PARASYMPATHETIC NERVOUS SYSTEM

In parasympathetic system, acetylcholine is the principal NT secreted by

preganglionic as well as postganglionic fibres. Therefore, it is also known as
cholinergic nervous system. ACh is synthesized (from acetyl Co-A and
choline) and stored within the cholinergic neurons.

Fig. 2.2: Drugs acting at cholinergic neurons

Uptake of choline by the neurons is the rate limiting step in the biosynthesis of
this NT. After its synthesis, ACh is stored in the vesicles. It is released in the
synaptic cleft (by exocytosis) when nerve impulse stimulates the neuron.
Here, it stimulates post-ganglionic as well as pre-ganglionic cholinergic
receptors and produces the response.
catecholamines during surgical removal of the tumor in patients with
pheochromocytoma. L-dopa is converted to dopamine by the action of a non
specific decarboxylase (that also decarboxylates 5-hydroxytryptophan to
serotonin), which can be inhibited by carbidopa and benserazide. Dopamine is
transported to the storage vesicles (inhibited by reserpine, tetrabenazine,
deutetrabenazine and valbenazine), where it is converted to nor-adrenaline
by dopamine β hydroxylase. This enzyme is inhibited by disulfiram. Action
of NA is terminated mainly by reuptake in the vesicles (inhibited by cocaine
and TCA) and partly by the metabolism through MAO and COMT. Further
conversion of NA to adrenaline (A) is carried out in the adrenal medulla. This
methylation step occurs in the cytoplasm with the help of phenyl
ethanolamine-N-methyl transferase. Sympathetic neurons lack this enzyme;
therefore catecholamine synthesis is stopped at NA level.
NA remains stored in the vesicles. Stimulation of this neuron by the
action potential increases the influx of Ca2+ and results in exocytosis of NA in
the synaptic cleft. Exocytosis is inhibited by bretylium and guanethidine. NA
released in the synapse acts on post-synaptic receptors (to produce various
effects) as well as presynaptic receptors (to modulate its own release).

Fig. 2.4: Drugs acting at adrenergic neurons

Bradykinin is involved in the causation of dry cough and angioedema.
Angiotensin II acts on AT1 (main action) and AT2 (less important) receptors.
AT1 stimulation causes vasoconstriction (by direct action, by release of
adrenaline from adrenal medulla and by increasing central sympathetic
outflow) and stimulation of aldosterone release. Aldosterone is involved in
salt and water retention as well as in the causation of cardiac remodeling.
Thus RAAS results in vasoconstriction as well as salt and water retention
leading to increase in blood pressure. Therefore, drugs that antagonize the
action of RAAS can be used for decreasing the blood pressure. This group of
drugs is more effective in sodium depleted states (like diuretic use) because
activity of RAAS is more in such cases (to compensate for salt loss). These
drugs may cause postural hypotension in diuretic treated patients, which otherwise
is a relatively rare adverse effect. Beta blockers, renin inhibitors, ACE
inhibitors, AT1 antagonists and aldosterone antagonists can act by decreasing
the activity of RAAS (Fig. 4.5).

Fig. 4.5: Renin angiotensin aldosterone system and target of drugs

Renin Inhibitors
Aliskiren, remikiren and enalkiren are the drugs that inhibit the enzyme renin.
So these drugs decrease the activity of RAAS causing fall in blood pressure.
These drugs can be used orally for the treatment of chronic hypertension.
situations like myxedema coma. use in hypothyroidism.

INDICATIONS
Main indication of thyroid hormones is hypothyroidism (cretinism,
myxedema and myxedema coma). Levo-thyroxine (T4) is preferred for all these
indications due to its long half life and requirement of less frequent dosing.
Myxedema coma is an emergency situation, in which liothyronine (only
indication) can also be used (It should be used cautiously in patients with
heart diseases like AF).

DRUGS USEFUL FOR HYPERTHYROIDISM

Drugs can inhibit various steps in thyroid hormone synthesis and release
(Fig. 6.2).

Fig. 6.2: Synthesis and action of thyroid hormones with drug targets

1. Inhibitors of Na+–I– Symporter

Iodine is trapped in the follicular cells with Na+:I- symporter. Thiocyanate,
 UTERINE STIMULANTS

These drugs increase uterine contractions and are known as

oxytocics or ecbolics.
Oxytocin
It is secreted by posterior pituitary along with ADH. It increases the
uterine contractions with complete relaxation in between. It increases the
contraction of upper segment (fundus and body) of uterus whereas
lower segment is relaxed facilitating the expulsion of the fetus.
Estrogen increases whereas progesterone decreases the sensitivity of uterus
to oxytocin.
• Oxytocin is involved in milk ejection reflex whereas prolactin
causes milk secretion.
• High doses of oxytocin cause fall in BP (due to vasodilation)
resulting in reflex tachycardia.
• It also has ADH like action in high dose and can result in fluid
 Fig. 9.2: Mechanism of action of antiplatelet drugs.

NEW ANTIPLATELET AGENTS

• Two groups of newer antiplatelet agents are in advanced stages of

development.
• Ticagrelor and cangrelor are direct-acting reversible P2Y12 receptor
antagonists. Ticagrelor is orally effective.
As compared to clopidogrel, it produces greater and more predictable
antiplatelet action. It also has more rapid onset and offset of action as
compared to clopidogrel. It is the first new antiplatelet drug to
demonstrate a greater reduction in cardiovascular death than
clopidogrel in patients with acute coronary syndromes. It has
recently been approved by FDA. Cangrelor is intravenous reversible
P2Y12 receptor antagonist recently approved as an adjunct to PCI.
• Vorapaxar is an orally active inhibitor of thrombin receptors on platelets
called protease-activated receptor 1 (PAR-1). It has recently been
 1. ORAL ANTICOAGULANTS

• Drugs in this group include warfarin, bishydroxycoumarin (dicumarol),

acenocoumarin, phenindione etc. Phenindione causes orange coloured
urine as well as liver and kidney damage.
• These drugs act by inhibiting the activation of vitamin K dependent
clotting factors. These factors are synthesized by liver and activated by
gamma- carboxylation of glutamate residues with the help of vitamin K.
Hydroquinone form of vitamin K is converted to epoxide form in this
reaction and regeneration of hydroquinone form by enzyme vitamin K
epoxide reductase (VKOR) is required for this activity. Oral
anticoagulants prevents this regeneration by inhibiting VKOR, thus
vitamin K dependent factors are not activated (Fig 9.3). These factors
include clotting factors II, VII, IX and X as well as anti-clotting proteins,
protein C and protein S. As already activated factors are not affected, the
effects of these drugs depend on disappearance of already activated
factors from the blood.

Fig. 9.3: Mechanism of action of warfarin.

• Warfarin is a racemic mixture of R and S isomers. S-warfarin is more

active and is metabolized by CYP2C9. Polymorphisms in CYP2C9 may
affect the activity of warfarin among different persons.
• Protein C has shorter half life than most clotting factors (8 hours) so it is
the first factor to decline and its deficiency may lead to dermal vascular
necrosis and hypercoagulation (protein C is anti-clotting) as early
appearing (3-10 days after initiation of therapy) adverse effects of
warfarin and other drugs of this group. Among clotting factors, first to
disappear is factor VII (t1/2= 6 hours) and last to disappear is factor II
 Fig. 12.1: Mechanism of action of different antimicrobials

BASED ON THE TYPE OF ACTION

According to this classification, drugs may be bacteriostatic or bactericidal
(see Table 12.1).
Table 12.1: Classification of antibiotics according to the type of action
Bacteriostatic Bactericidal
Protein synthesis inhibitors Protein synthesis inhibitors
Tetracyclines Aminoglycosides
Tigecycline Streptogramins
Chloramphenicol
Macrolides
Lincosamides
Linezolid
Drugs affecting DNA Drugs affecting DNA
Nitrofurantoin Quinolones
Novobiocin Metronidazole
Drugs affecting metabolism Polypeptide antibiotics
Sulfonamides Polymixin B
Dapsone Colistin
PAS Amphotericin B
Trimethoprim
Ethambutol
The drugs that are able to interfere with the role of an endogenous compound
in the cellular metabolism are called antimetabolites e.g. sulfonamides,
trimethoprim, pyrimethamine, proguanil and methotrexate. Most important
metabolic step amenable to inhibition by the drugs is folic acid synthesis.
• Drugs inhibiting folic acid synthesis: Folic acid synthase
(dihydropteroate synthase) results in the formation of folic acid by
incorporation of PABA. Sulfonamides, dapsone and paraaminosalicylic acid
(PAS) are structural analogues of paraaminobenzoic acid (PABA). There
drugs act as competitive inhibitors of folic acid synthase.
• Dihydrofolate reductase (DHFRase) inhibitors: DHF-Rase is the
enzyme responsible for conversion of dihydrofolic acid to
tetrahydrofolic acid. Latter is the active form required for the transfer of
one carbon units. Drugs inhibi-ting this enzyme are trimethoprim,
pyrimethamine, proguanil and methotrexate.

• Arabinogalactan synthesis inhibitors: Ethambutol inhi-bits

arabinogalactan synthesis and thus incorporation of mycolic acid in the
cell wall of mycobacteria.

SULFONAMIDES

• These drugs are bacteriostatic agents and act by inhibiting folate

synthase competitively.
• The selective toxicity to bacteria is due to the reason that
mammalian cells do not synthesize folic acid and utilize preformed
folic acid in the diet.
 Fig. 13.1: Mechanism of action of anti-tubercular drugs

Isoniazid (H)
• It is a prodrug activated by catalase-peroxidase (coded by KatG). Active
metabolite inhibits the enzyme ketoenoylreductase (coded by inh A),
required for mycolic acid synthesis, an essential component of
mycobacterial cell wall. It acts by O2 dependent pathway such as catalase
peroxidase reaction.
• It is bacteriostatic against resting and bactericidal against rapidly multiplying
organisms.
• It is effective against intra- as well as extra-cellular mycobacteria.
• Action is most marked against rapidly multiplying bacilli (less effective
against slow multipliers).
• It is widely distributed in the body and has maximum CSF penetration.
• It is effective orally and metabolized by ACETYLATION which is
genetically controlled. Fast acetylators require high dose and slow
acetylators are predisposed to toxicity (particularly peripheral neuritis).
• It is an essential component of multi-drug therapy of tuberculosis and is
drug of choice (used solely) for prophylaxis of tuberculosis and for
treatment of latent tuberculosis infection.
• Resistance occurs due to mutation in Kat G (gene for catalse-peroxidase)
 Fig. 13.2: Mechanism of action of anti-fungal drugs

Amphotericin B
• It is a polyene antibiotic similar to nystatin. It is not absorbed orally so
administered by slow i.v. infusion. It is widely distributed except in the CNS.
• It binds to ergosterol and causes the formation of artificial pores in fungal cell
membrane.
• Amphotericin B has the widest antifungal spectrum [except Pseudoallescheria
boydii (also called Scedosporium apiospermum) and Fusarium] and is the drug of
choice or co-drug of choice for most systemic fungal infections. It is drug of
choice for cryptococcal meningitis, mucormycosis and disseminated
infections by sporothrix. It can be used intrathecally in fungal meningitis
and locally for corneal ulcers and keratitis.
• Infusion related reactions are seen frequently with this drug and require
premedication with antihistaminics or glucocorticoids.
• Dose limiting toxicity is nephrotoxicity manifested by renal tubular
acidosis, hypokalemia and hypomagnesemia. Infusion of normal saline
before giving AMB decreases nephrotoxicity but solution of AMB should
not be made in normal saline (It is made in dextrose.) Saline loading (IL of
 Fig. 13.3: Mechanism of action of anti-viral drugs

ANTI-HERPES DRUGS

• Most of these drugs are antimetabolites and inhibit viral DNA polymerase
after bioactivation by kinases.

Acyclovir and its Congeners

• Acyclovir is a guanosine analogue active against herpes simplex virus
(HSV-1 and 2) and varicella zoster virus (VZV).
• Acyclovir is not active against CMV infections.
• It is activated first by a virus specific kinase (thymidine kinase) to form acyclovir
monophosphate (virus develops resistance due to mutation of this kinase)
and then by host kinases to form acyclovir triphosphate. This product
competitively inhibits the action of DNA polymerase (by competing with GTP)
and also gets incorporated into the DNA and causes chain termination.
 Fig. 13.4: Pathogenesis of HIV and target of various drugs

a. NRTIs
These are prodrugs and are activated by host cell kinases to form triphosphates.
These drugs competitively inhibit reverse transcriptase and also act as chain
terminators by incorporation into the DNA chain (because these lack 3’
hydroxyl group on ribose ring, attachment of next nucleotide is not possible).
Resistance to these drugs emerges rapidly if used alone.
• Zidovudine is frequently used NRTI in the treatment of HIV
infections. It can also be used for the prophylaxis of needle stick injury patients
and for the prevention of vertical transmission of HIV from mother to fetus.
Major adverse effect of zidovudine is bone marrow suppression leading to
megaloblastic anemia, neutropenia and thrombocytopenia (ganciclovir should
not be combined). It is contraindicated in patient with Hb < 8g%. It can also
cause myopathy. Rifampicin increases the clearance of this drug. Chronic
administration is associated with lipodystrophy syndrome, nail
hyperpigmentation and lipoatrophy.
 Fig. 13.6: Life cycle of malarial parasite with target of drugs
• Sporonticides or gametocides: These drugs kill the gametes and thus
prevent transmission of malaria. Chloroquine, mepacrine and quinine kill
the gametes of P. vivax only whereas proguanil, pyrimethamine, primaquine
and artemisinin kill gametes of both P. vivax as well as P. falciparum.
Stage Clinical Use

Pre-Erythrocytic Causal prophylaxis

Erythrocytic Clinical cure
Exo-Erythrocytic Suppressive prophylaxis
Gametocytic Radical cure
Prevention of transmission

Chloroquine
It is the drug possessing largest volume of distribution (>1300 L). It
accumulates in the food vacuole of the plasmodium. Thus, it is selectively
concentrated in the parasitized erythrocytes. It prevents polymerization of heme
to hemozoin resulting in accumulation of heme that is toxic for the parasite. It
is the drug of choice for treatment and prophylaxis of non-falciparum malaria and
chloroquine sensitive P. falciparum malaria. It is an erythrocytic schizonticide
Contd...
Contd...

Fig. 13.7: Site of action of anti-amoebic drugs

Nitroimidazoles
This group includes metronidazole and related drugs. These are effective
orally as well as i.v. and eliminated by hepatic metabolism. Nitro group of
these drugs gets bioactivated (by reduction) to form reactive cytotoxic
products that damage DNA.

• Metronidazole is the drug of choice for intestinal wall disease and

amoebic liver abscess. It is usually combined with a luminal
amoebicide for these indications. It is not a very good drug for luminal
amoebiasis because it is almost completely absorbed in the proximal
intestine and very little amount reaches the colon.
pathogenesis of psoriasis. Efalizumab is a monoclonal antibody against
LFA-1 whereas Alefacept is a fusion protein against LFA-3. Both of these
drugs are used for psoriasis.

Fig. 15.4: Pathogenesis of psoriasis and drug targets