20. Pharmacology of protein and peptide mediators, the purinergic system and nitric oxide

Last updated on December 5, 2019 at 12:14

What’s important from this topic are the drugs (antiplatelets, organic nitrates, NK1 antagonist antiemetics, SST, ADH) and side effects (dry cough) related to the topic and some physiology of peptide synthesis.

Proteins and peptides

Proteins and peptides are used as signalling molecules in many systems in the body:

  • Nervous system (neuropeptides, like neuropeptide Y, serotonin, MSH, ACTH)
  • Endocrine system (like insulin, glucagon and somatostatin)
  • Immune system (cytokines and chemo are small proteins)
  • GI tract (cholecystokinin, gastrin)
  • Heart (atrial natriuretic peptide)
  • Adipose tissue (leptin)

Peptides and proteins vary in size from 3 to around 200 amino acid residues. We call them peptides if they’re around 50 amino acids or less, and proteins if they are longer than 50.

Endogenous peptides and proteins act on receptors, either G-protein coupled receptors or tyrosine-kinase receptors.

Synthesis:

Peptide hormones are usually synthesized like this: from prepro-hormone -> pro-hormone -> hormone. Preprohormones are long peptides with an N-terminal signal peptide that can contain many smaller peptide hormones, or many copies of one smaller peptide hormone. When the signal peptide is cleaved off does it become a prohormone. The prohormone is then further cleaved at many places to release the smaller peptide hormones. You might know this process from how POMC works.

Synthesis of many hormones from the preprohormone pre-POMC (the one on the top, with the signal peptide).

Peptides as drugs:

Peptides don’t work well as drugs, for the following reasons:

  • They can’t be given orally because they are hydrolysed in the gut and poorly absorbed
  • They are difficult to manufacture
  • They are quickly hydrolysed in the plasma (have short half-life)
  • They don’t penetrate the blood-brain barrier
  • They may be immunogenic (act as antigens)
The kinin system

The kinin system has three major components:

  • Kininogens
  • Kallikreins
  • Kinins

Kininogens are protein precursors that are cleaved by enzymes called kallikreins into hormones called kinins, which are biologically active and act on receptors.

There are two kininogens: High-molecular-weight kininogen (HMW kininogen) and low-molecular-weight kininogen (LMW kininogen). HMW is cleaved by kallikreins into the most famous kinin, bradykinin. LMW kininogen is cleaved into another kinin, kallidin.

The most important part of the kinin system.

To make things more complicated the kallikreins must themselves be activated by another enzyme which should be familiar, factor XII, a part of the coagulation cascade. As you may or may not recall from physiology is factor XIIa activated by the intrinsic pathway of coagulation, which is activated by tissue injury.

From this we can understand that the kinin system is activated by tissue injury, and that the end result is that kinins like bradykinin and kallidin are formed.

Effects:

They act on receptors called B1 and B2 receptors, to elicit the following effects:

  • Vasodilation in arteries, vasoconstriction in veins and large arteries, causing hyperaemia
  • Increased capillary permeability
  • Release histamine
  • Bronchoconstriction
  • Activate nociceptors to produce pain in the skin and viscera
  • Increase renal blood flow
  • Induce production of inflammatory cytokines by macrophages

From these effects we can understand that kinins are important in eliciting all effects of inflammation (hyperaemia, swelling, pain and so on).

Accumulation of bradykinin during ACE inhibitor treatment causes dry cough as a side effect.

There are some drugs that act on the kinin system, namely icatibant and aprotinin, but I don’t think they’re important to know. Icatibant is a bradykinin B2 antagonist used to treat angioedema.

Neuropeptides

Neuropeptides are endogenous peptides produced by sensory neurons. They exist in very low concentration in the brain.

Certain neuropeptides are also neurotransmitters (like tachykinins and endogenous opioids), although they act slightly differently than conventional neurotransmitters (like GABA, glutamate, dopamine and so on). Peptide neurotransmitters aren’t produced as quickly as conventional neurotransmitters, so they don’t function as “fast” neurotransmitters between synapses but instead as “neuro-modulators”. The “neuro-modulators” regulate neurons more more “permanently” than neurotransmitters.

Tachykinins are pro-inflammatory neuropeptides. The most famous of them is substance P. Tachykinins have similar effects as bradykinin, and act on receptors called NK1, NK2 and NK3.

Two drugs called aprepitant and netupitant are NK1-receptor antagonists and have anti-emetic effect. You’ll learn more about them in pharma 2.

CGRP is another pro-inflammatory neuropeptide. It’s a potent vasodilator and is involved in nociception. It binds to CGRP1 and CGRP2 receptor.

No drugs targeting these receptors are in the market now, but some are under development in the treatment of migraine.

Somatostatin doesn’t just exist in the GI tract but also as an anti-inflammatory neuropeptide produced by the hypothalamus. It inhibits growth hormone and TSH secretion.

Somatostatin analogues like octreotide and lanreotide are used to treat cancers that secrete any of the hormones that are inhibited by somatostatin. They’re also used to treat acromegaly, a condition characterised by too much growth hormone.

Endogenous opioids like endorphin, enkephalin and dynorphins play an important role in motivation, emotion, and stress and pain control, among other things.

Vasopressin and oxytocin regulated water reabsorption in the kidney and contract the uterus, respectively.

Purines

In case you’ve forgotten what purines are – they, together with pyrimidines, are the bases that makes up the nucleotides that make up DNA, RNA, AMP, GMP and other stuff.

However, they don’t just severe as components of other molecules, but they serve as signalling molecules as well. Adenosine, which is an adenine with a ribose attached to it, binds to its own special receptor called adenosine receptor, also known as receptor P1.

Receptor Mechanism Effects Agonists Antagonist
Adenosine receptor 1 (A1) Gi (cAMP ↓)
  • Mast cell activation
    • Enhance mucus secretion
    • Bronchoconstriction
    • Leukocyte activation
  • Negative bathmotropic and chronotropic effect
  • Inhibit CNS
Adenosine Caffeine, theophylline
Adenosine receptor 2A (A2A) Gs (cAMP ↑)
  • Protective, anti-inflammatory
  • Inhibit CNS
Adenosine Caffeine, theophylline
Adenosine receptor 2B (A2B) Gs (cAMP ↑) Mast cell activation Adenosine Theophylline

The CNS stimulation you get from caffeine occurs because caffeine is an adenosine antagonist, and adenosine in the CNS makes you feel tired.

Theophylline is used to induce bronchorelaxation in COPD and asthma patients. It has stimulatory cardiac side-effects.

There are some receptors that bind ADP and ATP as well:

Receptor Mechanism Effects Agonist Antagonist
P2Y family Mainly Gq (activates PLC) ADP and ATP
P2Y12 Gi (cAMP ↓) Platelet coagulation ADP Clopidogrel, prasugrel, ticlopidine
P2X family Receptor-gated cation channels
  • Pain
  • Neurotransmitter
  • Other shit
ATP

Platelets have secretory vesicles that contain ATP and ADP. When the platelets are activates are ATP and ADP released, which then bind to P2Y12 receptors on other platelets, enhancing platelet aggregation.

Clopidogrel, prasugrel and ticlopidine are P2Y12 antagonists that are used as antiplatelets to prevent clotting.

Nitric oxide

Gasotransmitters are signalling molecules that are small gases, like NO, CO and H2S. They all diffuse freely across membranes, so they don’t have membrane receptors. Nitric oxide is the most important one.

Synthesis:

Nitric oxide (NO) is produced from arginine by the enzyme nitric oxide synthase, NO synthase or simply NOS.

As you probably don’t remember from biochemistry we have three types of NO synthase:

  • Endothelial NO synthase (eNOS) is found in the endothelium and produces NO for use as a vasodilator
  • Neuronal NO synthase (nNOS) is found in neurons and produces NO for use as a neurotransmitter
  • Inducible NO synthase (iNOS) is found in immune cells and produces NO in response to inflammation

Effects:

NO activates soluble guanylyl cyclase inside cells, which produces cGMP, an important second messenger in nerves, smooth muscle, monocytes and platelets.

Increased cGMP causes vascular smooth muscle to relax, which is why it has vasodilatory effects. cGMP activates myosin light chain phosphatase which dephosphorylates the myosin light chain, causing muscle relaxation.

Summary:

Organ/cell Physiological role Pathological role
Too much Too little
Vascular smooth muscle, endothelium Control of blood pressure Hypotension (septic shock) Atherosclerosis, thrombosis
Platelets Control aggregation
Immune system Defence against microbes
CNS Neurotransmission, memory, appetite Excitotoxicity
PNS Neurotransmission Erectile dysfunction

Therapeutic role of NO

Many drugs have mechanisms of action related to NO.

  • Nitroprusside
  • Organic nitrates
  • Sildenafil
  • Inhaled NO

Indication:

Nitroprusside is used to treat hypertensive crises as it rapidly decreases blood pressure.

Organic nitrates are used to treat angina pectoris. They can be administered as soft capsules or as a sublingual spray.

Sildenafil (Viagra) is used to treat erectile dysfunction and pulmonary hypertension.

NO is inhaled to treat respiratory distress syndrome.

Mechanism of action:

Nitroprusside is rapidly broken down into NO, which causes peripheral vasodilation.

Organic nitrates are also broken down into NO. They vasodilate the arterial circulation, decreasing the afterload of the heart, and they vasodilate the venous circulation, decreasing the preload.

Sildenafil is a phosphodiesterase 5 inhibitor. PDE inactivates cGMP, and so sildenafil increases the level of cGMP intracellularly.


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19. Adrenergic receptor antagonists

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21. Local anesthetics

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