLE FIBROUS CAP
- ) Unstable atheromatous plaque
- Increased cell apoptosis and formation of a plaque
- Calcification
- -> RUPTURE OF FIBROUS CAP
- -> THROMBUS FORMATION AND COAGULATION CASCADE ACTIVATED
ACS symptoms?
What is lipoprotein(a)
Similar to LDL, but has apolipoprotein(a)
Competes with plasminogen, but does not elicit fibrinolytic effects.
This leads to prothrombotic and profibrotic effects.
Contributes to foam cell formation when oxidised
CV risk factor and proatherogenic marker
Name some symptoms of familial hypercholesterolaemia
Cornal Arcus
Tendons Xanthomata
Xanthoma
Skin Xanthomata
Regarding Adipocytes,
what are white, brown and brite fats?
White fat
- major function is to store energy in the form of triglyceride
Brown fat
- High levels in neonates
- Key role in thermogenesis
- Level falls with age
Brite fat
- potentially important in balancing storage and expenditure
What do adipocytes secret?
Adipokines
- Leptin
- Adiponectin
- TNF
- IL-6
- Resistin
what is Leptin (adipokines)?
Hormones secreted by adipose tissue
- produced by adipose tissue
- primary action: hypothalamus (stimulates satiety - suppress hunger)
Increased in obesity
- but resistance to its action occurs
- decreased ratio of CSF to serum leptin in obesity
Metraleptin
- synthetic analogue
what is Adiponectin (adipokines)?
- Secreted by adipose tissue
: but decreased in obesity - Low plasma adiponectin is risk factor for metabolic syndrome
- Stimulates fatty acid catabolism
- Decreases hepatic glucose production
- Increase insulin sensitivity
- Increased by thiazolidinediones
What are the mechanisms of vascular dysfunction in metabolic syndrome?
- Decreased nitric oxide signalling
- Increased oxidant stress
- Triglyceridaemia
What does Nitric Oxide do in terms of blood vessel?
- NO is a vasodilator produced by endothelium and some nerves by nitric oxide synthase (NOS)
- Produced from L-Arginine
What is Advanced Glycation end product (AGEs)?
- Glycation is covalent binding of sugar to protein or lipids
- Dietary source from browning meat or fats
- Main source if formation in body (blood)
- Increased by hyperglycaemia/hyperlipidemia
- Fructose much higher glycation capacity than glucose
- Increased AGEs associated with cardiovascular disease
- Oxidise LDL
What is irisin and what is its role?
- Irisin made by skeletal muscle in response to exercise
- Activates adipose tissue
: Conversion of White fat to Brown fat(Brite)
: Increased mitochondrial UCP expression
: Thermogenesis - Benefits of exercise more tha njust immediate wor kdone
Describe role of blood vessels in control of BP
BP = CO x TPR (total peripheral resistance)
CO = HR x SV
- Vasocontriction & Vasodilation occurs on TPR and SV
How does blood vessel act as a functional syncyitum?
- Cells are coupled within each layer via intercellular gap junctions
- Cells are coupled between layers (smooth muscle and endothelial cells via myoendothelial gap junctions)
- Chemical coupling by release of neuromediators and local mediators
: from sympathetic nerves
: from endothelial cells
Give 3 main mechanisms leading to contraction of vascular smooth muscle
- Initiated by intracellular Ca2+ increase via two parallel pathways (additive)
a) Agonist-induced (Gq), IP3-mediated Ca2+ release from SR (sarcoplasmic reticulum)
b) Depolarisation-activated Ca2+ influx via voltage-activated calcium channel of L-type (L-VACCs) - Determined by phosphorylated state of Myosin Light Chain (MLC)
a) Phosphorylation of MLC by MLC Kinase (activated by Ca2+-CaM) causes contraction
b) De-phosphrylation of MLC by MLC phosphatase (MLCP) causes relaxation - Enhance contraction at a constant level of calcium by inhibiting activity of MLCP (calcium sensitisation)
a) Agonists via DAG/PKC and phosphorylation of CPI-17 phosphorylation
b) Agonists via RhoA & activation of the Rho-associated kinase 2 (ROCK2)
How do statins work
Reversible competitive inhibition of HMG-CoA Reductase
This reduces the conversion of HMG-CoA to mevalonate
Hence, reduction in the formation of cholesterol
It also decreases the amount of LDL circulating in the body by increasing the number of LDL-receptors, and increasing its clearance from the body
Name 2 statins produced via fungi
Simvastatin
Pravastatin
Which drugs should simvastatin/atorvastatin and lovastatin not be prescribed with?
Antibiotics – erythromycin, clarithromycin
Antifungals – itraconazole
CCB - Verapamil
Immunosuppressants – cyclosporin
–> These drugs inhibit CYP3A4, which metabolise the listed drugs.
–> Potential for toxicity at therapeutic doses of the statins
(muscle aches)
Name some of the clinical uses for statins. What are the cautions and contraindications of statins?
Primary prevention of CHD in patients with other risk factors (kidney disease/diabetes)
Secondary prevention of CHD
Familiar hypercholesterolaemia
Cautioned in those with liver disease and can cause hypothyroidism
CONTRAINDICATED IN PREGNANT WOMEN
What are the CV benefits of using statins?
Improved endothelial function Anti-inflammatory effects Anti-thrombotic/anti-platelets effects Increase in vasodilating effects Increase in neovascularisation of ischaemic tissue - improved blood supply
What are the side effects of statins.
Myalgia – muscle pain
Myopathies (rare):
- -Myositis -> muscles inflamed
- -Rhabdomyolysis -> muscle breakdown
Very rare:
- Hepatitis
- Interstitial lung disease
How does ezetimibe work
Inhibits NPC1L1 transport protein in enterocytes.
This reduces the amount of cholesterol absorption in the gut and reduces LDL
What are the clinical uses of ezetimibe? What are the side effects?
Hypercholesterolaemia
- Along side with statins
- By itself (when patients are contraindicated against statins)
Diarrhoea
Abdominal pain
Headaches
Myalgia
How do fibrates work
They bind to and activate the transcription factor PPAR-alpha
This activation results in dimerisation with RXR to produce the heterodimer PPAR-Alpha/RXR.
The heterodimer produced activates transcription of lipoprotein lipase (LPL).
LPL strips the triglycerides from lipoproteins –> results in less circulating cholesterol in the blood.
It also increases expression of Apo-A1 and Apo-A2 (constituents of HDL) causing a greater expression of HDL-lipoproteins
What is the effect of using fibrates?
Increased LPL activity
Reduction in circulating VLDL and triglycerides
Increased plasma levels of HDL
Increased LDL uptake into cells
What are the indications of fibrates?
- Mixed dyslipidaemia – cholesterol and triglycerides!!!!
- Patients that have a high risk of atherosclerosis and low HDL (increases HDL)
- Severe treatment-resistant dyslipidaemia with statins
Give an example of a fibrate
Fenofibrate
Gemfibrozil
–> -fibrate drugs
When are fibrates contraindicated and what are the side effects.
PREGNANCY
Abdominal distension
Anorexia
Diarrhoea
Nausea
RARE:
Myositis
Rhabdomyolysis
Myotoxicity can be increased in patients with:
Renal impairment
Hypertriglyceridaemia (alcoholics)
Give some examples of lipid lowering drugs, and how do they work.
Colestyramine
Colestipol
Colesevelam
Bind to bile acids in the gut and reduce cholesterol reabsorption via enterohepatic circulation
Decreases LDL, BUT, increases triglycerides.
When are lipid lowering drugs used clinically.
Hepatic impairment where statins are not recommended
Dylipidaemia unresponsive to diet
In pregnant women (cautioned)
What are the side effects of lipid lowering drugs.
GI disturbance
Constipation
Bleeding (Vit K deficiency)
What is the lipid lowering mechanism of nicotinic acid?
Activates Gi/o coupled HCA2 receptors in adipocytes.
Inhibits lipolysis, so there is a reduction in triglycerides causing less VLDL and hence LDL.
There is also an increase in expression of Apo-A1, causing an increase in HDL
Give an example of a nicotinic acid.
Niacin/Vitamin B3
What is the indication of Niacin? What are some side effects?
Hypercholesterolaemia with statins
Dyslipoproteinaemia with statins
Facial flushes due to PGD2
Other effects are: N&V Allergy Lightheadedness and syncope Tachycardia and palpitations Skin itching/rashes
How do fish oil derivatives reduce lipids?
Not understood well.
Precursors for:
Prostaglandin 3
Thromboxane 3
Leukotriene 5
Results in lower triglycerides and LDL
What are some recent developments in lowering LDL.
Anti-PCSK9 monoclonal antibodies
- -Evolocumab
- -Alirocumab
Prevents PCSK9 levels from reaching high enough to bind to LDL receptors and causing their breakdown
Indicated for hypercholesterolaemia and mixed dyslipidaemia
Describe the metabolic autoregulation of CBF in the normal heart
Catecholamine binds to the beta 1 receptors in the heart, stimulating a higher heart rate.
Due to the heart beating faster, the diastolic time is reduced. This reduces the coronary blood flow.
The increase in heart rate also increases the cardiac workload and hence cardiac metabolism.
Local metabolites (Adenosine and potassium) are released and hypoxia can occur due to increased oxygen usage. To balance this effect, vasodilation of the coronary arteries occur.
How does adenosine cause an increase in coronary blood flow?
Increased heart rate results in an increase of the cardiac workload –> ATP breakdown increased.
In cardiac myocytes, ATP->ADP->AMP->Adenosine
AMP-> Adenosine is facilitated by 5’-nucleotidase
Adenosine binds to Adenosine-A2 receptors on the smooth muscle cells (G⍺s).
Adenylyl cyclase stimulates cAMP release
cAMP levels increase and causes vasodilation.
Thus, coronary blood flow increases.
Adenosine will also bind to Adenosine-A1 receptors which are G⍺i linked. This reduces the heart rate, and reduces the cardiac workload.
How does hypoxia and potassium cause an increase in coronary blood flow?
An increased workload results in oxygen to be used up at a quicker rate, and hence is less available. This also results in less ATP in the coronary smooth muscle.
ATP-sensitive K+ channels are opened, causing hyperpolarisation in the smooth muscles.
–> vasodilation increases causing an increase in CBF
The increase in workload will also increase the number of action potentials, resulting in a higher extracellular [K+].
Na/K+-ATPase in the coronary SM is activated resulting in a greater electronegativity, and hence hyperpolarisation.
–> Greater vasodilation and CBF
What is the issue with atheromatous disease regarding the regulation of coronary blood flow.
The increased workload causes a decrease in coronary blood flow.
The vasodilation is stimulated.
However, due to partial or full occlusion of the blood vessels, this does not properly reduce cardiac workload.
Adenosine here reduces the heart rate via adenosine A1 receptor binding, and prevents the necessary compensatory increase in the heart rate.
–> This results in the characteristic cardiac pain
What are the types of angina, and what are the causes as well as when it occurs
Unstable angina
- Atheromatous plaque rupture and platelet aggregation
- Occurs at rest
Stable angina
- Partial coronary artery occlusion
- Occurs on exertion or stress
Variant angina
- Coronary vasospasm
- At rest
What are the symptoms of stable angina?
Tight/dull/heavy pain – some can get sharp stabbing pain
Spread to left arm, neck, jaw or back
Triggered by physical exertion or stress
Stops within a few minutes of rest
–
Angina can also cause:
- Breathlessness
- Nausea
- Pain in lower chest or abdomen (Similar to indigestion)
- Fatigue
How can stable angina be treated
Reduce oxygen demand
Increase oxygen supply
Use lipid lowering drugs to prevent the progression of the atheromatous disease
First Line = BB (B1 selective) / CCB (dihydropyridines)
Second line = Organic nitrates/Ivabradine/Nicorandil/Ranolazine
How do Organic Nitrates work?
They are metabolised to release NO –> increasing levels of cGMP…which causes relaxation
Causes the systemic vasodilation of veins (decreases preload) and arteries (decrease afterload), which causes a decrease in cardiac oxygen demand
Also causes an increase in the dilation of collateral vessels, which increase oxygen supply
How do Nicorandil, Ivabradine and Ranolazine work?
Nicorandil –> Activates vascular ATP-sensitive K+ channels, and is also an NO donor – arteriodilation
Ivabradine –> Inhibits the pacemaker IF current in the SAN, which decreases HR
Ranolazine –> Inhibits late Na+ channels that are activated by ischaemia in cardiac myocytes
How do you treat variant angina
Nitrate vasodilator and CCB
Beta blockers are not effective – only spasms present, heart is not affected
Aim to dilate coronary arteries
Compare pulmonary and periphery oedema
Pulmonary = left ventricular hypertrophy Peripheral = CHF
Give some common adverse effects in organic nitrates
Dizziness
Postural hypotension
Reflex tachycardia
Headaches
What is Endothelin-1 and where/how does it act?
- Endothelin-1 is a vasoactive and mitogenic polypeptide synthesised and secreted by endothelial cells
- It acts on specific receptor ET.A on vascular smooth muscle, causing sustained powerful vasoconstriction, where as binding to ET.B receptor on endothelial cells cause the release of nitric oxide that lead to vascular relaxation
Compare T1DM and T2DM.
Type 1 = autoimmune disease
- -Destruction of Beta-islet cells in the pancreas via immune system
- -Require insulin injections (None is produced)
Type 2
- -Lack of insulin produced, or lack of a response to insulin
- -Insulin is typically only used when other method have not worked well
Typically diagnosed in patients about 40yrs +
Type of ET receptors on endothelial cells and their role
- Stimulates production of vasodilators (NO, PGI2)
- ET-1 clearance
Examples of endothelin receptor antagonist drugs?
Ends in ‘-entan’
- Bosentan (2001)
- first oral dual ET.A/B antagonist - Macientan (2013)
- dual ET.A/B antagonists (50 folds more ET.A selective) - Ambrisentan (2007)
- selective ET.A antagonists
Compare insulin and glucagon.
Insulin:
Anabolic
Reduces glucose/FFA/AA in the plasma
Stimulates glucose utilisation via glycolysis and glycogenesis
Inhibits gluconeogenesis and glycogenolysis
Glucagon:
Catabolic
Increases plasma glucose/ketones
What are meglitinides?
Same MoA as sulfonylureas
Greater rapidity in action due to increased rate of absorption
Hypoglycaemic effects are elicited via insulin – ineffective drug in T1DM
Can be used with metformin
What are some of the effects of insulin resistance?
Increased thirst/urination
Fatigue
Hypertension
Low HDL
Increased fat stores
Hyperglycemia
Describe how sulfonylureas work. What are the differences between first generation and second generation sulfonylureas?
Stimulate insulin secretion
They inhibit the ATP-sensitive K+ channel, causing more depolarization…..causing Ca2+ release…..which stimulates insulin secretion
___
e. g Tolbutamide vs gliclazide
- Gliclazide has a greater potency with the same MoA
- Second generation drugs have altered onset and duration
What are some side effects associated with sulfonylureas.
What are some contraindications
Hypoglycaemia
Can stimulate weight gain due to the promotion of fat storage (esp the potent sulfonyureas)
Secondary pancreatic Beta cell failure?
Caution when used in patients with renal or hepatic impairment
Contraindicated in pregnancy (crosses placenta)
What are biguanides?
Metformin is the only drug licensed in this group
Acts only in the presence of endogenous insulin – ineffective in T1DM
Decreases hepatic glucose production (by inhibiting gluconeogenesis)
Inhibits the mitochondrial respiratory complex 1 (decreased synthesis from ADP –> ATP)
– less gluconeogenesis
Stimulates insulin receptor expression and tyrosine kinase activity (Insulin sensitising)
Drug of choice in overweight patients as it does not stimulate weight gain
What are thiazolidinediones?
Insulin sensitising/anti-hyperglycaemic drugs
Agonists at Peroxisome Proliferator-Activated Receptors (PPARs), and so decrease Beta-oxidation of fatty acids and cholesterol synthesis
Due to the mechanism, it may take several weeks before effects are fully observed
Weight gain is a major side effect (H/e, it is only subcut fat)
Regulate complex dyslipidaemia in T2DM
Metabolised by CYP450s
-glitazone drugs
What are some side effects of Metformin?
Acute, transient GI fx – metallic taste, diarrhoea, N&V
Lactic acidosis in contraindicated patients
- -history of alcoholism
- -Renal disease
- -Liver disease
- -Pregnancy
Potential interaction if taken with other drugs that are eliminated renally.
What are incretins
GLP- Glucagon-like peptide
GIP- Gastric inhibitory polypeptide
They are hormones released in the GI in response to increased post prandial glucose levels.
–> stimulates insulin release from pancreas
GLP-1 affects insulin biosynthesis and secretion, but only under hyperglycaemic conditions
GLP-1 inhibits glucagon release, and is a satiety signal leading to a reduction in food intake –> So aimed at overweight patients
What are alpha-glucosidase inhibitors
They reduce the digestion of complex carbohydrates, and so slows their absorption from the gut.
– Reduces postprandial hyperglycaemia
Adverse effects are common (flatulence/diarrhoea),
–High discontinuation rate
Used when other drugs are not tolerated
Don’t cause hypoglycaemia or weight gain
What are SGLT2 and how do they work.
Reversibly inhibit the sodium glucose co-transporter 2 (SGLT2) in the renal proximal convulated tubule
This reduces glucose reabsorption and increases secretion
n. b. glucose in the urine of patients is indicative of diabetes
e. g. canagliflozin
- flozin drugs
Describe how a clot forms
Vascular endothelium is damaged, exposing collagen, and stimulating the release of Von Willebrand Factor (VWF)
Platelets adhere via VWF bridging between subendothelial macromolecules and platelet glycoprotein Ib (GPIb) receptors
Platelet shape changes from disks to spiny spheres
- -> driven by ADP binding to P2Y1 receptors on platelets
- -> ADP also bind to P2Y12 stimulating platelet action
Secretion of granule contents (2 types)
- -Dense
- -Alpha
Synthesis of release of Platelet-Activating Factor (PAF) and Thromboxane A2 (TXA2)
Aggregation –> caused by expression of GPIIb/IIIa receptors that bind fibrinogen….which links adjacent platelets
Exposure of acidic phospholipids on the platelet surface, promoting thrombin activation via thrombin receptors and fibrin formation from fibrinogen caused by the thrombin
–>Further platelet activation
What a DPP-4 inhibitors. How do they work?
Dipeptidyl peptidase.
These facilitate the breakdown of incretins.
DPP-4 inhibitors prevent this from occurring..
So, incretin effects are potentiated.
(Glucagon release inhibited, and insulin release increased)
Also reduces gastric emptying, so feel satiated for longer. (Less consumption of food – good for overweight patients.
E.g. sitagliptin
–gliptin drugs
Give an example of an adenosine P2Y12 receptor antagonist. How do they work.
Inhibits the P2Y12 (Gi) receptors on platelets, causing an increase in Adenylyl Cyclase (AC) –> cAMP –> deactivate platelet aggregation due to prostaglandin I2 production.
Destabilises:
PARs (Thrombin –> fibrinogen to fibrin)
P2Y1 (platelet conformational change)
TP (Thromboxane A2)
Does this by having its thiol group form a disulphide bond with the cysteine on the receptor (irreversible)
-grel drugs
Clopidogrel
Prasugrel
Reversible antagonists =
Ticagrelor
Compare prasugrel and clopidogrel.
Clopidogrel is a prodrug – requires CYP450 metabolism in the liver before it elicits its effects.
Prasugrel is less dependent on this to be activated.
How does aspirin elicit its effects?
Irreversible COX inhibition
Prevents platelet aggregation and activation
–platelets do not have a nucleus, so COX-1 cannot be resynthesised
Takes a moderate amount of time for platelets to be resynthesised
Compare prasugrel and clopidogrel.
Clopidogrel is a prodrug – requires CYP450 metabolism in the liver before it elicits its effects.
Prasugrel is less dependent on this to be activated.
What is a common side effect of antiplatelets?
Haemorrhages..
Though not in dipyridamole
What is an example of glycoprotein IIb/IIIa receptor inhibitor
Abciximab –> Chimeric monoclonal antibody that is long acting
Eptifibatide –> Synthetic cyclic heptapeptide that is reversible
Tirofiban –> Synthetic non-peptide agent that is a competitive reversible inhibitor
How do phosphodiesterase inhibitors work
Increase cAMP and cGMP levels by blocking PDEs
This inhibits platelet aggregation and causes vasodilation
Stimulates prostaglandin I2
Inhibits Thromboxane A2
Also blocks adenosine uptake by platelets/endothelial cells/blood cells
E.g. dipyridamole
What’s the difference between an Absolute and an Relative refractory period?
Absolute/Effective –> When a second AP isn’t possible regardless of the strength of the stimuli (as phase 0 can’t be reached)
Relative –> If a very strong stimulus is created, then a second AP can be caused
What do each parts of an ecg mean.
P Wave –> Depolarisation of the atria
QRS Complex –> Depolarisation of the ventricles
T Wave –> Repolarisation of the ventricles
What are the different classes of anti-arrhythmia drugs.
Vaughan Williams classification
Class 1 = Sodium channel blockers
- Blocks fast voltage activated sodium channels (Rapid depolarisation stage at phase 0)
- Slows down the rate of AP conduction
- The ability to block increases as the HR increases (good)
3 types
- Ia (Intermediate dissociation from sodium channel)
- Disopyramide
- > Atropine-like fx?
- Ib (Quick dissociation from sodium channel)
- Lidocaine
- > CNS fx
- Ic (Slow dissociation from sodium channel)
- > Flecainide
- > Sudden cardiac death in patients with MI
Class 2 = Beta blockers
- Block Beta 1 adrenoceptors
- Slows down the rate of AVN conduction
- Propanolol
- Bradycardia/bronchoconstriction..
Class 3 = AP duration prolongers
- Block voltage activated potassium channels in repolarisation of phase 3 in AP
- Amiodarone (reduces expression of Beta 1 adrenoreceptors)
- Sotalol (non specific beta blocker)
Class 4 = CCB
- L-type voltage gated calcium channel blockers
- Slows down AV node conduction
- Verapamil
How are arrhythmias classified
Effect on heart
Effect on the rhythm
Site of origin
Type of QRS complex
What are the causes of bradycardia – physiological and pathological
Trained athletes.
Increased vagal tone
Hypothermia
Endocrine issues
Electrolyte imbalance
Drugs (rate affecting drugs – verapamil)
Sick sinus syndrome
AV blockade/heart block
What are other anti-arrhythmic drugs available
Atropine Isoprenaline Adrenaline Adenosine Atropine Digoxin
What are the types of tachyarrhythmias?
SVT – supraventricular tachycardia
- Paroxysmal SVT (abrupt start and finish)
- AFib
- Atrial flutter (AVNRT early after polarisation, AVRT late after polarisation)
V. dangerous when these occur (blood supply is altered)
VFib
VT (ventricular tachycardia)
What are the types of AV blocks
First degree - PR interval increased (higher than 0.2s)
Second degree - missed beats to the ventricle.
- > Mobitz I = Increasingly greater PR intervals
- > Mobitz II = no pattern
Third degree - complete block
- > No ventricle conduction
- > Random P waves
- > Random QRS complexes
How can pathological bradycardia be treated? (AV block)
Atropine or isoprenaline in emergencies
Long term solution to 2nd and 3rd degree blocks
–>Implantable transcutaneous pacemaker (Controls the heart rate)
What are the 2 mechanisms for tachyarrhythmia?
Automaticity
Triggered
Describe 2 main mechanisms leading to relaxation of vascular smooth muscle
- Agonist-mediated and hyperpolarisation dependent relaxation
- agonists stimulate endothelial G-protein-coupled receptors , provoking an increase in endothelial cellular calcium, causing opening of endothelial K.ca channel and triggering processes of hyperpolarisation. - Mechanisms which reduce intracellular calcium levels
- Reduced calcium iflux via L-type VACCs
: Hyperpolarisation-mediated (opening of K+ channel, increased activity of NA+-K+-ATPase)
: Phosphorylation dependent inhibition (via PKA & PKG pathways) - Re-uptake by SERCA2 into the smooth muscle (main)
- Up-take by mitochondria (minor role in healthy vessels)
- Extrusion via
: Plasmalemmal Ca2+ -ATPase (Ca-pump)
: NA+-Ca2+ exchanger (NCX) (minor role in healthy vessel)
:
What is blood vessel relaxation faciliated by?
- Decrease of phosphorylated state of MLC via two major mechanisms
: phosphorylation-dependent inhibition of MLCK by PKA
:activation of MLCP via cGMP-PKG mediated pathway - Decrease in intracellular Ca2+ concentration mainly via: Hyperpolarisation-mediated decrease in L-VACC activity: SERCA-mediated reuptake into the SR(sacroplasmic reticulum)
: Extrusion by Ca-ATPase
What are the 3 main vasodilator derived from vascular endothelial cells?
- Nitric oxide (EDRF)
- Prostaglandin I2 (Prostacyclin)
- Endothelium-derived hyperpolarising factors (EDHFs)
What is Nitric Oxide Synthase (NOS) and its 3 isoforms?
Nitric oxide synthases (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine
- Endothelial NOS (eNOS)
- Consitutively expressed, calcium-dependent
- Effect on Blood vessels (via NO): Vasodilation
- Effect on platelets (via NO): Reduced platelet adhesion/aggregation - Neuronal NOS (nNOS)
- CNS: Neurotransmission, LTP, plasticity
- Peripheral NS: Gastric emptying, penile erection - Inducible NOS (iNOS) (calcium independent)
- Macrophages, neutrophils, leukocytes: host defence
What is
ADMA (Asymmetric dimethylarginine) ?
- Competitive NOS inhibitor: endogenous
- Increased in blood plasma of humans with
: Hypertension
: Atherosclerosis
: Kidney/heart failure - Marker of endothelial dysfunction & risk factor of CVD
Name 2 Nitro Oxide (NO) donor drugs
- Glyceryl trinitrate
( GTN, Nitroglycerin) - Sodium nitroprusside (SNP)
What is Slidenafil and its action?
- Selective PDE5 inhibitor
: prevents cGMP breakdown
Therapeutic use:
- Erectile dysfunction
- Pulmonary Arterial hypertension
What is prostacyclin?
- is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator
Name 3 prostacyclin analogues therapeutically used for pulmonary arterial hypertension
- Prostacyclin (Epoprostenol)
- iloprost (IV, inhaled)
- Selexipag (oral)
- Selective IP receptor agonist
What are the potential candidates for an EDH(endothelial-derived hyperpolarisation) factor?
- Ca2+ activated K+ channels in ECs
- Ca2+ activated K+ channels in SMs
- Electrogenic NA+- K+-ATPase in SMs
- Myoendothelial gap junctions
- Metabolites of arachidonic acid
What is aldosterone?
- Body’s main mineralcorticoid
: promotes reuptake of sodium, hence water, by the kidney - Produced exclusively in zona glomerulosa (ZG)
- Functions in regulation of ECFV and BP
: in circulation, 60% of aldosterone is protein bound (low affinity) - Receptor(MCR) is a member of nuclear receptor superfamily
- Synthesis and secretion increased by elevations in blood angiotensin II
How is aldosterone secretion regulated?
- Renin-angiotensin system
Triggers for renin release
: ↓ BP in afferent arteriole
: ↑ Sympathetic nervous activity
:↓ [NaCl] in DCT
Describe Primary hyperaldosteronism
- Accounts for 5-10% of cases of hypertension
: ↑plasma aldosterone:renin ratio (ARR)
: ↑ plasma aldosterone levels
: ↓ serum and increased urinary K+
of which,
66% is bilateral adrenal hyperpalsia
: treat with aldosterone antagonists
33% is unilateral, aldosterone-secreting adenoma
: surgical removal
What is Cortisol?
- Body’s main glucocorticoid
- produced in zonas fasciculate (ZF) and reticularis (ZR)
- Infleunces many cardiovascular, metabolic, immunologic and homeostatic functions
- Synthesis and secretion is stimulated by ACTH from the pituitary
What is Addison’s disease?
- Primary adrenal insufficiency
- rare, life-threatening condition
- most often caused by autoimmune disease
- Characterised by increased production of CRH/ACTH
What are the clinical features of primary hypoadrenalism?
- Weight loss
- Weakness
- Depression
- Pigmentation
- Postural hypotension
What is secondary adrenal insufficiency?
- Adrenal hypofunction due to a lack of adrenocorticotropic hormone (ACTH). Symptoms are the same as for Addison disease
- Most common cause is long-term corticosteroid medication for non-endocrine disease
Describe Adrenal insufficiency in childhood
- Most commonly congenital
- 90-95% cases due to deficiency in the CP21A2 steroid hydroxylase
What is Cushing’s syndrome?
- Hypercortisolism
- Metabolic disorder caused by overproduction of corticosteroid hormones by the adrenal cortex and often involving obesity and high blood pressure
- Primary or non-ACTH-dependent
: 25% of all cases - Secondary or ACTH-dependent
: 65% of all cases
What are clinical features of Cushing’s syndrome (hypercortisolism)?
- Weight gain
- Depression
- Insomnia
- Plethora
- Thin skin
- Bruising
- Hypertension
How is Cushing’s syndrome managed?
- Pharmacological inhibition of cortisol synthesis with Metyrapone
- Ketoconazole
: synergistic with metyrapone
Describe the functions of kidney
- Regulation of extracellular (body) fluid volume
- Maintenance of ion balance and pH
- Excretion of foregin substances
- Renin secretion
What is the basic functional unit of the kidney?
- Nephron
What is ultrafiltration?
- Blood filtered from Glomerular capillaries into Bowman’s capsule
- driving force
: Glomerular capillary hydrostatic pressure
: oncotic pressure in Bowman’s space - opposing force
: oncotic pressure of blood pressure
: pressure in Bowman’s space
Describe routes of tubular reabsorption and secretion
Reabsorption
- Tubular lumen -> Tubular enpithelial cell -> Interstitial fluid
Secretion
- Interstitial fluid -> tight junction -> Tubular lumen
Rank main sites for tubular sodium reabsorption by ability to reabsorb salt (NA+ and Cl-)
- Proximal Convoluted Tubule (PCT)
- 60-70% - Thick Ascending Limb (TAL)
- 20-30% - Disatal Tubule (DT)
- 5-10% - Collecting Tubule & Duct
- 1-3%
What is Diuresis?
Increased excretion of urine
What is Natriuresis?
Increased excretion of sodium in urine
What are the 5 groups of diuretics? Rank by ability to produce diuresis and natriuresis
- Loop Diuretics
- Act on Thick Ascending Limb (TAL) of Loop of Henle - Thiazides and Thiazide-like
- Act on Distal Tubule (DT) - Potassium Sparing Diuretics
- Act on Collecting Tubule & Collecting Duct - Osmotic Diuretics
- Act on Proximal convoluted tubule & Thin Descending Limb of loop of henle - Carbonic Anhydrase inhibitors
- Act on Proximal COnvoluted dtubule
In the Proximal Convoluted Tubule (PCT), which structures facilitate tubular reabsorption?
a) on the luminal membrane
b) on the basolateral membrane
a) On luminal membrane
- Na+/H+ exchanger (H+ secretion)
- Na+ coupled co-transporters
b) on basolateral membrane
- NA+ - K+ - ATPase (active Na+ reabsorption)
- Renal K+ channels
What is the driving force of tubular sodium reabsorption in PCT?
- Activity of the basolateral NA+-K+-ATPase
: creates Na+ concentration gradient between the tubular lumen and interstitial space
Give an example of Carbonic Anhydrase inhibitor drug and explain what it does
- Acetalzolamide
- Inhibition of carbonic anhydrase in the PCT
- Little use as diuretic agent due to
: weak diuretic
: self-terminating action - Renal effects of acetazolamide
: Moderate decrease in Na+ reabsorption
: Mild plasma acidosis
: Urine alkalosis
Give an example of Osmotic Diuretics and explain what it does
- Mannitol
- freely filtered in glomerulus
- increases osmolarity of
: tubular filtrate (decrease water absroption)
: blood plasma (increase fluid retention)
Acts on parts of nephron freely permeable to water
: PCT
: Descending limb of loop of henle
: CT and CD
Renal Primary effect
: decrease water absroption
Renal secondary effect
: Reduces Na+ reabsorption
In the Thick Ascending Limb (TAL), which structures facilitate tubular reabsorption?
a) on the luminal membrane
b) on the basolateral membrane
a) Luminal membrane
- Na+/K+/2Cl- co-transporter (NKCC2)
- Renal K+ channels (ROMK - Renal Outer medullary Potassium channel)
b) Basolateral membrane
- Na+-K+-ATPase
- K+/Cl- co-transporter
- Cl- channels
What does Loop diuretic do?
- Inhibition of the luminal Na+/K+/2Cl- co-transporter (NKCC2)
Renfal effets \: decrease Na+ reabsorption \: decrease Cl- reabsorption \: increase K+ excretion \: increase Ca2+ & Mg2+ secretion
Give 2 examples of Loop diuretic drugs and their therapeutic uses
- Furosemide & Bumetanide
- Acute pulmonary oedema
- Chronic heart failure
- Renal failure
- Hypertension with complicated renal impairment
In the Distal tubule (DT), which structures facilitate tubular reabsorption?
a) on the luminal membrane
b) on the basolateral membrane
a) Luminal membrane
: Na+/Cl- co-transporter (NCC)
: Renal K+ channels
b) Basolateral membrane
: Na+-K+-ATPase
: K+/Cl- co-transporter
What do Thiazide & Thiazide-related diuretics do?
- Inhibition of lunimal Na+/Cl- co-transporter (NCC)
- Renal effects \: decrease Na+ reabsorption - decrease Cl- reabsorption - increase K+ excretion - increase Ca2+ reabsorption
Give examples of Thiazide and Thiazide-related diuretics
Thiazides
- Hydrochlorothiazide
- Bendroflumethiazide
Thiazide-related
- Chrlotalidone
- Indapramide
- Metolazone
Compare Thiazide vs Loop Diuretics
Thiazide&Thiazide-related diuretics are
- less powerful
- have more prolonged action
- better tolerated than loop diuretics
- ave vasodilating properties after prolonged use
What are the effects of aldosterone in the kidney?
- Regulation of potassium secretion
Aldosteron
- activates renal Na+ channels
- increase synthesis of Na+-K+-ATPase
What are the 2 groups of Potassium-sparing diuretics and drug in each group
- Aldosterone antagonists
- Spironolactone (pro-drug)
- Eplerenone - Na+ channel blockers
- Amiloride
- Triamterene
What are the therapeutic uses of potassium-sparing diuretics?
Weak diuretics
- treat hypokalaemia ( due to thiazide or loop diuretics)
- Heart failure
- Aldosteronisms
What is Antidiuretic Hormone (ADH)?
- ADH is also called arginine vasopressin.
- It’s a hormone made by the hypothalamus in the brain and stored in the posterior pituitary gland.
- It tells your kidneys how much water to conserve
Describe mechanism of ADH action
- Acts in the collecting tubule & collecting duct
- Increases the expression of Aquaporin-2 on the luminal membrane
Renal effects of ADH
- Increases water absorption
- Controls the rate of urine formation
What is Diabetes Insipidus (DI)?
- ADH related disorder
- excessive urination (polyuria) and complications thereof, caused by an antidiuretice hormone called a vasopressin
What are the 2 types of DI, their causes & therapies?
- Neurohypophyseal (central) DI
- Reduced ADH secretion, normal kidney response
- Caused by
: Brain trauma
: Surgery
: Genetics - Treated by
: Desmopressin (synthetic ADH)
- Nephrogenic DI
- Normal ADH levels, impaired kidney response
- Caused by
: Lithium poisoning
: kidney disease
: genetics - Treated by
: Thiazides
How does Atrial Natriuretic Peptide (ANP) have diuretic action?
In order of
1. increased in cardiac preload
- Increased release of Pre-proANP
- Increased ANP
- Activation of NPR-1 & NPR-2 (Guanylyl Clycase coupled)
- Kidney
:decrease Na reabsorption
: decrease renin release
