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Hormonal contraception

The ideal contraceptive is fully reversible, 100% effective, very convenient and easy to use, free of adverse side-effects, effective against STDs, maintenance-free and cheap.

Combined Oral Contraceptive Pill (estrogen and progesterone) (the Pill)

  • Usually packaged either as a 21-pack or 28-pack that includes a week of sugar pills; there is withdrawal bleed during this week. The tablets most risky to miss are the first ones on either side of the sugar pills; if you miss these, the hormone-free period is lengthened, leaving greater time for the AP to recover from suppression
  • Available as monophasic (fixed amount of hormone in each of the 21 pills) or bi/triphasic (varying amounts of hormone reduces the total amount taken overall)
  • It works by negative feedback onto the anterior pituitary to inhibit secretion of LH and FSH; this suppresses development of follicles, and also prevents the mid-cycle FSH surge
    • Prevents ovulation (LH blocked)
    • Hostile cervical mucus that creates a thicker plug and resists penetration of sperm (progesterone)
    • Hostile endometrium that is less receptive to implantation (progesterone). Usually it is cyclic progesterone that primes the uterus for implantation; with constant levels of progesterone throughout the cycle, the endometrium becomes thin and atrophic
  • It is effective, with a failure rate of 0.2-3% per year. Theoretical effectiveness is 99.9%, but user effectiveness 97-98% due to not taking tablets daily, not absorbing from the gut (vomiting or diarrhoea), or other drugs interfering:
    • Drugs that induce liver metabolism of oestrogens by inducing CYP450 enzymes (e.g. rifampicin for TB, phenytoin, carbamazepine or barbiturates for epilepsy or the anti-fungal griseofulvin). This reduces the amount available, and negative feedback may not be sufficient to suppress ovulation
    • Broad spectrum antibiotics (amoxicillin, tetracyclines) affect normal bowel flora which would then affect blood levels of oestrogen. Oestrogen is normally conjugated in the liver before entering the bowel via the bile. Normal bowel flora then break down the estrogen and allow it to reabsorbed
  • Reversibility – median time for conception is 3 months. There may be post-Pill amenorrhea (unprotected sex but does not conceive) either because they weren't fertile to begin with, or the anterior pituitary remains suppressed (easily fixed using an estrogen antagonist to push the estrogen off the AP receptor)

Oestrogens

Naturally occurring Synthetic oestrogens
* Oestadiol – most biologically active, both males and females, main estrogen pre-menopause
  • Oestriol – largely placental estrogen, high levels in pregnancy
  • Oestrone – converted in peripheral adipose tissue from androgens, main oestrogen in postmenopausal women
* Ethinyl oestradiol (EE) – most commonly used in the Pill
  • Mestranol – prohormone, 3 methyl ester of EE converted to ethinyl oestradiol


Effects of synthetic estrogens are similar to natural estrogens – promote growth, cause ovulation (with LH), endometrial proliferation and vaginal cornification. Dosage of oestrogens in COCP is currently between 20-50µg, combined with progestin. There is not much variability in estrogen levels in pills; dosage of progestin often differs for different potency.

Progestins are synthetic progesterones (progesterone is virtually inactive when taken orally). They can bind to oestrogen, progesterone, testosterone and corticosteroid receptors, therefore effects are complex:

Derivatives of 19 nor-testosterone Derivatives of levonorgestrel (3rd generation) Other
* Norethisterone
  • Levonorgestrel – more potent, mildly androgenic
Possibly less androgenic, increased risk of thrombosis
  • Gestodene
  • Norgestimate
  • Desogestrel
* Cyproterone (17αOH progesterone derivative) – anti-androgenic
  • Drospirenone (17α spironolactone derivative), mildly androgenic and mildly diuretic
  • Medroxyprogesterone (17αOH progesterone derivative), must be injected

Side effects of COCP are usually dose-dependant

  • DVT and pulmonary embolism, both due to inappropriate blood clotting. Hypercoagulability is oestrogen-dependant, with increased coagulation factors (fibrinogen, prothrombin, factors VII, VIII, X). Smoking and age increases risk, as does surgery as this predisposes to clot formations.
  • Hypertension – not significant with low dose; more likely if older, heavier and have family history
  • Hepatic effects – estrogen has a proliferative, enzyme inducing effect (rise in transaminases) and cholestatic effects. Generally not a problem, but adversely effects predisposed individuals
  • Myocardial infarction and coronary artery disease – protective against atheromatous deposition in animal experiments; smokers over 35 have 8-fold increased risk
  • Stroke – increased risk related to hyper-coagulability; for non-smokers without other risks there is no increased risk
  • Cancer – small increased risk of breast cancer (1.2x), but decreased incidence of ovarian and endometrial cancer (progestins probably protective)

Minor side effects

    • Mild nausea, flushing, dizziness, sore breasts
    • Mood changes – irritability, short temperedness, depression
    • Abnormal glucose tolerance test – glucocorticoid receptor affented = progestagenic
    • Acne and hirsutism – due to androgenic effects of progestagen
    • Chloasma – estrogenic effect, blotchy brown pigmentation on face
    • Weight gain and fluid retention – due to progestagen binding to aldosterone receptors
Absolute contraindications Relative contraindications
* Presence or history of thromboembolic disease
  • Cerebral vascular disease
  • Myocardial infarction
  • Coronary artery disease
  • Congenital hyperlipidaemia
  • Known or suspected CA breast
  • Cancer of female reproductive tract or other hormone-responsive neoplasia
  • Abnormal undiagnosed vaginal bleeding
  • Pregnancy
  • Past or present liver tumours or impaired liver function
  • Women over 35 years who smoke more than 15 cigarettes per day
* Migraines, especially with aura (warning sign) – vasoconstriction of cerebral arteries that increases risk of blood clotting (as does the Pill)
  • Hypertension
  • Diabetes mellitus
  • Gallbladder disease
  • Obstructive jaundice of pregnancy


Progesterone-only pill (mini pill)

  • Progestin only (levonorgestrel or norethisterone), dose significantly lower than COCP
  • No hormone free interval, pill must be taken every day
  • Use – intolerance to estrogen or high doses of progesterone, or breastfeeding women (oestrogen inhibits lactation)
  • Mechanism – may suppress ovulation (if pituitary glands very sensitive), hostile cervical mucus and endometrium
  • Theoretical effectiveness 99%, user effectiveness 96-97.5% due to late or missed tablets (must take tablets at the same time every day) or not absorbing tablets. It is not affected by other drugs.
  • Side effects – episodes of irregular unpredictable spotting and breakthrough bleeding
  • Contraindications – undiagnosed vaginal bleeding, benign or malignant liver disease, breast cancer
  • Dysmenorrhea (painful menstruation) may be cured. Usually caused by high levels of prostaglandin α2 produced by a thick proliferative endometrium. As the pill inhibits growth of the endometrium, production of PG2α is decreased.

Progesterone injections (Depo Provera)

  • Intramuscular medroxyprogesterone acetate injection every 3 months
  • Use – intolerance to oestrogen, breast feeding, unreliable tablet-takers
  • Mechanism – hostile mucus and endometrium; suppression of ovulation (progesterone dose is high enough)
  • Effectiveness– failure rate of about 1% per year, usually due to patients getting injections late
  • Infertility may persist for many months after ceasing treatment

Progesterone implant (Implanon)

  • Rod inserted usually on the inner arm which releases progesterone (levonorgestrel) continuously at a very slow rate
  • Mechanism – suppression of ovulation, hostile cervical mucus and endometrium
  • Effectiveness – failure rate of 0-0.1% per year (most effective), failures probably due to errors in insertion

Progesterone Intra-Uterine device (Mirena)

  • Levonorgestrel – impregnated intrauterine device
  • Use – women with completed families, unreliable tablet-takers, intolerance to estrogens or systemic progestagens
  • Mechanism – hostile cervical mucus and endometrium inhibits sperm movement and function, reduces monthly endometrial proliferation
  • Effectiveness – failure rate 0.1% per year (rare), usually because IUD is expelled from uterus

Nuva ring

  • Small flexible vaginal ring containing oestrogen (low dose 15 µg) and progesterone that is efficiently absorbed through the vagina mucosa
  • Inserted at the beginning of a menstrual cycle and removed after 21 days, allowing the withdrawal bleed. New ring is inserted after a 7 day ring-free period
  • Fewer side effects than taking the pill orally, no need to remember to take it every day

Emergency contraception (Morning After Pill)

  • Postinor – levonorgestrel only, either two doses 12 hours apart or as a single double dose (effective either way)
  • Can be effective for up to 5 days
  • Mechanism – hostile endometrium and cervical mucus, delays or prevents ovulation, interferes with functioning of corpus luteum, causes alteration in tubular transport of sperm, egg and embryo (increases transport of fertilized ovum so it arrives when the uterus is not yet prepared for implantation)
  • Effectiveness – for every 10 pregnancies that would have occurred, 6-7 are prevented


Withdrawal bleed – during the hormone-free week, the blood levels of estrogen and progesterone fall, resulting in detachment of the endometrium from the uterus and loss from the vagina. There is also a loss of negative feedback with consequent rise in FSH and early follicular development; this is suppressed on resumption of the hormones after 7 days. If this period is extended, FSH levels can increase and follicular development progresses further, risking ovulation. A withdrawal bleed is no guarantee that she will not ovulate after the hormone-free week.



Breakthrough bleeding is mid-cycle bleeding, and indicates that the pill is not biologically effective, due to

  • Dose it too low or not being taken properly
  • GIT infection or malabsorption
  • Drug interactions

Pharmacology (ANS)

  Parasympathetic (rest and digest) Sympathetic (fight or flight)
  * Long preganglionic nerves which synapse at ganglia near or on the target organ
  • Excitatory effect on organs (except CardiVS)
* Short preganglionic nerves, long post-ganglionic nerve
  • Inhibitory effect on organs (except CVS)
Preganglionic neurotransmitter Ach Ach
Postganglionic neurotransmitter Ach Noradrenaline (except for sweat glands)






Cholinergic receptors Adrenergic receptors
Respond to Ach (acetylcholine) Respond to Adrenaline and Noradrenaline
Nicotinic receptors
  • NM (neuromuscular junction)
  • NN (autonomic ganglia, adrenal medulla, CNS)
α-adrenergic receptors
  • α1 (blood vessels , other smooth muscle)
  • α2 (presynaptic nerves)
Muscarinic receptors
  • M1 (CNS, glands)
  • M2 (heart and smooth muscle)
  • M3 (smooth muscle and glands)
  • M4 (nerve cells), M5 (unknown function)
β-adrenergic receptors
  • β1 (heart)
  • β2 (smooth muscle)
  • β3 (fat tissue)

ANS control of blood pressure:

Most blood vessels do not receive parasympathetic innervations, so vasodiation caused by M3 activation only occurs as a result of circulating muscarinic agonists, not due to ACh released from nerve terminals. Activation of M3 on endothelial cells stimulates the release of nitric oxide, causing relaxation of smooth muscle and hence vasodilation.

Cholinergic mechanisms

Baroreflex (reflex trigeerd by stimulation of baroreceptor) control of blood pressure:

'Cholinergic': a neuron or axon that is capable of releasing the neurotransmitter ACh (acetylcholine) when a nerve impulse passes. The system includes

  • Entire peripheral nervous system
  • Pre-ganglionic neurons of the sympathetic system; postganglionic sympathetic neurons for sweat glands
  • Somatic motor neurons –contraction of skeletal muscle fibres
  • CNS – regulates plasticity, arousal and reward

Cholinergic neurotransmission

  1. Re-uptake of choline \[inhibited by hemicholinium\]
  2. ACh synthesised from acetyl-A and choline; packed and stored in vesicles \[inhibition of vesicular ACh transporters\]
  3. When an action potential reaches the nerve ending, calcium influx causes exocytosis of ACh into the synaptic cleft \[exocytosis inhibited by Botox and calcium channel blockers\]
  4. Interactions between Ach and receptors \[inhibited or stimulated by antagonists and agonists\]
  5. Termination of ACh effects as it is hydrolysed (into acetate and choline) by the enzyme acetylcholinesterase \[inhibited by acetylcholinesterase inhibitors\]
Parasympathomimetics –act by stimulating/mimicking ACh Anticholinergics –reduce the effects of Ach (block)
* Muscarinic receptor agonists
    • Pilocarpine (glaucoma)
    • Bethanechol (post-operative urinary retention)
  • Nicotinic receptor agonists
    • Nicotine (smoking cessation)
  • Acetylcholinesterase inhibitors
    • Physostigmine (glaucoma)
    • Neostigmine, pyridostigmine (myasthenia gravis)
* Antimuscarinic agents (widely used) – atropine
  • Botulinum toxin – blocks exocytosis of ACh – (urinary incontinence, dystonia, cosmetics)
  • NMJ blocking drugs – depolarising (succinylcholine) and non-depolarising (tubocurarine) agents; (adjunct to general anaesthesia)
  • Ganglionic blockers – hexamethonium

Muscarinic receptors (G-protein-coupled receptors); 5 molecular subtypes:

  • 'Odd' receptors (M1,3,5) couple with Gqto activate the inositol pathway that increases calcium influx
  • 'Even' receptors (M2,4) act through Gi to inhibit adenylyl cyclase and thus reduce intracellular cAMP

Muscarinic receptor agonists limited clinical uses, mainly for the treatment of glaucoma where the aqueous humour pressure is raised due to blockage. Pilocarpine contracts ciliary muscle and increases aqueous humour outflow which results in reduced intraocular pressure. Side effects include excessive sweating and salivation, bronchospasm, bradycardia, hypotension, diarrhoea, ciliary spasms and miosis (pupil constriction).

ACh is the endogenous muscarinic receptor agonist, but has virtually no therapeutic use as it is very quickly hydrolysed (short life) and is non-selective for receptor sub-types. Structural features:

  • Positively charged quaternerary ammonium group
  • Ester group which has a partial negative charge and is easily hydrolysed by acetylcholinesterase

Muscarinic receptor antagonists (antimuscarinics), widely used in clinical practice. Common effects:

  • CNS – anti-tremor (Twitching results from ACh remaining in synapse for long time), used against motion sickness
  • Visual system – pupil dilation, poor accommodation (can't focus on near point)
  • Decreased secretions – tears, saliva, gastric acid, sweat
  • Bladder – reduced micturition
  • CVS – tachycardia, little effect on BP


Uses of antimuscarinics Side effects
* Urinary urge incontinence
  • Motion sickness
  • Parkinson's
  • Bronchodilation
  • Peptic ulcer
    (reduce gastric acid secretion)
* Gut motility reduced – constipation
  • Retention of urine
  • Blurred vision, photophobia
  • Decreased exocrine gland secretions– dry mouth, hyperthermia
  • Most do not cross the BBB but high doses of antagonists that do can cause CNS excitation (agitation, disorientation, hyperactivity)
  • Toxic doses lead to depression, circulatory and respiratory failure

Atropine uses:

  • Resuscitation – injection used in treatment of bradycardia in cardiac arrest after myocardial infarction
  • Premedication in anaesthesia – inhibition of bronchial and salivary secretions, and relax bronchoconstricton
  • First line antidote for organophosphate poisoning and acetylcholinesterase inhibitor overdose(creates to much Ach)
  • Anti-spasmodic and anti-diarrhoea – GIT inhibition
  • Mydriatic (pupil dilation) to facilitate eye examination (but tropicamide generally preferred because of shorter duration effect)

Nicotinic receptors (ligand-gated ion channels) are pentameric (5) proteins, made up of combinations of α, β, γ, δ, ε subunits. Neuronal-types (NN) are formed with α and β subunits; Muscle-types (NM) are formed with any of the 5.

Nicotinic receptor agonists Nicotine found primarily in the leaves of tobacco. Pharmacological effects are stimulation followed by depression at nicotinic receptors. There is strong psychological and physical dependence.

  • ↑ blood pressure, tachycardia, ↑ cardiac output, ↑ saliva secretion, variable effects on gut motility

Varenicline is new medication for smoking cessation. It is a partial agonist at α4β2 NN receptors. Mechanisms:

  • Agonist action – selectively stimulates the receptors to alleviate symptoms of craving and withdrawal
  • Antagonist – blockage of rewarding and reinforcing effects of smoking by preventing nicotine binding to receptors

Neuromuscular blocking agents

  Non-depolarising Depolarising
Type of block Competitive antagonist Agonist
AChE inhibitors ↑ ACh can reverse effect ↑ ACh has no effect
Muscle twitching Does not occur Occurs at onset
Tetanic fade ↓ ACh No change in ACh release
Example Vecuronium (pure NM blocker) used in surgery to relax muscles Succinylcholine has an ultra short action due to hydrolysis by plasma cholinesterase. Used as muscle relaxant during emergency intubation; can cause bradycardia, apnea, hyperkalemia

Exocytosis of ACh blocksBotulinum toxin is a neurotoxin produced by a bacterium that causes food poisoning. It inhibits calcium-dependent ACh release; and has several uses including cosmetics, incontinence, and many forms of dystonia (neurological movement disorder; sustained muscle contractions cause twisting and repetitive movements)

Acetylcholinesterase inhibitors – inhibit breakdown of ACh which thus accumulates at the cholinergic synaptic clefts and produces effects equivalent of excessive stimulation of ACh receptors (i.e. acts like an ACh agonist)

  • Autonomic actions – enhancement of ACh at parasympathetic synapses (bradycardia, ↑saliva, ↑gut contractility)
  • Neuromuscular junction – repeated firing of muscle fibre leading to twitching and increased muscle contraction
  • Medium duration (physostigmine for glaucoma, neostigmine for post-operative reversal of NMJ blockage, urinary retention and myasthenia gravis) – have an amine group and an ester group; similar to ACh. They bind to the active site of AChE where they are slowly hydrolysed
  • Irreversible anti-acetylcholinesterases – (organophosphate compounds), bind covalently to the AChE active site

Myasthenia Gravis (MG) is a neuromuscular autoimmune disease in which antibodies destroy the NMJ, resulting in muscle weakness and fatigue. AChE overdose is treated by administering atropine (and vice versa)

Adrenergic mechanisms

Catecholamines are compounds with the distinct structure of a benzene ring with two hydroxyl groups, an intermediate ethyl chain, and a terminal amine group. Endogenous catecholamines include epinephrine, norepinephrine, dopamine, para-octopamine, meta-octopamine. Synthesis of these requires several conversions and enzymes (e.g. tyrosine hydroxylase to convert tyrosine to dopa:


Metabolism of epinephrine and norepinephrine – the two are broken down by two enzymes; MAO (monoamine oxidase) and COMT (catechol-o-methyltransferase). The order depends on location in the body;


Storage and release of catecholamines – tyrosine is brought into the nerve terminal and converted into dopamine. This is taken up into vesicles and there converted into norepinephrine that can then be released. Release is controlled by:

  • α2 adrenergic receptors sit on the presynaptic side and work through negative feedback; activating the α2-AR turns inhibits release of norepinephrine. This is done through inhibition of adenylate cyclase= ↓cAMP = ↓opening of calcium channels = ↓release of vesicles (α2 receptors are on presynaptic nerves)
  • Norepinephrine transporter (NET, Uptake 1) take NE back into the neuron where it is repackaged into vesicles
Epinephrine vs. norepinephrine affinity –
  • α1, β1 – norepinephrine > epinephrine
  • α2, β2 – epinephrine > norepinephrine
  • β3 – norepinephrine = epinephrine (equal affinity)
Adrenoceptors belong to the GPCR superfamily. Subtypes:
  • α1 receptors couple through Gq= ↑calcium
  • α2 couple to Gi = inhibit adenylate cyclase, ↓cAMP

Effects of adrenergic stimulation

Eye α1 – contraction of radial muscle, mydriasis (pupil dilation)

β2 – ciliary muscle relaxation (allowing for far vision)

Heart β1 – ↑heart rate, ↑ conduction velocity, ↑ contractility (predominant heart receptor)
Abdominal blood vessels α1 – vasoconstriction

β2 – vasodilation

Kidneys β1 – ↑ rennin (=↑ blood pressure through actions of angiotensin)
Liver α1, β2 – glycogenolysis and gluconeogenesis
Pancreas α1 –↓ insulin secretion β2 –↑ insulin secretion
Adipose tissue β3 – ↑ lipolysis and thermogenesis
Lungs α1 – bronchoconstriction β2 – bronchodilation
Upper GIT α1 – sphincter contraction β2 – ↓ tone and motility
Bladder α1 – sphincter contraction β2 – detrusor relaxation
Prostate α1 – prostate contraction

Indirectly acting sympathomimetic amines – mimic epinephrine and norepinephrine, and activation of sympathetic nervous system –amphetamine, tyramine (in diet, but no action as it is destroyed by MAO in gut), ephedrine. All have a similar structure to NE, so can use the NET for transport into the nerve terminal. They are transported into the synaptic vesicles by VMAT (vesicular monoamine transporter); this is a reciprocal transporter, so uptake of the sympathomimetic amine leads to export of NE out of the vesicles, and release of NE that can then activate the postsynaptic receptor.

  • CNS action, bronchodilation, ↑ arterial pressure, ↑ heart rate, ↓ gut motility
  • Uses – CNS stimulant in narcolepsy, hyperactive children, appetite suppressant, nasal decongestion (ephedrine)
  • Adverse– tachycardia, insomnia, acute psychosis with overdose, dependence

Norepinephrine transporter inhibitors – no transport = higher concentration in the post-synaptic cleft = activation of SNS

  • Tricyclic antidepressants – despiramine – causes postural hypotension and sedation
  • Psychomotor stimulants – amphetamine, cocaine – locomotor stimulation, euphoria, excitement, anorexia
  • Adverse effects – dry mouth, constipation, headache, drowsiness, dizziness, excessive sweating and insomnia, tremors, anxiety, loss of appetite, agitation, increased risk of seizure

Monoamine oxidase inhibitors – Moclobemide anti-depressant; adverse effects include postural hypertension, weight gain, CNS stimulation – restlessness, insomnia. '<u>Cheese effect'</u>: hypertensive crisis when foods containing tyramine are eaten (liver, red wine, cheese and vegemite). Tyramine in the gut is normally metabolized by MAO-A; if this is inhibited (to increase NE in synaptic cleft), the tyramine is not broken down in the gut and can act (as indirectly acting sympathomimetic amines) = hypertensive crisis (vasoconstriction)

DIRECT AGONISTS Major actions Uses Adverse effects
α1 – phenylephrine. Metabolised by MAO when taken orally Smooth muscle contraction Nasal decongestion, treatment of uveitis, mydriasis for eye surgery Hypertension
α2 – clonidine (selective over α1 and β, but not between the 3 α2 types) ↓ blood pressure, heart rate hypotensive response

↓ aqueous humour production

Inhibits release of NE – Systemic hypertension, glaucoma, migraine Dry mouth and sedation, bradycardia, sexual dysfunction
β1 – dobutamine (low dose will activate only β1, high dose will activate β2 and β3) Selectively increases inotropy without effecting chronotropy or blood pressure. ↑ blood flow in coronary, renal and femoral arteries Angina pectoris which is refractory to treatment with nitrate and calcium channel blockers Dysrhythmias
β2 – salbutamol, formoterol, terbutaline Relax bronchial smooth muscle. Will affect β1 in heart in high conc. Asthma, COPD Skeletal muscle tremor, tachycardia
Non-selective β – isoproterenol

(same affinity in all β).

↑ strength (inotropic) and rate (chronotropic) of heart contraction. Relaxes smooth muscle Stimulate heart rate Palpitations, tachycardia, headache and flushing
ANTAGONISTS Major actions Uses Adverse effects
α –phenoxy-benzamine phentolamine Decreased arterial pressure

Postural hypotension

Rarely used

Phaeochromocytoma surgery

Hypotension, flushing, tachycardia, impotence
α1 – prazosin Inhibits vasoconstriction

Inhibits smooth m. contraction

Hypertension, heart failure Hypotension, tachycardia, impotence flushing, nausea
α1A – tamsulosin Inhibits smooth muscle contraction Benign prostate hyperplasia Failure of ejaculation, hypotension, cough, poor pupil dilation, diarrhoea,
α2 – yohimbine ↑ sympathethic ouflow = release of NE from nerve endings = activation of α1 and β1 AR in the heart and peripheral vasculature No clinical use Hypertension, CNS (anxiety, antidiuresis, dizziness, flushing, headache, increased motor activity)
β – propranolol, timolol Non-selective full antagonists, therefore inhibit both the β1 and β2 AR to the same extent at a given dose. Glaucoma, angina, HT, migraine, cardiac arrhythmias, congestive heart failure, tremor Cardiac failure, bronchospasm, bradycardia, cold extremities, fatigue, hypoglycemia.

Not suitable for asthmatics, as B2 antagonist causes bronchoconstriction

β1 – atenolol Negative chronotropy and inotropy, ↓ sympathetic outflow from the CNS, suppression of renin release from the kidneys, ↓ serum free fatty acid concentration, ↑ triglycerides Glaucoma, hypertension, angina, myocardial infarct, migraine Postural hypotension, bradycardia, hypoglycaemia, bronchospasm (high dose). Selectivity reduces pulmonary and glucose metabolism side effects, so safe for those with asthma and diabetes

β-blockers have no effect on resting heart rate when sympathetic cardiac tone is minimal. Antagonists have no action of their own; they only inhibit the actions of agonists. At rest there is little agonist present therefore the antagonists do not change heart rate. During exercise there is agonist present and the β-adrenoceptor antagonist inhibits the actions of norepinephrine and epinephrine at the β1-AR of the heart. Activation of β1-AR leads to increased heart rate therefore the β-AR antagonists will inhibit this increase in exercise heart rate