Fundamentals of Pharmacology Lecture 10/100 - Drugs affecting the sympathetic nervous system

Describe the physiological importance of the sympathetic nervous system, including the role of the adrenal medulla

The sympathetic nervous system (SNS) prepares us for fear, flight, or fright, but is also involved in minute-tominute regulation of key body functions to maintain homeostasis

Efferent nerves of the sympathetic nervous system (SNS) leave the spinal cord in the thoracic and lumbar regions
Both ACh and noradrenaline  (also called norepinephrine) act as neurotransmitters in the sympathetic nervous system

Describe the process of chemical synaptic transmission at synapses where noradrenaline is the neurotransmitter

Most post-ganglionic nerves in the SNS release noradrenaline (NA) as their neurotransmitter - noradrenergic nerves

Unlike many other nerves, postganglionic nerves in the SNS have swellings along their length called varicosities, and noradrenaline can be released from each varicosity

• Exocytosis is triggered by an increase in the intracellular concentration of calcium ions caused by calcium entry through voltage-gated calcium channels, opened by arrival of the action potential.

• Some of the released noradrenaline will act on receptors found on the target tissue (see later).

• Some however will act on α₂-adrenoreceptors found on the varicosity.  When activated, these receptors will reduce calcium entry by inhibiting the voltage-gated calcium channels and so inhibit any further release of noradrenaline.

• This is a form of “negative feedback”, preventing excessive release of the neurotransmitter.

• Release can also be inhibited by the “noradrenergic neurone blocking” drug  guanethidine.   This drugs acts by a complex, poorly understood mechanism.

Drugs affecting chemical synaptic transmission at synapses where noradrenaline is the neurotransmitter

The norepinephrine transporter (NET) is a member of a family of transporters that remove neurotransmitters from synapses.

Drugs that inhibit such transporters will prolong the lifetime of the neurotransmitter in the synapse, increasing its effects.

One such drug is cocaine, which inhibits NET and so increase the extracellular concentration of noradrenaline in both the peripheral and central nervous systems.

Another such drug is the antidepressant fluoxetine (Prozac®) which inhibits the uptake of the neurotransmitter serotonin in the brain. Fluoxetine is called a Selective Serotonin Reuptake Inhibitor (SSRI).

Explain what is meant by the term “indirectly acting sypathomimetic amines”

tyramine, and the amphetamines

cause release of norepinephrine from its storage vesicles in the sympathetic nerve endings, thereby increasing synaptic concentration and postsynaptic effects

Explain why patients being treated with mono amine oxidase inhibitors (MAOIs) should avoid cheese

Most noradrenaline released will be recycled and end up repackaged into vesicles ready to be released again

the amount recycled can be increased further by inhibniting the enzyme monoamine oxidase so that more gets repackaged into vesifles rather than being destroyed.

Monoamine oxidase inhibitor drugs (MAOIs) have been used to treat some forms of depression (less common these days)

One of the reasons they are not used is because patients taking MAOIs have to avoid certein foods like cheese, pickled herring, and chianti wine that contain large amounts of tyramine

If they do eat cheese containing tyramine, it can lead to a severe increase in b.p., a so-called hypertensive crisis, because, as well as beingfound in nerves, MAO is also found in cells of the gut wall where it is responsible for nreaking down dietary tyramine. Normally when we eat cheese, very little tyramine actually reaches our bloodstream, but when you take a MAOI, lots reaches the bloodstream and eventually reaches sympathetic nerves

Tyramine is an indirectly acting sympathomimetic drug - itgets taken up into sympathetic nerve vericosities (through NET) and into the synaptic vesicles (through VMAT) ewhere is displaces noradrenaline out of the vesicle and into cell cytoplastm.

Normally, this would be destroyed by MAO, but the enzyme is ingibited so the concentration of noradrenaline in the cytoplas,m builds up until it eventually leaks out of the nerve, activating reeptors, leading to hypertension.

List the sites at which alpha and beta receptors are present in the periphery and describe the effects of their activation.

1. Alpha-1 Receptors

• Location:

  • Blood vessels (arterioles in the skin, mucosa, GI tract, kidneys).

  • Smooth muscle (including those in the urinary bladder, urethra, and gastrointestinal tract).

  • Iris of the eye (radial muscle).

• Effects of Activation:

  • Vasoconstriction: Increased vascular resistance, raising blood pressure (common in skin, mucosa, and viscera).

  • Mydriasis: Dilation of the pupil (via contraction of radial muscle).

  • Contraction of smooth muscle: In urinary bladder and GI tract sphincters, leading to reduced urinary outflow and GI motility.

2. Alpha-2 Receptors

• Location:

  • Presynaptic nerve terminals (in both the central and peripheral nervous systems).

  • Platelets.

  • Post-synaptic in some tissues, such as vascular smooth muscle.

• Effects of Activation:

  • Inhibition of norepinephrine release: Negative feedback mechanism reducing sympathetic output.

  • Platelet aggregation: Promotes clot formation.

  • Vasoconstriction (in certain vascular beds).

  • Reduced insulin release: Decreases glucose uptake in tissues.

1. Beta-1 Receptors

• Location:

  • Heart (myocardium, SA node, AV node).

  • Kidneys (juxtaglomerular cells).

• Effects of Activation:

  • Increased heart rate (chronotropy): Stimulation of SA node.

  • Increased cardiac contractility (inotropy): Enhanced force of myocardial contractions.

  • Increased conduction velocity (dromotropy): Faster impulse transmission through AV node.

  • Renin release: Promotes the renin-angiotensin-aldosterone system (RAAS), increasing blood pressure.

2. Beta-2 Receptors

• Location:

  • Smooth muscle of bronchi (bronchial tree).

  • Vascular smooth muscle (arterioles in skeletal muscle and coronary arteries).

  • Uterus.

  • Liver.

• Effects of Activation:

  • Bronchodilation: Relaxation of bronchial smooth muscle, improving airflow.

  • Vasodilation: In skeletal muscle and coronary vessels, enhancing blood flow.

  • Relaxation of uterine smooth muscle: Prevents premature labor.

  • Glycogenolysis and gluconeogenesis: Increased glucose availability from the liver.

List the actions of alpha-1, alpha-2, beta 1 and beta 2 adrenoceptor agonists and relate these to their clinical use where relevant (simply)

1. Alpha-1 Adrenoceptor AgonistsActions:

• Vasoconstriction: Increases blood pressure by constricting blood vessels.

• Mydriasis: Pupil dilation by contracting the radial muscle of the iris.

• Contraction of sphincters: Reduces urinary outflow.

Clinical Uses:

• Hypotension: Used in conditions like septic shock to raise blood pressure (e.g., phenylephrine).

• Nasal decongestion: Reduces nasal mucosal swelling by vasoconstriction (e.g., phenylephrine, oxymetazoline).

• Ophthalmology: Induces pupil dilation for eye examinations (e.g., phenylephrine).

2. Alpha-2 Adrenoceptor AgonistsActions:

• Inhibition of norepinephrine release: Reduces sympathetic outflow.

• Decreased blood pressure: Through central actions to reduce SNS activity.

• Sedation: Central nervous system depressant effects.

Clinical Uses:

• Hypertension: Used to lower blood pressure by reducing SNS activity (e.g., clonidine, methyldopa).

• Sedation/Analgesia: For procedural sedation (e.g., dexmedetomidine).

• ADHD: As an adjunct for attention deficit hyperactivity disorder (e.g., clonidine).

3. Beta-1 Adrenoceptor AgonistsActions:

• Increased heart rate (chronotropy): Stimulates the SA node.

• Increased cardiac contractility (inotropy): Boosts heart pumping strength.

• Renin release: Activates the renin-angiotensin-aldosterone system (RAAS).

Clinical Uses:

• Heart failure: Enhances cardiac output in acute settings (e.g., dobutamine).

• Cardiogenic shock: Improves cardiac function in low-output states (e.g., dobutamine).

4. Beta-2 Adrenoceptor AgonistsActions:

• Bronchodilation: Relaxes bronchial smooth muscle.

• Vasodilation: In skeletal muscle and coronary vessels.

• Uterine relaxation: Prevents premature labor.

• Increased glucose release: Stimulates glycogenolysis and gluconeogenesis.

Clinical Uses:

• Asthma and COPD: Relieves bronchospasm (e.g., salbutamol, formoterol).

• Preterm labor: Delays delivery by relaxing the uterus (e.g., terbutaline).

• Hyperkalemia: Drives potassium into cells as a temporary measure (e.g., salbutamol).

List the actions of alpha-1, alpha-2, beta 1 and beta 2 adrenoceptor antagonists and relate these to their clinical use where relevant (simply)

1. Alpha-1 Adrenoceptor AntagonistsActions:

• Vasodilation: Lowers blood pressure by relaxing vascular smooth muscle.

• Relaxation of smooth muscle in the urinary tract: Eases urination by relaxing the bladder neck and prostate.

Clinical Uses:

• Hypertension: Lowers blood pressure in patients with high blood pressure (e.g., prazosin, doxazosin).

• Benign Prostatic Hyperplasia (BPH): Relieves urinary obstruction symptoms (e.g., tamsulosin, alfuzosin).

2. Alpha-2 Adrenoceptor AntagonistsActions:

• Increased norepinephrine release: Enhances sympathetic activity by blocking presynaptic inhibition.

• Enhanced central nervous system stimulation: Can increase arousal and mood.

Clinical Uses:

• Depression: Used in some cases to augment antidepressant effects (e.g., mirtazapine, which also acts as an antidepressant via other mechanisms).

3. Beta-1 Adrenoceptor Antagonists (Selective Beta-Blockers)Actions:

• Reduced heart rate (negative chronotropy): Slows the SA node.

• Decreased cardiac contractility (negative inotropy): Lowers the heart's workload.

• Reduced renin release: Reduces blood pressure through RAAS inhibition.

Clinical Uses:

• Hypertension: Lowers blood pressure (e.g., atenolol, metoprolol).

• Angina pectoris: Reduces oxygen demand of the heart.

• Heart failure: Improves survival and reduces symptoms in chronic heart failure (e.g., bisoprolol, metoprolol).

• Post-myocardial infarction: Prevents recurrent events.

• Arrhythmias: Controls heart rate in conditions like atrial fibrillation.

4. Beta-2 Adrenoceptor Antagonists

(Note: Rarely used alone and are typically blocked as part of non-selective beta-blockers.)

Actions:

• Bronchoconstriction: May exacerbate breathing issues in asthmatic or COPD patients.

• Reduced glycogenolysis: Can impair glucose mobilization, caution in diabetes.

Clinical Uses:

• Non-selective beta-blockers: Used when both beta-1 and beta-2 blocking actions are desired (e.g., propranolol). Applications include:

  • Hypertension and angina.

  • Migraine prophylaxis.

  • Essential tremor.

  • Thyrotoxicosis: Reduces symptoms of adrenergic overactivity.

Explain the mechanism of action of cocaine and why people who snort cocain risk damaging their nasal septum

Cocaine works by blocking the reuptake of three important neurotransmitters in the brain: dopamine, norepinephrine, and serotonin. This means that these chemicals stay in the brain longer, increasing feelings of euphoria, alertness, and energy. It also causes increased heart rate and blood pressure.

When you snort cocaine, it gets absorbed through the nose and causes vasoconstriction (narrowing of blood vessels). This limits blood flow to the nasal septum, which has a poor blood supply. Over time, this reduced blood flow can lead to:

• Tissue damage and ulceration (sores).

• A hole in the septum (perforation), which can lead to chronic nosebleeds, trouble breathing through the nose, and infections.

This damage is caused by the long-term reduction in oxygen and nutrients to the tissues due to the constricted blood vessels.