PCL 302: SYSTEMIC PHARMACOLOGY
DRUGS AFFECTING BLOOD AND BLOOD FORMATION
TREATMENT OF ANAEMIA
Introduction to Anaemia and their causes
Anaemia is a common nutritional deficiency disorder and global public health problem which
affects both developing and developed countries with major consequences for human health and
their social and economic development. It is a condition in which the body lacks the amount of red
blood cells to keep up with the body’s demand for oxygen.
There are several types and classifications of anaemia. The occurrence of anaemia is due to the
various red cell defects such as production defect (aplastic anaemia), maturation defect
(megaloblastic anaemia), defects in haemoglobin synthesis (iron deficiency anaemia), genetic
defects of haemoglobin maturation (thalassaemia) or due to the synthesis of abnormal
haemoglobin (haemoglobinopathies, sickle cell anaemia and thalassaemia) and physical loss of
red cells (haemolytic anaemias).
Haematinics are substances required in the formation of blood, and are used for treatment of
anaemias.
Iron-Deficiency Anaemia
Iron is essential for the various activities of the human body especially in the haemoglobin
synthesis. Iron deficiency anaemia is a condition in which the body has too little iron in the
bloodstream. This form of anaemia is more common in adolescents and in women before
menopause. Blood loss from heavy periods, internal bleeding from the gastrointestinal tract, or
donating too much blood can all contribute to this disease.
A low level of iron, leading to anaemia, can result from various causes. The causes of iron
deficiency anaemia are pregnancy or childhood growth spurts, heavy menstrual periods, poor
absorption of iron, bleeding from the gut (intestines), dietary factors (iron poor or restricted diet),
medication (aspirin, ibuprofen, naproxen and diclofenac), lack of certain vitamins (folic acid and
vitamin B12), bleeding from the kidney, hookworm infection, red blood cell problems and bone
marrow problems.
Symptoms of Iron-Deficiency Anaemia
These include: tiredness, lethargy, feeling faint and becoming breathless easily, headaches,
irregular heartbeats (palpitations), altered taste, sore mouth and ringing in the ears (tinnitus).
Anaemia in pregnancy increases the risk of complications in both mother and baby such as low
birth weight baby, preterm delivery and postnatal depression. Low iron reserves in the baby may
also lead to anaemia in the newborn baby.
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Pernicious anaemia
Pernicious anaemia is the most common cause of Vitamin B12 deficiency. Vitamin B12 is needed
to make new cells in the body such as the many new red blood cells which are made every day.
Vitamin B12 is found in meat, fish, eggs, and milk.
Certain medicines used also may affect the absorption of vitamin B12. The most common example
is metformin, colchicine, neomycin, and some anticonvulsants used to treat epilepsy.
Symptoms of Pernicious anaemia
These include: Psychological problems like depression, confusion, difficulty with memory or even
dementia and nervous problems like numbness, pins and needles, vision changes and unsteadiness
can develop. Prolonged or severe vitamin B12 deficiency may therefore cause permanent brain or
nerve damage.
Haemolytic Anaemia
Haemolytic anaemia is a condition in which red blood cells are destroyed and removed from the
bloodstream before their normal lifespan is up. Haemolytic anaemia can affect people of all ages,
races and sexes. Inherited haemolytic anaemias include Sickle cell anaemia, Thalassaemias,
hereditary spherocytosis, Glucose-6-phosphate dehydrogenase (G6PD) deficiency, Pyruvate
kinase deficiency. Acquired haemolytic anaemias include Immune haemolytic anaemia,
Autoimmune haemolytic anaemia, Drug-induced haemolytic anaemia, Paroxysmal nocturnal
haemoglobinuria.
The most common symptom of anaemia is fatigue. A low red blood cell count can also cause
shortness of breath, dizziness, headache, coldness in your hands or feet, pale skin, gums and nail
beds, as well as chest pain. Symptoms of haemolytic anaemia include jaundice, pain in the upper
abdomen, leg ulcers and pain.
Sickle cell anaemia
This is a form of anaemia in which the body makes sickle-shaped ("C"-shaped) red blood cells. It
contain abnormal haemoglobin which causes sickle shape and can’t move easily through the blood
vessels. The clumps of sickle cells block blood flow that leads to the limbs and organs. Blocked
blood vessels cause pain, serious infections, and organ damage. Sickle cells usually die after about
10 to 20 days and the body can’t reproduce red blood cells fast enough to replace the dying ones,
which causes anaemia. Sickle cell anaemia is an inherited, lifelong disease and most common in
Africa, South or Central America, Caribbean islands, Mediterranean countries, India and Saudi
Arabia
Symptoms include Fatigue, Shortness of breath, dizziness, headache, coldness in the hands and
feet, pale skin, chest pain.
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Aplastic Anaemia
Aplastic anaemia is a blood disorder in which the body’s bone marrow doesn’t make enough new
blood cells. This may result in a number of health problems including arrhythmias, an enlarged
heart, heart failure, infections and bleeding.
A number of acquired diseases, conditions, and factors can cause aplastic anaemia including
Toxins, such as pesticides, arsenic, and benzene, Radiation and chemotherapy, Drugs such as
chloramphenicol, Infectious diseases such as hepatitis, Epstein-Barr virus, cytomegalovirus, and
HIV and Autoimmune disorders such as lupus and rheumatoid arthritis. The most common
symptoms of aplastic anaemia are fatigue, shortness of breath, dizziness, headache, coldness in
your hands or feet, pale skin, gums and nail beds, chest pains.
Iron
Iron absorption
The average daily diet contains 10–20 mg of iron. Its absorption occurs all over the intestine, but
majority in the upper part. Dietary iron is present either as haeme or as inorganic iron. Absorption
of haeme iron is better (up to 35% compared to inorganic iron which averages 5%) and occurs
directly without the aid of a carrier. However, it is a smaller fraction of dietary iron. The major
part of dietary iron is inorganic and in the ferric form. It needs to be reduced to the ferrous form
before absorption.
Iron Preparations and Dose
Oral iron
The preferred route of iron administration is oral. Dissociable ferrous salts are inexpensive, have
high iron content and are better absorbed than ferric salts, especially at higher doses. Gastric
irritation and constipation (the most important side effects of oral iron) are related to the total
quantity of elemental iron administered.
Some simple oral preparations are:
1. Ferrous sulfate: (hydrated salt 20% iron, dried salt 32% iron) is the cheapest; may be
preferred on this account. It often leaves a metallic taste in mouth; (FERSOLATE® -200
mg tab.
2. Ferrous gluconate (12% iron): FERRONICUM® 300 mg tab, 400 mg/15 ml elixir.
3. Ferrous fumarate (33% iron): is less water soluble than ferrous sulfate and tasteless;
NORI-A ®200 mg tab
4. Colloidal ferric hydroxide (50% iron): FERRI DROPS® 50 mg/ml drops.
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Other forms of iron present in oral formulations are: Ferrous succinate (35% iron), Ferric
ammonium citrate (20% iron) Ferrous aminoate (10% iron). These are claimed to be better
absorbed and/or produce less bowel upset, but this is primarily due to lower iron content.
They are generally more expensive.
The elemental iron content and not the quantity of iron compound per dose unit should be
taken into consideration. A total of 200 mg elemental iron (infants and children 3–5 mg/kg)
given daily in 3 divided doses produces the maximal haemopoietic response. Prophylactic
dose is 30 mg iron daily.
Adverse effects of oral iron
These are common at therapeutic doses and are related to elemental iron content.
Individuals differ in susceptibility. Side effects are: Epigastric pain, heartburn, nausea,
vomiting, bloating, staining of teeth, metallic taste, colic, etc. Tolerance to oral iron can be
improved by initiating therapy at low dose and gradually increasing to the optimum dose.
Constipation is more common (believed to be due to astringent action of iron) than
diarrhoea (thought to reflect irritant action).
Parenteral iron
Iron therapy by injection is indicated when:
1. Oral iron is not tolerated (excessive bowel upset)
2. Failure to absorb oral iron: malabsorption (inflammatory bowel disease.) Chronic
inflammation (rheumatoid arthritis) decreases iron absorption, as well as the rate at
which iron can be utilized.
3. Non-compliance to oral iron.
4. In presence of severe deficiency with chronic bleeding.
5. Along with erythropoietin: oral ion may not be absorbed at sufficient rate to meet the
demands of induced rapid erythropoiesis.
The rate of response with parenteral iron is not faster than with optimal doses given orally,
except probably in the first 2–3 weeks when dose of oral iron is being built up. However,
iron stores can be replenished in a shorter time by parenteral therapy
The ionized salts of iron used orally cannot be injected because they have strong protein
precipitating action and free iron in plasma is highly toxic. Four organically complexed
formulations of iron currently available include: Iron-dextran, Iron-sorbitol citric acid,
Ferrous sucrose and Ferric carboxymaltose .
Iron-dextran is a high molecular weight colloidal solution containing 50 mg elemental iron/
ml. It is the only preparation that can be injected i.m. as well as i.v.
Adverse effects associated with this preparation include: Local Pain at site of i.m. injection,
pigmentation of skin, Fever, headache, joint pains, flushing, palpitation, chest pain,
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dyspnoea, lymph node enlargement while an anaphylactoid reaction resulting in vascular
collapse and death occurs rarely.
Iron-sorbitol-citric acid is a low molecular weight complex which can be injected only
i.m. Ferrous-sucrose is a newer formulation that is a high molecular weight complex of
iron hydroxide with sucrose and it is given as i.v. injection.
Ferric carboxymaltose is the latest formulation of iron in which a ferric hydroxide core is
stabilized by a carbohydrate shell and the iron released and delivered subsequently to the
target cells.
The use of Iron preparation is in the treatment of Iron deficiency anaemia which is the most
important indication for medicinal iron. Iron deficiency is the commonest cause of
anaemia, especially in developing countries. Apart from nutritional deficiency, chronic
bleeding from g.i. tract (ulcers, inflammatory bowel disease, hookworm infestation) is a
common cause. Iron deficiency also accompanies repeated attacks of malaria and chronic
inflammatory diseases. The cause of iron deficiency should be identified and treated. Iron
should be normally administered orally; parenteral therapy is to be reserved for special
circumstances.
ACUTE IRON POISONING AND TREATMENT
It occurs mostly in infants and children: 10–20 iron tablets or equivalent of the liquid
preparation (> 60 mg/kg iron) may cause serious toxicity in them. It is very rare in adults.
Desferrioxamine (an iron chelating agent) is the drug of choice. It should be injected i.m.
(preferably) 0.5–1 g (50 mg/kg) repeated 4–12 hourly as required, or i.v. (if shock is
present) 10–15 mg/kg/hour; max 75 mg/kg in a day till serum iron falls below 300 µg/dl.
Early therapy with desferrioxamine has drastically reduced mortality of iron poisoning.
MATURATION FACTORS
Deficiency of vit B12 and folic acid, which are B group vitamins, results in megaloblastic
anaemia characterized by the presence of large red cell precursors in bone marrow and their
large and short lived progeny in peripheral blood. Vit B12 and folic acid are therefore
called maturation factors
VITAMIN-B12
Cyanocobalamin and hydroxocobalamin are complex cobalt containing compounds
present in the diet and referred to as vit B12.
Manifestations of deficiency include
(a) Megaloblastic anaemia (generally the first manifestation), neutrophils with
hypersegmented nuclei, giant platelets.
(b) Glossitis, g.i. disturbances: damage to epithelial structures.
(c) Neurological: subacute combined degeneration of spinal cord; peripheral neuritis.
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Preparations of Vitamin B12
Cyanocobalamin: 35 μg/5 ml liq. Hydroxocobalamin: 500 μg, 1000 μg inj. Both oral and
injectable vit B12 is available mostly as combination preparation along with other vitamins,
with or without iron.
Prophylactic dose is 3–10 μg/day orally in those at risk of developing deficiency.
Therapeutic dose: Oral vit B12 is not dependable for treatment of confirmed vit B12
deficiency because its absorption from the intestine is unreliable. Injected vit B12 is a must
when deficiency is due to lack of intrinsic factor (pernicious anaemia, other gastric causes),
since the absorptive mechanism is totally non-functional.
Adverse effects
Large doses of vit B12 are quite safe. Allergic reactions have occurred on injection,
probably due to contaminants. Anaphylactoid reactions (probably to sulfite contained in
the formulation) have occurred on i.v. injection
FOLIC ACID
Folate deficiency occurs due to:
(a) Inadequate dietary intake
(b) Malabsorption: especially involving upper intestine
(c) Biliary fistula (bile containing folate for recirculation is drained).
(d) Chronic alcoholism: intake of folate is generally poor. Moreover, its release from liver
cells and recirculation are interfered.
(e) Increased demand: pregnancy, lactation, rapid growth periods and haemolytic anaemia
.
(f) Drug induced: prolonged therapy with anticonvulsants (phenytoin, phenobarbitone,
primidone) and oral contraceptives—interfere with absorption and storage of folate.
Preparations and dose
Folic acid: FOLVITE, FOLITAB 5 mg tab; Liquid oral preparations and injectables are
available and in combination formulation . Oral therapy is adequate except when
malabsorption is present or in severely ill patient—given i.m.
Dose: therapeutic 2 to 5 mg/day, prophylactic 0.5 mg/day
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ANTICOAGULANTS
These are drugs used to reduce the coagulability of blood. They may be classified into:
I. Used in -vivo
A. Parenteral anticoagulants
(i) Indirect thrombin inhibitors: Heparin, Low molecular weight heparins etc
(ii) Direct thrombin inhibitors: Lepirudin, Bivalirudin
B. Oral anticoagulants
(i) Coumarin derivatives: Bishydroxycoumarin (dicumarol), Warfarin sodium, Acenocoumarol
(Nicoumalone), Ethylbiscoumacetate
(ii) Indandione derivative: Phenindione.
(iii) Direct factor Xa inhibitors: Rivaroxaban
(iv)Oral direct thrombin inhibitor: Dabigatran etexilate
II. Used in vitro
A. Heparin: 150 U to prevent clotting of 100 ml blood.
B. Calcium complexing agents: Sodium citrate: 1.65 g for 350 ml of blood; used to keep blood in
the fluid state for transfusion.
HEPARIN
PHARMACOLOGY ACTIONS OF HEPARIN
1. Anticoagulant
Heparin is a powerful and instantaneously acting anticoagulant, effective both in vivo and in vitro.
It acts indirectly by activating plasma antithrombin III (AT III). The heparin-AT III complex then
binds to clotting factors of the intrinsic and common pathways (Xa, IIa, IXa, XIa, XIIa and XIIIa)
and inactivates them but not factor VIIa operative in the extrinsic pathway.
At low concentrations of heparin, factor Xa mediated conversion of prothrombin to thrombin is
selectively affected. The anticoagulant action is exerted mainly by inhibition of factor Xa as well
as thrombin (IIa) mediated conversion of fibrinogen to fibrin. Low concentrations of heparin
prolong activated partial thromboplastin time (aPTT) without significantly prolonging
prothrombin time (PT). High concentrations prolong both. Thus, low concentrations interfere
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selectively with the intrinsic pathway, affecting amplification and continuation of clotting, while
high concentrations affect the common pathway as well.
2. Antiplatelet
Heparin in higher doses inhibits platelet aggregation and prolongs bleeding time.
3. Lipaemia clearing
Injection of heparin clears turbid post-prandial lipaemic plasma by releasing a lipoprotein
lipase from the vessel wall and tissues, which hydrolyses triglycerides of chylomicra and very
low density lipoproteins to free fatty acids. These then pass into tissues and the plasma looks
clear. This action requires lower concentration of heparin than that needed for anticoagulation.
PHARMACOKINETICS
Heparin is a large, highly ionized molecule; therefore not absorbed orally. Injected i.v, it acts
instantaneously, but after s.c. injection anticoagulant effect develops after approximately 60
min. Bioavailability of s.c. heparin is inconsistent. Heparin does not cross blood-brain barrier
or placenta, hence it is the anticoagulant of choice during pregnancy. It is metabolized in liver
by heparinase and fragments are excreted in urine. Heparin released from mast cells is
degraded by tissue macrophages—it is not a physiologically circulating anticoagulant. After
i.v. injection of doses < 100 U/kg, the t½ averages 1 hr. Beyond this, dose-dependent
inactivation is seen and t½ is prolonged to 1–4 hrs. The t½ is longer in cirrhotics and kidney
failure patients, and shorter in patients with pulmonary embolism.
Heparin should not be mixed with penicillin, tetracyclines or hydrocortisone in the same
syringe or infusion bottle. Heparinized blood is not suitable for blood counts (alters the shape
of RBCs and WBCs), fragility testing and complement fixation tests.
ADVERSE EFFECTS
1. Bleeding due to overdose is the most serious complication of heparin therapy. Haematuria
is generally the first sign. With proper monitoring, serious bleeding occurs only in 1–3%
patients.
2. Thrombocytopenia is another common problem. Generally it is mild and transient; occurs
due to aggregation of platelets. Occasionally serious thromboembolic events result. In some
patients antibodies are formed to the heparin platelet complex and marked depletion of platelets
occurs—heparin should be discontinued in such cases. Even low molecular weight (LMW)
heparins are not safe in such patients.
3. Transient and reversible alopecia is infrequent. Serum transaminase levels may rise.
4. Osteoporosis may develop on long-term use of relatively high doses.
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5. Hypersensitivity reactions are rare; manifestations are urticaria, rigor, fever and
anaphylaxis. Patients with allergic diathesis are more liable.
Contraindications
1. Bleeding disorders, history of heparin induced thrombocytopenia.
2. Severe hypertension (risk of cerebral haemorrhage), threatened abortion, piles, g.i. ulcers
(risk of aggravated bleeding).
3. Subacute bacterial endocarditis (risk of embolism), large malignancies (risk of bleeding in
the central necrosed area of the tumour), tuberculosis (risk of hemoptysis).
4. Ocular and neurosurgery, lumbar puncture.
5. Chronic alcoholics, cirrhosis, renal failure.
6. Aspirin and other antiplatelet drugs should be used very cautiously during heparin therapy.
LOW MOLECULAR WEIGHT (LMW) HEPARINS
Heparin has been fractionated into LMW forms (MW 3000–7000) by different techniques.
LMW heparins have a different anticoagulant profile; i.e. selectively inhibit factor Xa with
little effect on IIa. They act only by inducing conformational change in AT III and not by
providing a scaffolding for interaction of AT III with thrombin. As a result, LMW heparins
have smaller effect on aPTT and whole blood clotting time than unfractionated heparin (UFH)
relative to antifactor Xa activity. Also, they have lesser antiplatelet action—less interference
with haemostasis. Thrombocytopenia is less frequent. A lower incidence of haemorrhagic
complications compared to UFH has been reported in some studies, but not in others. However,
major bleeding may be less frequent. They are eliminated primarily by renal excretion; are not
to be used in patients with renal failure. The more important advantages of LMW heparins are
pharmacokinetic:
• Better subcutaneous bioavailability (70–90%) compared to UFH (20–30%): Variability in
response is minimized.
• Longer and more consistent mono exponential t½: (4–6 hours); making possible once daily
s.c. administration.
• Since aPTT/clotting times are not prolonged, laboratory monitoring is not needed; dose is
calculated on body weight basis.
• Risk of osteoporosis after long term use is much less with LMW heparin compared with
UFH. Most studies have found LMW heparins to be equally efficacious to UFH except during
cardiopulmonary bypass surgery, in which high dose UFH is still the preferred anticoagulant,
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because LMW heparin are less effective in preventing catheter thrombosis and their effects
are not fully reversed by protamine.
Indications of LMW heparins are:
1. Prophylaxis of deep vein thrombosis and pulmonary embolism in high-risk patients
undergoing surgery; stroke or other immobilized patients.
2. Treatment of established deep vein thrombosis.
3. Unstable angina and MI: they have largely replaced continuous infusion of UFH.
4. To maintain patency of cannulae and shunts in dialysis patients.
HEPARIN ANTAGONIST
Protamine sulfate is a strongly basic, low molecular weight protein obtained from the sperm
of certain fish. Given i.v. it neutralizes heparin weight for weight, i.e. 1 mg is needed for every
100 U of heparin. For the treatment of heparin induced bleeding, due consideration must be
given to the amount of heparin that may have been degraded by the patient’s body in the mean
time. However, it is needed infrequently because the action of heparin disappears by itself in a
few hours, and whole blood transfusion is needed to replenish the loss when bleeding occurs.
Protamine is more commonly used when heparin action needs to be terminated rapidly, e.g.
after cardiac or vascular surgery.
ORAL ANTICOAGULANTS
Warfarin and its congeners act as anticoagulants only in vivo, not in vitro. This is so because
they act indirectly by interfering with the synthesis of vit K dependent clotting factors in liver.
They apparently behave as competitive antagonists of vit K and lower the plasma levels of
functional clotting factors in a dose-dependent manner. In fact, they inhibit the enzyme vit K
epoxide reductase (VKOR) and interfere with regeneration of the active hydroquinone form of
vit K which acts as a cofactor for the enzyme γ-glutamyl carboxylase that carries out the final
step of carboxylating glutamate residues of prothrombin and factors VII, IX and X. This
carboxylation is essential for the ability of the clotting factors to bind Ca2+ and to get bound
to phospholipid surfaces, necessary for the coagulation sequence to proceed. Factor VII has
the shortest plasma t½ (6 hr), its level falls first when warfarin is given, followed by factor IX
(t½ 24 hr), factor X (t½ 40 hr) and prothrombin (t½ 60 hr). Though the synthesis of clotting
factors diminishes within 2–4 hours of warfarin administration, anticoagulant effect develops
gradually over the next 1–3 days as the levels of the clotting factors already present in plasma
decline progressively. Thus, there is always a delay between administration of these drugs and
the anticoagulant effect. Larger initial doses hasten the effect only slightly. Therapeutic effect
occurs when synthesis of clotting factors is reduced by 40–50%.
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Racemic Warfarin sod.
It is the most popular oral anticoagulant. The commercial preparation of warfarin is a mixture
of R (dextrorotatory) and S (levorotatory) enantiomers. The S form is more potent while R
form is less potent
Bishydroxycoumarin (Dicumarol)
It is slowly and unpredictably absorbed orally. Its metabolism is dose dependent—t½ is
prolonged at higher doses. Has poor g.i. tolerance; not preferred now.
Acenocoumarol (Nicoumalone) The t½ of acenocoumarol as such is 8 hours, but an active
metabolite is produced so that overall t½ is about 24 hours. Acts more rapidly.
Ethyl biscoumacetate
It has a rapid and brief action; occasionally used to initiate therapy, but difficult to maintain.
Phenindione
Apart from risk of bleeding, it produces more serious organ toxicity and should not be used.
Adverse effects
Bleeding as a result of extension of the desired pharmacological action is the most important
problem causing ecchymosis, epistaxis, hematuria, bleeding in the g.i.t. Intracranial or other
internal haemorrhages may even be fatal. Bleeding is more likely if therapy is not properly
monitored.
Cutaneous necrosis is a rare complication that can occur with any oral anticoagulant.
Phenindione produces serious toxicity; should not be used. Warfarin and acenocoumarol are
considered to be the most suitable and better tolerated drugs.
Treatment:
Treatment of bleeding due to oral anticoagulants include:
1. Withhold the anticoagulant.
2. Give fresh blood transfusion; this supplies clotting factors and replenishes lost blood.
Alternatively fresh frozen plasma may be used as a source of clotting factors.
3. Give vit K1 which is the specific antidote , but it takes 6–24 hours for the clotting factors
to be resynthesized and released in blood after vit K administration.
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Contraindications
All contraindications to heparin apply to these drugs as well. Oral anticoagulants should not
be used during pregnancy. Warfarin given in early pregnancy increases birth defects, especially
skeletal abnormalities. It can produce foetal warfarin syndrome—hypoplasia of nose, eye
socket, hand bones, and growth retardation. Given later in pregnancy, it can cause CNS defects,
foetal haemorrhage, foetal death and accentuates neonatal hypoprothrombinemia.
Drug interactions
A large number of drugs interact with oral anticoagulants at pharmacokinetic or
pharmacodynamic level, and either enhance or decrease their effect. These interactions are
clinically important (may be fatal if bleeding occurs)
A. Enhanced anticoagulant action
1. Broad-spectrum antibiotics: These inhibit gut flora and reduce vit K production.
2. Newer cephalosporins (ceftriaxone, cefoperazone) cause hypoprothrombinaemia by the
same mechanism as warfarin hence additive action.
3. Aspirin: This inhibits platelet aggregation and causes g.i. bleeding—this may be hazardous
in anticoagulated patients. High doses of salicylates have synergistic hypoprothrombinemic
action and also displace warfarin from protein binding site.
4. Long acting sulfonamides, indomethacin, phenytoin and probeneci, all displace warfarin
from plasma protein binding.
5. Chloramphenicol, erythromycin, celecoxib, cimetidine, allopurinol, amiodarone and
metronidazole all inhibit warfarin metabolism.
6. Liquid paraffin (habitual use): reduces vit K absorption.
B. Reduced anticoagulant action
1. Barbiturates (but not benzodiazepines), carbamazepine, rifampin and griseofulvin induce
the metabolism of oral anticoagulants and appropriate dose adjustment is required
2. Oral contraceptives increase blood levels of clotting factors and reduces warfarin action.
Uses of Anticoagulants
The aim of using anticoagulants is to prevent thrombus extension and embolic complications
by reducing the rate of fibrin formation. They do not dissolve already formed clot, but prevent
recurrences. Heparin is utilized for rapid and short lived action, while oral anticoagulants are
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suitable for maintenance therapy. Generally, the two are started together; heparin is
discontinued after 4–7 days when warfarin has taken effect. The uses of anticoagulants include
1. Deep vein thrombosis (DVT) and pulmonary embolism (PE)
Since venous thrombi are mainly fibrin thrombi, anticoagulants are expected to be highly
effective. The best evidence of efficacy of anticoagulants comes from treatment and prevention
of venous thrombosis and pulmonary embolism. Prophylaxis is recommended for all high risk
patients including bedridden, elderly, postoperative, postpartum, post stroke and leg fracture
patients. When deep vein thrombosis/pulmonary embolism has occurred, immediate
heparin/LMW heparin followed by warfarin therapy should be instituted. Three months
anticoagulant therapy (continued further if risk factor persists) has been recommended
2. Myocardial infarction (MI)
Arterial thrombi are mainly platelet thrombi; anticoagulants are of questionable value. Their
use in acute MI has declined. They do not alter immediate mortality of MI. Patients may
benefit by preventing mural thrombi at the site of infarction and venous thrombi in leg veins.
Thus, anticoagulants may be given for a short period till patient becomes ambulatory. For
secondary prophylaxis against a subsequent attack, anticoagulants are inferior to antiplatelet
drugs.
3 Unstable angina
Short-term use of heparin has reduced the occurrence of MI in unstable angina patients;
aspirin is equally effective. Current recommendation is to use aspirin + heparin/LMW
heparin followed by warfarin.
4. Rheumatic heart disease- Atrial fibrillation (AF)
All atrial fibrillation patients should be protected against thromboembolism from
fibrillating atria and the resulting stroke. For this purpose, the effective options are
warfarin/low dose heparin/low dose aspirin.
5. Vascular surgery, prosthetic heart valves, retinal vessel thrombosis and haemodialysis
Anticoagulants are indicated along with antiplatelet drugs for prevention of
thromboembolism. Heparin flushes (200 U in 2 ml) every 4–8 hr are used to keep patent
long-term intravascular cannulae/catheters.
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FIBRINOLYTICS (Thrombolytics)
These are drugs used to lyse thrombi/clot to re-canalize occluded blood vessels (mainly coronary
artery). They are therapeutic rather than prophylactic and work by activating the natural
fibrinolytic system. In general, venous thrombi are lysed more easily by fibrinolytics than arterial,
and recent thrombi respond better. They have little effect on thrombi greater 3 days old. The
clinically important fibrinolytics are: Streptokinase, Urokinase, Alteplase (rt-PA), Reteplase,
Tenecteplase
Streptokinase
Obtained from β haemolytic Streptococci group C, it is the first fibrinolytic drug to be used
clinically, but is not employed now except for considerations of cost. Streptokinase is inactive as
such, it combines with circulating plasminogen molecules to form an activator complex which
then causes limited proteolysis of other plasminogen molecules to generate the active enzyme
plasmin. Streptokinase is non-fibrin specific, i.e. activates both circulating as well as fibrin bound
plasminogen. Therefore, it depletes circulating fibrinogen and predisposes to bleeding. Compared
to newer more fibrin-specific tissue plasminogen activators (Alteplase, etc.), it is less effective in
opening occluded coronary arteries, and causes less reduction in MI related mortality. There are
several other disadvantages as well with streptokinase. Anti-streptococcal antibodies due to past
infections inactivate considerable fraction of the initial dose of streptokinase. A loading dose
therefore is necessary. Plasma t½ is estimated to be 30–80 min. streptokinase is antigenic hence
can cause hypersensitivity reactions. Anaphylaxis occurs in 1–2% patients. It cannot be used
second time due to neutralization by antibodies generated in response to the earlier dose. Fever,
hypotension and arrhythmias are reported.
Urokinase
It is an enzyme isolated from human urine; but commercially prepared from cultured human
kidney cells. It activates plasminogen directly and has a plasma t½ of 10–15 min. It is nonantigenic. Fever occurs during treatment, but hypotension and allergic phenomena are rare.
Urokinase is indicated in patients in whom streptokinase has been given for an earlier episode, but
is seldom used now.
Alteplase (recombinant tissue plasminogen activator (rt-PA)
Produced by recombinant DNA technology from human tissue culture, it is moderately specific
for fibrin-bound plasminogen, so that circulating fibrinogen is lowered only by approximately
50%. It is rapidly cleared by liver and inactivated by plasminogen activator inhibitor-1 (PAI-1).
The plasma t½ is 4–8 min. Because of the short t½, it needs to be given by slow i.v. infusion and
often requires heparin co-administration. It is non-antigenic, but nausea, mild hypotension and
fever may occur. It is expensive.
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Tenecteplase
This has higher fibrin selectivity, slower plasma clearance (longer duration of action) and
resistance to inhibition by PAI-1. It is the only fibrinolytic agent that can be injected i.v. as a single
bolus dose over 10 sec, while alteplase requires 90 min infusion. This feature makes it possible to
institute fibrinolytic therapy immediately on diagnosis of ST segment elevation myocardial
infarction (STEMI), even during transport of the patient to the hospital . It efficacy in STEMI is
found to be at least similar to alteplase. Risk of non-cerebral bleeding may be lower with
tenecteplase, but cranial bleeding incidence is similar. Dose: 0.5 mg/kg single i.v. bolus injection.
Uses of fibrinolytics
1. Acute myocardial infarction is the chief indication. Fibrinolytics are an alternative first line
approach to emergency percutaneous coronary intervention (PCI) with stent placement.
Recanalization of thrombosed coronary artery has been achieved in 50–90% cases. Time lag in
starting the infusion is critical for reducing area of necrosis, preserving ventricular function and
reducing mortality. Aspirin with or without heparin is generally started concurrently or soon after
thrombolysis to prevent re-occlusion. Alteplase has advantages over streptokinase, including
higher thrombolytic efficacy.
2. Deep vein thrombosis in leg, pelvis, shoulder etc: Up to 60% of patients can be successfully
treated. Thrombolytics can decrease subsequent pain and swelling, but the main advantage is
preservation of venous valves and may be a reduced risk of pulmonary embolism, though at the
risk of haemorrhage. Comparable results have been obtained with streptokinase, urokinase and
alteplase.
3. Pulmonary embolism : Fibrinolytic therapy is indicated in large, life-threatening PE. The lung
function may be better preserved, but reduction in mortality is not established.
4. Peripheral arterial occlusion: Fibrinolytics re-canalise approximately 40% limb artery
occlusions, especially those treated within 72 hr. However, it is indicated only when surgical
thrombectomy is not possible. Regional intraarterial fibrinolytics have been used for limb arteries
with greater success. Peripheral arterial thrombolysis is followed by short term heparin and longterm aspirin therapy. Fibrinolytics have no role in chronic peripheral vascular diseases.
5. Stroke: Thrombolytic therapy of ischaemic stroke is controversial. Possibility of improved
neurological outcome is to be balanced with risk of intracranial haemorrhage.
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ANIONS AND CATIONS
The body contains a large variety of ions, or electrolytes, which perform a variety of functions.
Some ions assist in the transmission of electrical impulses along cell membranes in neurons and
muscles. Other ions help to stabilize protein structures in enzymes. Still others aid in releasing
hormones from endocrine glands. All of the ions in plasma contribute to the osmotic balance that
controls the movement of water between cells and their environment.
Roles of Electrolytes
These ions aid in nerve excitability, endocrine secretion, membrane permeability, buffering body
fluids, and controlling the movement of fluids between compartments. These ions enter the body
through the digestive tract. More than 90 percent of the calcium and phosphate that enters the
body is incorporated into bones and teeth, with bone serving as a mineral reserve for these ions.
In the event that calcium and phosphate are needed for other functions, bone tissue can be broken
down to supply the blood and other tissues with these minerals. Phosphate is a normal
constituent of nucleic acids; hence, blood levels of phosphate will increase whenever nucleic
acids are broken down.
Excretion of ions occurs mainly through the kidneys, with lesser amounts lost in sweat and in
feces. Excessive sweating may cause a significant loss, especially of sodium and chloride. Severe
vomiting or diarrhea will cause a loss of chloride and bicarbonate ions. Adjustments in respiratory
and renal functions allow the body to regulate the levels of these ions in the extracellular fluid, and
electrolytes and proteins are important in fluid balance. The body is 60% water by weight. Twothirds of this water is intracellular, or within cells. One-third of the water is extracellular, or outside
of cells. One-fourth of the extracellular fluid is plasma, while the other 3/4 is interstitial (between
cells) fluid. Thus, when considering total body water, around 66% is intracellular fluid, 25% is
interstitial fluid, and 8% is plasma.
ANIONS
Different anions exist in the body, some of the anions exist freely and some combined. Some of
these anions that are of physiological importance are bicarbonates, phosphates, fluoride, iodide
and chlorides.
BICARBONATES
It is difficult to estimate how much bicarbonate one has. The amount of bicarbonate fluctuates, as
it is constantly dissociating into carbon dioxide and water; water is massively abundant and carbon
dioxide is massively volatile, so the total body bicarbonate relies largely on total body carbon
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dioxide. Bicarbonate is easily converted to CO2 which is highly lipid-soluble, and thus diffuses
effortlessly in and out of cells
Bicarbonate is a major element in our body. Secreted by the stomach, it is necessary for digestion.
When ingested, for example, with mineral water, it helps buffer lactic acid generated during
exercise and also reduces the acidity of dietary components. Finally, it has a prevention effect on
dental cavities.
Bicarbonate is present in all body fluids and organs and plays a major role in the acid-base balances
in the human body. The first organ where food, beverages and water stay in our body is the
stomach. The mucus membrane of the human stomach has 30 million glands which produce gastric
juice containing not only acids, but also bicarbonate. The flow of bicarbonate in the stomach
amounts from 400 µmol per hour (24.4 mg/h) for a basal output to 1,200 µmol per hour (73.2
mg/h) for a maximal output. Thus at least half a gram of bicarbonate is secreted daily in our
stomach. This rate of gastric bicarbonate secretion is 2-10% of the maximum rate of acid secretion.
In the stomach, bicarbonate participates in a mucus-bicarbonate barrier regarded as the first line
of the protective and repair mechanisms. On neutralization by acid, carbon dioxide is produced
from bicarbonate. A study has underlined that a dose of 6.17 g of sodium bicarbonate rapidly
leaves the stomach with the liquid phase of the meal.
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Effects of ingested bicarbonate
For digestion, bicarbonate is naturally produced by the gastric membrane in the stomach. This
production will be low in alkaline conditions and will rise in response to acidity. In healthy
individuals this adaptive mechanism will control the pH perfectly. To modify this pH with
exogenous doses of bicarbonate, some clinical experiments have been conducted with sodium
bicarbonate loads as high as 6 g. Only a transient effect on pH has been obtained. It is quite possible
that bicarbonate in water may play a buffering role in the case of people sensitive to gastric acidity.
Thus bicarbonate may be helpful for digestion.
The most important effect of bicarbonate ingestion is the change in acid-base balance as well as
blood pH and bicarbonate concentration in biological fluids. It has been studied particularly in
physically active people. Among the types of acid produced, lactic acid generated during exercise
is buffered by bicarbonate.
Prevention of renal stones
Bicarbonate also reduces the acidity of dietary components such as proteins. High protein diet
known to acidify urine leading to hypercalciuria (high level of calcium in urine). A study highlights
that a bicarbonate-rich mineral water could be useful in the prevention of the recurrence of calcium
oxalate.
Many oral hydration solutions contain bicarbonate showing the usefulness of bicarbonate to
control water absorption in patients at risk of dehydration.
Sodium intake is restricted in patients with hypertension, but it is demonstrated that the
accompanying anion, such as bicarbonate or chloride, plays an important role. It is now well
established that sodium bicarbonate as well as citrate and phosphate salts do not raise blood
pressure to the same extent as do the corresponding amounts of sodium chloride. A study on
mineral water containing sodium bicarbonate has confirmed the absence of effect on blood
pressure in elderly individuals.
Dental Effects
Bicarbonate has been shown to decrease dental plaque acidity induced by sucrose and its buffering
capacity is important to prevent dental cavities. Other studies have shown that bicarbonate inhibits
plaque formation on teeth and, in addition, increases calcium uptake by dental enamel. This effect
of bicarbonate on teeth is so well recognized that sodium bicarbonate-containing tooth powder was
patented in the USA in October 1985. Sodium bicarbonate has been suggested to increase the pH
in the oral cavity, potentially neutralizing the harmful effects of bacterial metabolic acids. Sodium
bicarbonate is increasingly used in dentifrice and its presence appears to be less abrasive to enamel
and dentine than other commercial toothpaste.
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Bicarbonate helps physically active people combat fatigue
An ingestion of 300 mg/kg of body weight of bicarbonate before exercising will help you reduce
muscular fatigue and so increase the performance of short- term physical exercise. Thus drinking
mineral water containing bicarbonate may contribute to this beneficial intake.
Sportsmen continuously have two problems to solve: the other athletes to overtake and fatigue to
overcome. The causes of fatigue are multifactorial, either they have physiological or psychological
origins. From the physiological point of view, fatigue can have a central or peripheral origin.
Among the peripheral causes, fatigue could be due to the accumulation of metabolites in muscle,
such as lactates, hydrogen ions and ammonia. During prolonged submaximal effort, the major
cause of fatigue is the energy substrate depletion (namely carbohydrates), but it has been shown
that hyperthermia (over 40.1 C) or dehydration (over 1 or 2 % of body weight loss) could also
contribute to the occurrence of fatigue.
In fact, to optimize performance, it is important to minimise fatigue and to delay its appearance.
Athletes are aware of substances which could offset fatigue and since the 90s the use of sodium
bicarbonate has become usual among sportsmen to buffer the acids produced during exercise.
PHOSPHATES
Phosphate is an essential component of all body tissues, it is present in plasma, extracellular fluid,
cell membrane, phospholipids, collagen and bones (>80%). Phosphorus exist in both organic and
inorganic forms, the organic forms includes phospholipids and various inorganic esters. The
inorganic forms are found mostly in the ECF in the form NaHPO4 and Na2HPO4; in the bone it is
usually found complexed with calcium. Phosphate is the most abundant intracellular anion
Pharmacokinetics
Phosphates being a ubiquitous component of many foods are absorbed from the GIT. The
absorption of phosphates from the intestinal lumen requires the presence of vitamin D and is an
active transport. It is excreted via the urine. Plasma concentration of Phosphates is higher in
growing children than adults.
The renal excretion of phosphate is dependent on the hormone PTH (parathyroid hormone) and
dietary phosphate deficiency. Dietary phosphate deficiency causes an increase absorption and
increased reabsorption of phosphate by the kidney, while the opposite is the case for excess
phosphate. 90% of plasma phosphate is freely filtered and 80% is actively reabsorbed.
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ACTIONS: Phosphate salts are employed as mild laxatives; but if excessive salts are introduced
either intravenously or orally, they may reduce the concentration of ca2+ in the circulation and
induce precipitation of calcium phosphate in soft tissues.
Disturbed Phosphate Metabolism: Dietary inadequacy rarely causes phosphate depletion, but
sustained use of antacids (especially Aluminium containing antacids), inhibition of phosphate in
the GIT and excessive renal excretion owing to PTH action are the chief causes of phosphate
depletion. Inadequate blood phosphate level i.e hypophosphatemia is manifested as malaise,
muscle weakness and osteomalacia.
Hyperphosphatemia is often seen in chronic renal failure; the increased serum phosphate level
reduces the serum ca2+ concentration which in turn activates PTH secretion and this exacerbates
the hyperphosphatamia. The sustained hyperphosphatemia can be alleviated by administration of
aluminium hydroxide gel or calcium carbonate supplements.
FLOURIDE: Flouride (F) is important because of its toxic properties and its effect on dentition
and bone.
Pharmacokinetics: Human beings obtain F from water, plant and animal sources and absorption
takes place mostly in the small intestine. Soluble F such as sodium fluoride is completely absorbed
while insoluble F such as cryolite(Na3AIF6) and the Flouride in bone meal is poorly absorbed.
Flouride inhaled through the lungs especially from industrial exposures constitutes the major route
of toxicity.
Pharmacological actions: Because it is concentrated in bones, the radionuclide 18F has been used
in skeletal imaging. Low doses of NaF2 stimulate osteoblast activity while high doses depress
activity. Other actions of F include toxic actions such as inhibition of several enzymes and
diminishing tissue respiration and anaerobic glycolysis.
Flouride Toxicity
Acute fluoride poisoning results from accidental ingestion of Flouride-containing rodenticides or
insecticides. Local symptoms include salivation, abdominal pain, vomiting and diarrhoea. While
systemic effects include irritability of the CNS, cardio toxicity, hypocalcemia, hypotension and
respiratory depression.
Chronic poisoning results in osteosclerosis and mottled enamel. Osteosclerosis is characterized by
increased bone density. Treatment include
-
Intravenous administration of glucose saline
Gastric lavage with lime water (0.15% Ca(OH)2 or other calcium salts to precipitate the
Flouride. Calcium gluconate is given i.v for tenany
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Flouride and dental carries: People living in areas where their water supply is deficient of Fl are
likely to experience dental carries especially in children and growing children. Topical application
of Flouride by dental experts e.g early use of toothpaste containing fluoride is one of the strategies
for combating this carries.
CHLORIDE
Chloride
Chloride is the predominant extracellular anion. Chloride is a major contributor to the osmotic
pressure gradient between the ICF and ECF, and plays an important role in maintaining proper
hydration. Chloride functions to balance cations in the ECF, maintaining the electrical neutrality
of this fluid. The paths of secretion and reabsorption of chloride ions in the renal system follow
the paths of sodium ions.
Hypochloremia, or lower-than-normal blood chloride levels, can occur because of defective renal
tubular absorption. Vomiting, diarrhea, and metabolic acidosis can also lead to hypochloremia.
Hyperchloremia, or higher-than-normal blood chloride levels, can occur due to dehydration,
excessive intake of dietary salt (NaCl) or swallowing of sea water, aspirin intoxication, congestive
heart failure, and the hereditary, chronic lung disease, cystic fibrosis. In people who have cystic
fibrosis, chloride levels in sweat are two to five times those of normal levels, and analysis of sweat
is often used in the diagnosis of the disease.
CATIONS
Calcium (Ca)
The skeleton contains 99% of total body calcium in crystalline form resembling the mineral
hydroxyapatite Ca10(PO4)6(OH)2. The ionized form of calcium (Ca2+) is essential for flow of
current across excitable tissues, fusion and release of storage vesicles and muscle contraction. Ca
also act as second messengers. Healthy adults possess about 1000-1300g of calcium of which 99%
is in bone and teeth. It is the major divalent Cation in the ECF. The normal serum calcium level
ranges between 8.5-10.4 mg/dl. Plasma calcium exists in three forms: ionized (50%), protein
bound (46%), and complexed to organic ions (4%). Ionized calcium is the physiologically relevant
Ca. It mediates calcium’s biological effects and produces characteristic signs of hypo- or
hypercalcaemia when perturbed. The extracellular Ca2+ concentration is tightly controlled by
hormones (parathyroid hormone (PTH) and vitamin D (D3).) that affect its entry at the intestine
and exit at the kidney.
Pharmacokinetics: About 75% of dietary calcium is obtained from milk and dietary products.
The average daily requirement is 1300mg/day in adolescents and 1000mg/day in adults. Calcium
enters the body only through the intestine. Active vitamin D dependent transport occurs in the
duodenum whereas facilitated diffusion occurs throughout the intestine.
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The efficiency of intestinal Ca2+ absorption is inversely related to calcium intake ie a diet low in
Ca leads to a compensatory increase in fractional absorption owing to absorption of vitamin D.
Disease states such as diarrhoea, steatorrhoea, or chronic malabsorption promotes faecal loss of
Ca, whereas drugs such as glucorcoticoids and Phenytoin depress intestinal Ca2+ transport. The
efficiency of reabsorption is highly regulated by PTH but also influenced by filtered sodium, the
presence of non reabsorbed anions and diuretic agents. Loop diuretics eg Furosemide increases
calcium excretion.
Pharmacological Effects
Hypercalcemia: Hypercalcemia can result from a number of conditions, although ingestion of
large amount does not cause hypercalcemia, exceptions are in hyperthyroid states because the
subject absorbs Ca2+ with increased frequency. Symptoms include Fatigue, muscle weakness,
anorexia, depression, abdominal pain and constipation.
Generally the most common cause of Hypercalcemia is primary hyperparathyroidism which result
from hyper secretion of PTH by one or more parathyroid glands.
Hypercalcemia, in contrast, results in calcitonin synthesis and release, while PTH release and
formation of 1,25-(OH)2D2 are inhibited. Calcitonin inhibits bone resorption directly by reducing
osteocyte activity. Calcitonin also induces an initial phosphate diuresis, followed by increased
renal calcium, sodium, and phosphate excretion.
Hypocalcemia: Hypocalcemia occur as a result of malabsorption, chronic renal failure and
vitamin D deficiency. Symptoms include tetany, paraesthesia, increased neuromuscular
excitability, muscle cramps and tonic-clonic convulsions.
Hpocalcemia directly increases PTH synthesis and release and inhibits calcitonin release. PTH in
turn restores plasma calcium by initially stimulating transport of free or labile calcium from bone
into the blood. Hypocalcemia is accompanied by hyperphosphatemia, reflecting decreased PTH
action on renal phosphate transport.
Treatment: Calcium salts preparations eg calcium gluconate, calcium lactate and calcium
carbonate.
Vitamin D preparations
Side effects: Peripheral vasodilation and cardiac arrythmias.
Sodium
Sodium is the major cation of the extracellular fluid. It is responsible for one-half of the osmotic
pressure gradient that exists between the interior of cells and their surrounding environment.
People eating a typical Western diet, which is very high in NaCl, routinely take in 130 to 160
mmol/day of sodium, but humans require only 1 to 2 mmol/day. This excess sodium appears to be
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a major factor in hypertension (high blood pressure) in some people. Excretion of sodium is
accomplished primarily by the kidneys. Sodium is freely filtered through the glomerular capillaries
of the kidneys, and although much of the filtered sodium is reabsorbed in the proximal convoluted
tubule, some remains in the filtrate and urine, and is normally excreted.
Hyponatremia is a lower-than-normal concentration of sodium, usually associated with excess
water accumulation in the body, which dilutes the sodium. An absolute loss of sodium may be due
to a decreased intake of the ion coupled with its continual excretion in the urine. An abnormal loss
of sodium from the body can result from several conditions, including excessive sweating,
vomiting, or diarrhea; the use of diuretics; excessive production of urine, which can occur in
diabetes; and acidosis, either metabolic acidosis or diabetic ketoacidosis.
A relative decrease in blood sodium can occur because of an imbalance of sodium in one of the
body’s other fluid compartments, like IF, or from a dilution of sodium due to water retention
related to edema or congestive heart failure. At the cellular level, hyponatremia results in increased
entry of water into cells by osmosis, because the concentration of solutes within the cell exceeds
the concentration of solutes in the now-diluted ECF. The excess water causes swelling of the cells;
the swelling of red blood cells—decreasing their oxygen-carrying efficiency and making them
potentially too large to fit through capillaries—along with the swelling of neurons in the brain can
result in brain damage or even death.
Hypernatremia is an abnormal increase of blood sodium. It can result from water loss from the
blood, resulting in the hemoconcentration of all blood constituents. Hormonal imbalances
involving ADH and aldosterone may also result in higher-than-normal sodium values.
Potassium
Potassium is the major intracellular cation. It helps establish the resting membrane potential in
neurons and muscle fibers after membrane depolarization and action potentials. In contrast to
sodium, potassium has very little effect on osmotic pressure. The low levels of potassium in blood
and CSF are due to the sodium-potassium pumps in cell membranes, which maintain the normal
potassium concentration gradients between the ICF and ECF. The recommendation for daily
intake/consumption of potassium is 4700 mg. Potassium is excreted, both actively and passively,
through the renal tubules, especially the distal convoluted tubule and collecting ducts. Potassium
participates in the exchange with sodium in the renal tubules under the influence of aldosterone,
which also relies on basolateral sodium-potassium pumps.
Hypokalemia is an abnormally low potassium blood level. Similar to the situation with
hyponatremia, hypokalemia can occur because of either an absolute reduction of potassium in the
body or a relative reduction of potassium in the blood due to the redistribution of potassium. An
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absolute loss of potassium can arise from decreased intake, frequently related to starvation. It can
also come about from vomiting, diarrhea, or alkalosis.
Some insulin-dependent diabetic patients experience a relative reduction of potassium in the blood
from the redistribution of potassium. When insulin is administered and glucose is taken up by cells,
potassium passes through the cell membrane along with glucose, decreasing the amount of
potassium in the blood and IF, which can cause hyperpolarization of the cell membranes of
neurons, reducing their responses to stimuli.
Hyperkalemia, an elevated potassium blood level, also can impair the function of skeletal
muscles, the nervous system, and the heart. Hyperkalemia can result from increased dietary intake
of potassium. In such a situation, potassium from the blood ends up in the ECF in abnormally high
concentrations. This can result in a partial depolarization (excitation) of the plasma membrane of
skeletal muscle fibers, neurons, and cardiac cells of the heart, and can also lead to an inability of
cells to repolarize. For the heart, this means that it won’t relax after a contraction, and will
effectively “seize” and stop pumping blood, which is fatal within minutes. Because of such effects
on the nervous system, a person with hyperkalemia may also exhibit mental confusion, numbness,
and weakened respiratory muscles.
Regulation of Sodium and Potassium
Sodium is reabsorbed from the renal filtrate, and potassium is excreted into the filtrate in the renal
collecting tubule. The control of this exchange is governed principally by two hormones—
aldosterone and angiotensin II.
Aldosterone
Recall that aldosterone increases the excretion of potassium and the reabsorption of sodium in the
distal tubule. Aldosterone is released if blood levels of potassium increase, if blood levels of
sodium severely decrease, or if blood pressure decreases. Its net effect is to conserve and increase
water levels in the plasma by reducing the excretion of sodium, and thus water, from the kidneys.
In a negative feedback loop, increased osmolality of the ECF (which follows aldosteronestimulated sodium absorption) inhibits the release of the hormone.
This flow chart shows how potassium and sodium ion concentrations in the blood are regulated by
aldosterone. Rising K+ and falling NA+ levels in the blood trigger aldosterone release from the
adrenal cortex. Aldosterone targets the kidneys, causing a decrease in K+ release from the kidneys,
which reduces the amount of K+ in the blood back to homeostatic levels. Aldosterone also increases
sodium reabsorption by the kidneys, which increases the amount of NA+ in the blood back to
homeostatic levels.
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Angiotensin II
Angiotensin II causes vasoconstriction and an increase in systemic blood pressure. This action
increases the glomerular filtration rate, resulting in more material filtered out of the glomerular
capillaries and into Bowman’s capsule. Angiotensin II also signals an increase in the release of
aldosterone from the adrenal cortex.
In the distal convoluted tubules and collecting ducts of the kidneys, aldosterone stimulates the
synthesis and activation of the sodium-potassium pump. Sodium passes from the filtrate, into and
through the cells of the tubules and ducts, into the ECF and then into capillaries. Water follows
the sodium due to osmosis. Thus, aldosterone causes an increase in blood sodium levels and blood
volume. Aldosterone’s effect on potassium is the reverse of that of sodium; under its influence,
excess potassium is pumped into the renal filtrate for excretion from the body.
For the hormone cascade that that increases kidney reabsorption of NA+ and water, the first step
involves the release renin from the kidneys into the blood stream. At the same time, the liver
releases angiotensinogen into the blood, which combines with the renin, yielding angiotensin one.
The blood flow then leads to the lungs. Within the pulmonary blood, angiotensin-converting
enzyme (ACE) converts angiotensin one to angiotensin two. The blood then flows to the adrenal
cortex, where angiotensin two stimulates the adrenal cortex to secrete aldosterone. Aldosterone
causes the kidney tubules to increase reabsorption of NA+ and water into the blood.
Regulation of Calcium and Phosphate
Calcium and phosphate are both regulated through the actions of three hormones: parathyroid
hormone (PTH), dihydroxyvitamin D (calcitriol), and calcitonin. All three are released or
synthesized in response to the blood levels of calcium.
PTH is released from the parathyroid gland in response to a decrease in the concentration of blood
calcium. The hormone activates osteoclasts to break down bone matrix and release inorganic
calcium-phosphate salts. PTH also increases the gastrointestinal absorption of dietary calcium by
converting vitamin D into dihydroxyvitamin D (calcitriol), an active form of vitamin D that
intestinal epithelial cells require to absorb calcium.
PTH raises blood calcium levels by inhibiting the loss of calcium through the kidneys. PTH also
increases the loss of phosphate through the kidneys.
Calcitonin is released from the thyroid gland in response to elevated blood levels of calcium. The
hormone increases the activity of osteoblasts, which remove calcium from the blood and
incorporate calcium into the bony matrix.
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