PHARMACOLOGY FOR M.B.B.S, PHARM.D, B.D.S, D.P.T

2. Structure
 A thiazolidine ring which is attached to β-lactam ring
 6- aminopenicillanic acid nucleus is essential for activity
 If the β-lactam ring is enzymatically cleaved by bacterial β-
lactamases, the resulting product, penicilloic acid lacks
antibacterial activity

3. Classification
 Natual penicillins
 Penicillin G (Benzyl penicillin)
 Penicillin V has a spectrum similar to that of penicillin G, but it is
not used for treatment of bacteremia because of its poor
absorption, narrow spectrum and need for dosing four times.
 Anti staphylococcal penicillins
 The semi synthetic penicillins Methicillin, nafcillin, oxacillin, and
dicloxacillin are penicillinase resistant penicillins.
 Because of its toxicity (interstitial nephritis), methicillin is not used
clinically except to identify resistant strains of S. aureus. Methicillin
resistant Staphylococcus aureus (MRSA) is currently a source of
serious community and nosocomial (hospital-acquired) infections
and is resistant to all commercially available β-lactam antibiotics,
including antistaphylococcal penicillins. This organism is usually
susceptible to Vancomycin.

4.  The penicillinase-resistant penicillins have no activity versus
gram-negative infections.
 However, for infections caused by methicillin susceptible strains
of staphylococci these are considered the drugs of choice.
 Extended spectrum penicillins
 Ampicillin and Amoxicillin have an antibacterial spectrum
similar to that of penicillin G but are more effective against
gram-negative bacilli. Therefore, they are referred to as
extended-spectrum penicillins
 Resistance to these antibiotics is now a major clinical problem
because of inactivation by plasmid mediated penicillinases.
 Formulation with a β-lactamase inhibitor, such as clavulanic acid
or sulbactam, protects amoxicillin or ampicillin, respectively,
from enzymatic hydrolysis and extends their antimicrobial
spectrum
 Synergistic effect with aminoglycosides

5. Anti pseudomonal penicillins
 Carbenicillin, ticarcillin, and piperacillin are called
antipseudomonal penicillins because of their activity
against P. aeruginosa
 These drugs have activity against several gram-negative
rods, including Pseudomonas, Enterobacter, and in some
cases Klebsiella species.
 susceptible to penicillinases and are often used in
combination with penicillinase inhibitors (eg, tazobactam
and clavulanic acid) to enhance their activity.
 Synergism with aminoglycosides

8. Mechanism of action
 The transpeptidation reaction in Staphylococcus aureus that is
inhibited by β-lactam antibiotics. The cell wall of gram-positive
bacteria is made up of long peptidoglycan polymer chains
consisting of the alternating N-acetylglucosamine (G) and N-
acetylmuramic acid (M) with pentapeptide side chains linked
(in S. aureus) by pentaglycine bridges. The exact composition of
the side chains varies among species. The diagram illustrates
small segments of two such polymer chains and their amino
acid side chains. These linear polymers must be cross-linked by
transpeptidation of the side chains at the points indicated by
the asterisk to achieve the strength necessary for cell viability.
0 UDP-acetylmuramyl-L-Ala-D-Glu-L-Lys-D-Ala-D-Ala sequence is
also called as “Park nucelotide”, formerly called as “Park
peptide”

9.  Penicillin binding proteins (PBPs) catalyze the
transpeptidase reaction that removes the terminal alanine to
form a cross link with a nearby peptide.
 This gives cell wall its structural rigidity
 β- lactam antibiotics are structural analogs of the D-ala-D-
ala substrate.
 This substrate is bound by PBP at active site
 When a β- lactam is attached PBP, transpeptidation reaction
is blocked which leads to inhibition of peptidoglycan
synthesis and the cell dies
 Exact mechanism of bacterial cell death is unknown but
involvement of autolysins activation and destabilization of
bacterial membrane against high internal osmotic pressure
is suggested.

10. Resistance
1. Inactivation of antibiotic with β-lactamase
2. Modification of target PBPs
3. Impaired penetration of drug to target PBPs
4. Presence of efflux pump
 β-lactamase production is the most common mechanism of
resistance
 Some β-lactamase hydrolyze penicillins but not
cephalosporins e.g. those produced by E. coli, S. aureus.
 Whereas, those produced by P. aeruginosa and enterobacter
hydrolyze both.
 Carbapenems are highly resistant to hydrolysis by
penicillinases and cephalosporinases but are hydrolyzed by
metallo-β-lactamase.

11. Pharmacokinetics
 Absorption differs for different penicillins, depending
upon their acid stability and protein binding.
 Methicillin is acid labile
 Gastrointestinal absorption of nafcillin is erratic
 Both are not suitable for oral administration.
 Amoxicillin, ampicillin and dicloxacillin are acid stable
and relatively well absorbed
 Absorption of most oral penicillins are impaired by food
(except amoxicillin), therefore, should be administered
1-2 hrs before meal.
 Absorption through IV route is preferred due to local
irritation and pain produced by IM injection of large
doses.

12.  Penicillins are usually excreted by kidney through urine
and small amounts are excreted by other routes
 Those penicillins which are excreted through kidney, dose
must be adjusted according to renal function e.g. normal
half life of Penicillin G is usually 30 min and in renal failure
it may increase upto 10 hours.
 Nafcillin is primarily cleared by biliary excretion
 Oxacillin, dicloxacillin and cloxacillin are cleared by both
kidney and biliary excretion.
 No dose adjustments are required for these drugs in renal
failure.

13. Adverse reactions
 Penicillins are remarkably non toxic
1- Hypersensitivity reactions
 Due to penicilloic acid (metabolite of penicillin)
 From skin rash to anaphylactic shock (includes fever,
nephritis, pruritis, urticaria, joint swelling etc.)
 Methicillin cause interstitial nephritis while nafcillin
causes neutropenia
 Incidence of allergic reaction in small children is negligible
2-GIT disturbances
 Due to over growth of G+ organisms or by direct irritation
 Nausea, vomiting, diarrhea
 Pseudomembranous colitis (Inflammation of colon)
 Ampicillin (rare).

14.  MOA: Penicillin causes normal flora to alter. When an
antibiotic kills competing bacteria in the intestine, the
remaining bacteria will have less competition for space
and nutrition. The net effect is to permit more extensive
growth than normal of certain bacteria. E.g. C. difficile.
 Vaginal candidiasis can also occur.
3- Seizures
 Penicillin G causes seizures if given intra-thecal in
patients especially with renal failure patients. They also
can cause confusion and psychosis (neurotoxicity).
 MOA: Most widely accepted theory involves binding to
GABA receptors which are involved in inhibitory
neurotransmission
 Benzodiazepines and Barbiturates are used as treatment
 Cessation of seizure activity has been reported 12-72 hrs
after therapy is discontinued. The epilepticogenic
activity may be due to β-lactam ring

15. Treatment / Anti-dot
 Allergy is treated by Anti-histamine
 Desensitization can be accomplished with gradually
increasing doses of penicillin
 Anaphylactic shock is treated by Adrenaline and
corticosteroids.
 MOA: Vasodilation (Fall in BP) and bronchoconstriction are
important symptoms of anaphylactic shock, whereas,
adrenaline causes vasoconstriction and bronchodilation.
 Corticosteroids have anti-inflammatory effects
 Penicillins and carbapenems are both neurotoxic. Dose
adjustment in renal failure is key strategy to avoid
neurotoxicity.

16. Contraindications / drug
interactions
 Captopril (capotein) – Increase potassium level.
 Spironolactone (Aldactone) – K+ sparing diuretics
 K+ suppliments (KCl).
 Especially with those penicillins which are available in
potassium salts.
 Hyperkalemia can generate arrhythmia in cardiac patients.
 Sodium salts should be avoided in hypertensive patients.
 Ticarcillin and carbencillin have antiplatelet aggregation
effect.
 Be careful when administering Streptokinase, warfarin,
heparin, clopidogrel etc to patients who are already taking
these penicillins.

17.  Penicillins inhibit the excretion of methotrexate (anti-
cancer) due to which toxic effects of methotrexate occur,
such as, bone marrow depression.
 Probencid is a uricosuric agent. It increases the
concentration of penicillin and inhibit its excretion.
 Penicillins decrease the effectiveness of estrogens in
contraceptive pills.
 Dose of penicillins should be increased in
immunocompromised patients.
 Should not be taken with acidic juices and should be
administered with full glass of water.

18. Patient history
 Allergy
 Hypertensive (having low salt diet)
 Impaired renal function
 GIT problems
 Tendency to bleed