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
