First Pass | Ach Synthesis, Storage, Release, Elimination, Dales Experiment | Anemia Treatment

Question 1

First Pass Effect

Answer 1

The systems that is considered as First pass are:
- Enzymes of GI lumen
- Bacterial enzymes
- Enterocytes
- Hepatic enzymes

Examples of drugs undergoing high first pass effect:
- Aspirin
- Lidocaine
- Metoprolol
- Propranolol
- Morphine
- Verapamil
- Salbutamol

Routes of administration that bypass the first pass effect:
- Sublingual
- Rectal suppositories
- Inhalation aerosols
- Intravenous infusion
- Subcutaneous injection
- Intramuscular injection

Question 2

Ach metabolism and synthesis | Dale’s experiment

Answer 2

Acetyl-CoA + Choline = Acetylcholine in preganglionic neurons of both SNS and PNS, and postganglionic neurons of PNS

Acetyl-CoA comes from Mitochondria
Choline comes from Na/Choline uptake pumps [Rate limiting step - inhibited by Hemicholinium]

Calcium influx [membrane depol triggers influx] helps mobilize and attach vesicles to presynaptic neuron membrane [uses Synaptobrevin, tagmin, V-SNARE, T-SNARE - Synaptobrevin blocked by Botulinum toxin]

Acetylcholine in synaptic terminal either binds to nAchR/mAchR or gets broken down by Acetylcholine Esterases for recycling [Acetate and Choline]. It can also bind autoreceptor on presynaptic terminal and induce negative feedback

Dale’s Experiment helped discover Acetylcholine and its role in the autonomic nervous system as a neurotransmitter. It helped differentiate between nAchR and mAchR by a simple experiment with Ach and Atropine
- 2 microg Ach causes lowering of BP
- 50 microg Ach causes significant lowering of BP and Bradycardia
- In presence of 2mg Atropine, 50 microg Ach causes no effect
- In presence of 2mg Atropine, 5mg Ach causes potent vasoconstriction and increase in BP, Tachycardia, secretion of adrenaline
- This experiment shows that in low to medium doses, Ach acts on mAchR as a Parasympathomimetic but in high doses Ach can act as a Sympathomimetic by targeting Ganglion nAchR

Question 3

Agents used in Anemias

Answer 3

Anemia is defined as an absolute decrease in circulating RBC mass. Which means, a decrease in production of RBC, morphology or structure that increases its sequestration in spleen, or its destruction in blood will all lead to anemia

Anemia can be of the following types:
- Iron deficient Microcytic Anemia [Tx: Iron supplements, Ferrous sulphate, Ferrous fluconate, Iron dextran and Iron sucrose parenteral]
- Macrocytic Megaloblastic Anemia due to Folic acid or VitB12 deficiency [seen in vegetarians and/or VitB9 deficiency leading to impaired DNA incorporation | Tx: Folate and Cobalamine supplements, Cynocobalamine IM, Cynocobalamine PO]
- Pernicious Anemia [Intrinsic factor deficiency in turn due to parietal cell in stomach destruction or dysfunction; Intrinsic factor binds to VitB12 and helps in absorption | Supplements and Corticosteroids to counter immune destruction of Parietal cells]
- Sideroblastic Anemia [Iron trapping in mitochondria that prevents its incorporation in hemoglobin | VitB6 supplementation]
- Aplastic Anemia [Complete lack to RBC precursors in bone marrow, often needs full Bone Marrow Transplant or Blood transfusions]

Exogenous EPO is another way to stimulate RBC proliferation in bone marrow indirectly, in cases of Anemia of Chronic disease, Malignancies [Epoetin-alpha]