Final Flashcards
Adrenergic Receptors
-GPCRs
-Desensitization occurs via down-regulation of receptors - some of the signaling factors go back to the receptor to act on it and ultimately down regulate the receptor, usually via phosphorylation
-Agonist therapeutic effects will decrease over time due to this
-Types and Subtypes
+ALPHA Adrenergic Receptors: ALPHA 1 and ALPHA 2
+BETA Adrenergic Receptors: BETA 1, BETA 2, and BETA 3
Alpha 1 Adrenergic Receptor
- Postsynaptic-Causes smooth muscle contraction
- Expressed in most vascular smooth muscle (arterial and venous) - activation results in contraction and increased peripheral resistance and decreased venous capacitance, leading to increased BP
- Vessels of the skin and nasal mucosa predominantly express alpha 1 receptors (nasal decongestants)
- Contract pupillary radial (dilator) muscles
Alpha 2 Adrenergic Receptor
- Presynaptic
- Inhibit neurotransmitter release
- In the CNS, they are expressed postsynaptically and can cause decrease in BP
Beta 1 Adrenergic Receptor
- Predominantly expressed in the heart
- Positive chronotropy and ionotropy
- Juxtaglomerular cells increase renin secretion
Beta 2 Adrenergic Receptor
- Smooth muscle relaxation (respiratory, uterine and vascular)
- Liver - stimulates glycogenolysis
- Pancreas - increases insulin and glucagon production
- Eye - regulates aqueous humour production
Beta 3 Adrenergic Receptor
- Expressed in adipose tissue and in the bladder
- Recently being used for overactive bladder
Adrenergic Agonists: Cardiovascular Effects
HEART -Positive ionotropy -Positive chronotropy - increased automaticity and shortened refactory period VASCULAR SMOOTH MUSCLE -Alpha 1 - vasoconstriction -Beta 2 - vasodilation -Alpha 2 - vasodilation
Baroreflex
-Any effect a sympathomimetic drug has on BP can induce a compensatory baroreflex aimed at restoring homeostasis
-Baroreceptors are located all over and they sense the change in BP and by way of a very simple reflex, sends signal straight to the MEDULLA, which immediately sends a signal back to the heart to invoke change
+Increase in BP –> PARASYMPATHETIC signal –> mAChR decreases BP and HR
+Decrease in BP –> SYMPATHETIC signal –> adrenergic receptors increase HR and BP
Cardiovascular Effects of Noradrenaline
- Causes significant vasoconstriction due to ALPHA 1 AGONISM and because it has low affinity for beta 2
- Reflex bradycardia overrides the agonism at beta 1
Cardiovascular Effects of Adrenaline
- Variable effects on peripheral resistance due to agonism at both BETA 2 and ALPHA 1 receptors
- Initial increase in BP due to ALPHA 1 effect and then the HR increases due to BETA 1 (but the effect is not as high as isoproterenol because there is the baroreflex acting to decrease HR)
- Rapid infusion can result in baroreflex induced bradycardia
- Slower infusion may escape baroreflex
Cardiovascular Effects of Isoproterenol
- Selective for only BETA receptors
- Decreases peripheral resistance due to BETA 2 effects (BP decreases)
- Increases HR and contractility due to direct BETA 1 effect and due to baroreflex induced tachycardia
Cardiovascular Effects of Phenylephrine
- Selective for only ALPHA receptors
- Significant vasoconstriction due to ALPHA 1 AGONISM (BP increases)
- Baroreflex-induced bradycardia (HR decreases)
Adrenergic Agonists: Metabolic Effects of Lipids
Lipolysis
- Stimulated by BETA 3
- Inhibited by ALPHA 2
Adrenergic Agonists: Metabolic Effects of Carbohydrates
Glycogenolysis
- Stimulated by ALPHA 1 and BETA 2 receptors in the liver
- Increases glucose release in the liver
Adrenergic Agonists: Metabolic Effects of the Endocrine System
- INSULIN secretion is stimulated by BETA 2, but inhibited by ALPHA 2 activation
- RENIN secretion is stimulated by BETA 1, which is very important for controlling BP by setting off cascade to produce angiotensin (leading to eventual increase in BP)
Adrenergic Agonists: Metabolic Effects of the CNS
- Endogenous catecholamines are restricted by the BBB
- Effects of exogenous include: nervousness, fear, anxiety, and euphoria
Alpha 1 Agonists
USES
-Treat hypotension, nasal decongestant, produce mydriasis
Drugs
- METHOXAMINE increases peripheral resistance to treat hypotension
- PHENYLEPHRINE treats hypotension, topically used to produce mydriasis, as well as decongestant
Oxymetazoline
ALPHA AGONIST used topically as a decongestant
Alpha 2 Agonists
USES
- Treat essential hypertension
- Receptors present in the CNS in CV control centers reduce sympathetic outflow and subsequently decrease sympathetic vascular tone (decrease peripheral resistance)-In periphery, agonists inhibit the release of catecholamines (predominant effect is to decrease peripheral resistance)
Beta 1 Agonists
USES
-Treat congestive heart failure and post-myocardial infarction
Drug: DOBUTAMINE strongly increases ionotropy, therefore useful in increases cardiac output
-Low affinity for beta 2 receptors ensures little decrease of peripheral resistance, which is important for keeping BP levels normal
Beta 2 Agonists
USES
- Asthma and COPD - Pulmonary receptors are targeted by inhalation, and so B2 stimulation results in bronchodilation and also decreased leukotriene and histamine release from pulmonary mast cells
- Premature labour
- Anaphylactic shock
Drugs:
- RITODRINE is administered systemically to stop premature labour-Effects last several days which is long enough to treat mother with corticosteroids to reduce risk neonatal respiratory distress
- Short acting B2 agonists: METARAMINOL, ALBUTEROL, TERBUTALINE are used to treat asthma flare ups
- Long acting B2 agonists: FORMOTEROL, SALMETEROL are used chronically to avoid flare ups
Epinephrine
USES
-Treat anaphylactic shock
Anaphylaxis is characterized by bronchospasm, mucous membrane congestion and severe hypotension
-Epinephrine is very effective in treating these symptoms
Indirect Sympathomimetics
- Indirectly increase noradrenaline neurotransmission by increasing levels in the synapse
1. AMPHETAMINE
2. EPHEDRINE
Amphetamine
INDIRECT SYMPATHOMIMETIC
-Stimulates release of NA from nerve terminal
-Uses
+CNS stimulant
+Stimulates respiration centres+Decreases perception of fatigue
+Euphorant
+Appetite suppressant
-Therapeutic uses are now limited due to strong abuse potential of the drug
-METHYLPHENIDATE (Ritalin) used to treat ADHD and narcolepsy
Ephedrine
INDIRECT SYMPATHOMIMETIC
-Stimulates release of NA and is an agonist of alpha and beta receptors
-Uses
+High bioavailability and long duration of action
+May enter the CNS and has some stimulant activity
+Increases HR and cardiac output
+Causes bronchodilation
-One of its enantiomers, PSUEDOEPHEDRINE, is commonly used as a decongestant
Alpha 1 and Alpha 2 Antagonists
USES
- Treat pheochromocytoma
- Very effective in decreasing hypertension resulting from high adrenergic tone
- Mixed alpha receptor antagonists are given pre-operatively or during surgery to prevent/treat hypertension
DRUGS
- PHENTOLAMINE
- PHENOXYBENZAMINE
Pheochromocytoma
- Tumour of the adrenal medulla that secretes large amounts of adrenaline and noradrenaline
- Symptoms reflect high sympathetic tone (hypertension, sweating, etc.)
Alpha 1 Antagonists BP and HR
PHENTOLAMINE ONLY
- Decreases BP, but not by much UNLESS someone has hypertension
- Increases HR due to baroreflex
EPINEPHRINE BEFORE PHENTOLAMINE
- Increase in BP (peripheral resistance, alpha 1) and cardiac output (beta 1)
- Increase in HR
EPINEPHRINE AFTER PHENTOLAMINE
- Decrease in BP
- Increase in HR (beta 1) + baroreflex
Phentolamine
ALPHA 1/2 SELECTIVE ANTAGONIST
- Reduces BP due to decreased peripheral resistance
- Major adverse effects are tachycardia due to baroreflex and orthostatic hypotension
- Used in the treatment of pheochromocytoma
Phenoxybenzamine
ALPHA 1/2 SELECTIVE ANTAGONIST
- Irreversible
- Due to irreversible activity, its duration of activity is longer than reversible antagonists
- Adverse effects include tachycardia, orthostatic hypotension and nasal stuffiness
Alpha 1 Antagonists
USES
- Essential hypertension (almost always given with diuretic)
- Benign prostatic hyperplasia (hyperactive smooth muscle of the bladder and prostate –> feel the need to pee all day err day)
- Raynaud’s phenomemnon
CV Effects - most common adverse effect
- Decrease arteriole and venous tone
- Decreased venous tone results in venous pooling and reduced venous return to heart-Venous pooling can result in orthostatic hypotension –> trigger reflex-induced tachycardia
DRUGS
- PRAZOSIN
- DOXAZOSIN
- TAMSULOSIN
Prazosin
ALPHA 1 SELECTIVE ANTAGONIST
- Moderate bioavailability
- Half life is about 3 hours
- Used primarily in treatment of essential hypertension, and also benign prostatic hyperplasia
Doxazosin
ALPHA 1 SELECTIVE ANTAGONIST
- Used for both essential hypertension and BPH
- Half life about 22 hours and therefore requires less frequent dosing
Tamsulosin
ALPHA 1 SELECTIVE ANTAGONIST
- Primarily used to treat BPH (due to alpha 1 subtype specificity of bladder and prostate)
- Relatively greater potency in inhibiting contraction in prostate smooth muscle vs. vascular smooth muscle
Beta-Blockers
Can be:
- Nonselective B1 + B2 (PROPANOLOL and TIMOLOL)
- Nonselective B1 + A1 (LABETOLOL)
- Cardioselective B1 only (METOPROLOL, ATENOLOL, ACEBUTOLOL)
USES
1. Hypertension
+Used alone or in combo with vasodilator or diuretic
+Mechanism not well characterized
2. Stable angina pectoris (ischemic heart disease)
+Reduce frequency of anginal attacks and increase exercise tolerance in patients with angina
+Slows and regulates HR
3. Arrhythmias (class 1B anti-arrhythmic)
+Useful for treating both supraventricular and ventricular arrhythmias
4. Secondary prevention of myocardial infarction
5. Glaucoma
+Reduce intraocular pressure via decrease aqueous humor production
6. Hyperthyroidism (symptomatic treatment)
7. Migraine prophylaxis
8. Psychiatric disorders (performance anxiety)
Respiratory Effect - Blockage of B2 receptors may lead to increased bronchoconstriction, especially in asthmatics
Propanolol
NON SELECTIVE BETA BLOCKER
- Prototypical beta blocker
- Short half life, so often used in hospitals
USES
- Essential hypertension
- Angina
- Certain arrhythmias
- Migraine prophylaxis
Timolol
NON SELECTIVE BETA BLOCKER
- Ocular Use: Treatment of glaucoma
- Systemic effects are common even after local application
- Contraindications: asthmatics and congenital heart failure
Metoprolol and Atenolol
SELECTIVE BETA 1 BLOCKER
- As potent as propanolol at B1 receptors
- Used to treat angina and hypertension
- Safer in those with asthma or diabetes because they have no B2 action
Acebutolol
SELECTIVE BETA 1 BLOCKER
- Partial B1 agonist
- Less efficacious than antagonists but are less likely to cause bradycardia and affect plasma lipids
- Aka “beta blockers with intrinsic sympathomimetic activity”
Labetolol
NONSELECTIVE B1 + A1 ANTAGONIST
- Decreases BP without reflex tachycardia (A1 treats hypertension, B1 blocks reflex)
- Useful in treating hypertensive emergencies and pheochromocytoma
Beta-Blockers: Toxicity
CNS
- Sedation
- Sleep disturbances
- Depression
- Precipitation of asthma
- Exacerbation of hypoglycemia
Cardiac - In patients after myocardial infarction or with CHF, cardiac output may be highly dependent on sympathetic signaling
Reserpine
INDIRECT ACTING SYMPHATHOLYTIC
-Alkaloid Rauwolfia serpentina
-Reduces the storage of catecholamines in nerve terminals
-Used occasionally for hypertension
-Depletion of catecholamines decreases BP over several days, the lack of catecholamine signaling causes an upregulation in adrenergic receptors and creates a super sensitivity to adrenergic agonists –> can be bad news bears
-Adverse effects
+Excessive bradycardia, flushing of skin, congestion, and postural hypotension
+Parkinsonism (depletion of dopamine)
+Depression (depletion of 5HT)
+Abdominal cramps and diarrhea
OTHER DRUGS
- Guanethidine
- alpha-Methyldopa
Endocrine Pharmacology
Study of drugs that are hormones or hormone derivatives, or drugs that may modify the synthesis or action of normally secreted hormones
Hypothalamus and Pituitary
- Portal venous system carries small regulatory hormones from the hypothalamus to the ANTERIOR PITUITARY
- POSTERIOR PITUITARY hormones are synthesized in the hypothalamus and transported by neurosecretory fibres (hypophyseal tract) into the stalk of the posterior pituitary where they are released into circulation
Posterior Pituitary Secretions
Neurohormones
- Oxytocin
- Vasopressin
Anterior Pituitary Secretions
- FSH/LH
- ACTH
- TSH
- GH
- Prolactin
Growth Hormone
- Produced by somatotropes in the anterior pituitary
- Release is stimulated by GH releasing hormone and inhibited by somatostatin
- Half of circulating GH is bound to a specific protein and binding results in decreased clearance and 10X increased half-life
- Plasma protein binding also reduces biological activity
- Estrogen and obesity increase plasma protein concentration
- Secretion varies throughout life but is highest during childhood, reaches maximal levels as puberty and declines during adulthood
- Secreted in pulsatile, irregular rhythms
- Amplitude of pulsatile secretion is greatest at night and begins shortly after the onset of deep sleep
Regulators of Growth Hormone Secretion
POSITIVE
- DA-5
- HT
- Alpha2 Agonists
- Hypoglycemia
- Exercise
- Stress
NEGATIVE
- Beta Agonists
- IGF-1
- GH
- Free Fatty Acids
- Glucose
Effects of Growth Hormone
- During childhood, GH is necessary for longitudinal bone growth (before epiphyseal closure)
- In adults, GH increases bone density
- In adults and children, GH increases lipolysis and gluconeogenesis (in liver)
- Most effects are mediated through IGF-1
- Growth promoting effects are mediated by increased IGF-1 secretion from liver
- Stimulates IGF-1 production in bone, cartilage, muscle and kidney where IGF-1 has an autocrine role
Growth Hormone Deficiency
-May be idiopathic or may be due to damage to the pituitary or hypothalamus
-In children, deficiency results in short stature, adiposity and low growth velocity
-In adults, GH deficiency is associated with increased mortality predominantly due to CV causes
+increased circulating lipids
+reduced exercise tolerance due to reduced muscle mass
+obesity
GH Replacement Therapy (SKIPPED)
Prader-Willi Syndrome \+Autosomal dominant disease \+Growth failure \+Obesity \+Carbohydrate intolerance
Turner Syndrome
+Treatment with GH increases height 4-6 inches
Any condition where there is a deficiency in GH, will respond much better to replacement therapy than conditions with no deficiency
-Children of short stature only respond modestly to therapy
Growth Hormone Preparations
- GH available in recombinant human form (rhGH)
- Two main preparations
1. SOMATOTROPIN - Identical to endogenous GH
2. SOMATREM - Same as endogenous GH but with added methionine
Growth Hormone Toxicity
- Generally well tolerated
- Sometimes increased intracranial hypertension
- Scoliosis due to rapid growth
Mecasermin (SKIPPED)
- Growth Hormone Treatment of Short Stature
- Complex of recombinant hIGF-1 and IGFBP-3
- Children with short stature may also be due to IGF-1 deficiency, or GH receptor failure
Treatment of Excess Growth Hormone
-GH producing tumors cause acromegaly in adults and gigantism in children
Method 1: Indirectly inhibit GH OCTREOTIDE -Somatostatin analog -Inhibits GH release -45X more potent and half-life is 80 minutes
Method 2: Target GH receptor (more direct)
PEGVISOMANT
-GH receptor antagonist
-Used in treatment of acromegaly
Vasopressin and Oxytocin
-Short peptide hormones (9 aa) only differ by 2 aa
-Cyclic peptides
-Synthesized in the cell bodies of hypothalamic neurons
+SON - vasopressin
+PVN - oxytocin
-Transported to nerve termini that terminate in posterior pituitary
Vasopressin
-Anti-Diuretic Hormone
-Released by posterior pituitary in response to changes in or the presence of
1. Decreased BP/blood volume (volume depletion)
2. Increased blood osmolality (hyperosmolality)
3. Certain drugs including nicotine
4. Pain/nausea
-Release inhibited by
+increased blood volume
+hypo-osmolality
+alcohol
+cold exposure and emotional stress
Vasopressin: Mechanism of Action (SKIPPED)
- 3 types of receptors (V1, V2, V3) that are all GPCRs
- V1 and V3 through Gq11
- V2 through Gs
- V1 is found in vasculature, causing vasoconstriction
- V2 is found in distal convoluted tubule, reabsorbing H20
- V3 is found in pituitary
- Binds to receptor and results in increase in cAMP, which stimulates insertion for aquaporins on the apical border –> water absorption in nephrons
Vasopressin: Effects
-Stimulates water reabsorption from collecting ducts (via V2 receptors; increases BP)
-Stimulates smooth muscle contraction (V1 receptors)
+In vasculature results in vasoconstriction
+increases intestinal motility
+stimulates uterine and cervical contractions
-Blood coagulation increases clotting factor VIII and von Willebrand factor
-ACTH secretion increases ACTH release from AP (V3)
Effects of Other Drugs on Vasopressin (SKIPPED)
- PGE1 and LITHIUM act as antagonists at V2 receptors
- ASA and INDOMETHECIN may potentiate the effects of vasopressin
Desmopressin
- Synthetic analogue of vasopressin
- Greater selectivity for V2 than V1 (ADH:Pressor 1:4000)
- Can be administered IV, SQ, intranasally or PO
- Half life is 1.5-2.5 hours (compared to 15 minutes for vasopressin)
- Nasal bioavailability is 3-4%
- Oral bioavailability is <1%
- Promotes release of factor VIII in the blood coagulation cascade - used for surgery in those with factor VIII deficiency
- May be used to try and control excessing bedwetting
Diabetes Insipidus
- Vasopressin deficiency
- Can be congenital or result from lesions in hypothalamus, posterior pituitary or pituitary stalk
- Characterized by dilute urine and extreme thirst
- Serum is hyper osmotic due to either decreased release or kidney insensitivity to ADH
Other Conditions Involving Vasopressin (SKIPPED)
- Syndrome of inappropriate ADH secretion (SIADH) results in ADH excess and water intoxication, hyponatremia etc
- Treatment of heart failure; V2 receptor antagonists are thought to reduce water retention and improve blood hemodynamics for individuals with heart failure
- Excessive sodium excretion and decreased serum osmolality (vaptans used to treat)
Vasopressin Receptor Antagonists
- Vaptans
- Used for treatment of hypervolemic and euvolemic hyponatremia
- CONIVAPTAN was first to be approved by FDA but does not differentiate between V1 and V2
- TOLVAPTAN targets V2
Oxytocin Effects
- Milk Ejection - primary physiological action is release of milk
- Uterine Contraction - in the pregnant uterus and stimulates prostaglandins that further stimulate contractions
- CNS Effects - acts as a NT and may be involved in social recognition and bonding
- Vascular Effects - Relaxation of circular smooth muscle fibres and lowers BP
Oxytocin Uses
-Labour induction/contraction promotion \+Given IV \+Short half life allows for increased control of effects -Control of post-partum bleeding -Stimulation of milk ejection
Oxytocin Toxicity
-Tetanic contractions that can result in fetal hypoxia
Clonidine
ALPHA 2 AGONIST
- Antihypertensive agent that has a long duration of action because mechanism involves CNS
- Adverse effects: dry mouth, sedation, sexual dysfunction
