Beta-Lactam Pharmacology & MedChem Part 2

Describe the structure of penicillins

beta-lactam ring attached to a 5 membered ring with a sulfur

What drugs are natural penicillins?

Penicillin G

Penicillin VK

Benzathine penicillin G

Describe the absorption of penicillin G

IV administration

Describe the absorption of penicillin VK

Oral administration, poorly absorbed

Penicillin VK = potassium salt for oral administration

Food reduces absorption

Describe the absorption of benzathine penicillin G

IM administration

Highly insoluble injection for IM administration

Slow release = absorbed over 2-4 weeks

Describe the distribution of natural penicillins

Distributed widely through most body tissues

Describe the metabolism of natural penicillins

Minimal = no CYP

Describe the elimination of natural penicillins

Rapid renal elimination

Half-life = 30-90 minutes (prolonged with renal dysfunction)

What yields a poorly soluble salt?

Addition of a weak base to penicillin G to form benzathine penicillin G

What yields a highly soluble salt?

Addition of a strong base to penicillin V to form penicillin VK

What drugs are aminopenicillins?

Amoxicillin

Ampicillin

Describe the absorption of ampicillin

Oral administration with variable absorption, food decreases absorption

IV administration also an option

Describe the absorption of amoxicillin

Oral administration

Absorbed more completely and rapidly than ampicillin

Describe the distribution of aminopenicillins

Widely through most body tissues

Describe the metabolism of aminopenicillins

Minimal = no CYP

Describe the elimination of aminopenicillins

Renal excretion

Renal impairment requires dose reduction

What do the amide side chains of aminopenicillins influence?

Chemical stability and % absorption

What seems to be driving oral absorption of aminopenicillins?

Side chains (R)

What is responsible for the improved bioavailability of ampicillin?

Improved acid stability due to positive charge in acidic environments

Better substrate for dipeptide transporter uptake in gut

What is responsible for the improved spectrum of activity of ampicillin?

Increased Gram negative activity due to improved cell wall penetration in Gram negatives

What further improves the stability of amoxicillin?

Hydroxyl group added to the left of the benzene ring

Generally speaking, what increases stability and spectrum of activity?

Positive charges

How do beta-lactamases inactivate beta-lactams?

By cleaving the 4 membered beta-lactam ring

What are two ways to deal with beta-lactamase inactivation?

1. Design penicillins that are resistant to beta-lactamase cleavage

2. Co-dose an inhibitor of beta-lactamase

What beta-lactams are resistant to beta-lactamase cleavage?

Oxacillin, nafcillin, dicloxacillin

What aspect of beta-lactamase resistant penicillins blocks beta-lactamase activity?

Steric hindrance on the penicillin side chain

What infections are beta-lactamase resistant penicillins often used for and why?

Staphylococcal infections

S. aureus has developed resistance to penicillins by expression of penicillinase, which is a subtype of beta-lactamase

Also called anti-staphylococcal penicillins

Describe the absorption of dicloxacillin

Oral administration, absorbed rapidly but incompletely

Absorption increases when administered 1 h before or 2 h after meals

Describe the absorption of nafcillin and oxacillin

IV administration

Describe the distribution of beta-lactamase resistant penicillins

Widely through most body tissues

Acceptable CNS penetration

Describe the metabolism of beta-lactamase resistant penicillins

CYP3A4 substrates

Describe the elimination of beta-lactamase resistant penicillins

Rapid renal and hepatic degradation and elimination in the bile

Half life = 30-60 min

What drugs are beta-lactams/beta-lactamase inhibitors?

Amoxicillin/Clavulanic acid

Piperacillin/Tazobactam

Ampicillin/Sulbactam

Amoxicillin/Clavulanic acid

Augmentin

Piperacillin/Tazobactam

Zosyn

Describe the absorption of piperacillin/tazobactam and ampicillin/sulbactam

IV administration only

Describe the absorption of amoxicillin/clavulanic acid

Well absorbed orally

Describe the distribution of piperacillin/tazobactam

High biliary concentrations

Does not penetrate CNS

Describe the metabolism of clavulanic acid

Hepatic = may cause hepatic injury

Describe the elimination of piperacillin/tazobactam

Renal excretion

Renal impairment requires dose reduction

Describe the structure of cephalosporins

beta-lactam ring attached to a 6 membered ring with a sulfur

What is the MOA of cephalosporins?

Similar to penicillins

Leaving group can facilitate activity

Describe the resistance mechanism of cephalosporins

beta-lactamases ring opening

Varying levels of susceptibility

Describe the allergenicity of cephalosporins

Less common and less severe than with penicillins

Cross allergenicity is possible, but depends on the side chain

Describe how cephalosporins are chemically fragile

Same issues as penicillins

Fragile to acids, bases, alcohols, and amines

Accelerates with heat

Stability SAR same as penicillins

What drugs are cephalosporins?

Cefazoline

Cephalexin

Cefuroxime

Cefoxitin

Ceftriaxone

Ceftazidime

Cefdinir

Cefepime

Ceftaroline

Which cephalosporins can be dosed orally?

Cephalexin

Cefdinir

Describe the absorption of all other cephalosporins

All besides cephalexin and cefdinir are only IV or IM administration (NO ORAL)

Describe the distribution of ceftriaxone

Reasonable CNS penetration

Describe the distribution of most cephalosporins

Cross the placenta

Found in high concentrations in synovial & pericardial fluids

Describe the metabolism of cephalosporins

Minimal = no CYP

Describe the elimination of ceftriaxone

Mixed renal/nonrenal elimination

No dose reduction required with renal insufficiency

Describe the elimination of cephalosporins (besides ceftriaxone)

Renal excretion

Renal impairment requires dose reduction

What drug slows renal tubular secretion of most cephalosporins?

Probenecid

What is different between the structures of penicillins and cephalosporins?

Unlike penicillins, cephalosporins have two points of diversity from the core

One on the left and one on the right

What do both penicillins and cephalosporins benefit from?

An amino-containing side chain attached to the beta-lactam

How do amino-containing side chains benefit penicillins and cephalosporins?

Allow for high oral absorption and an increased spectrum

What matters for allergenicity?

Side chains

Ex: if amoxicillin allergy, cephalexin or cefadroxil would NOT be a good choice, but cefazolin might be acceptable

How do oxime groups on the amino chain ring effect cephalosporins?

Renders better beta-lactamase stability = reduced beta-lactamase cleavage

How do 5 membered rings affect cephalosporins?

Provides improved activity against gram negative strains

How does the addition of a quaternary amine benefit cephalosporins?

Further improves antibacterial spectrum by allowing better membrane penetration

How do quaternary amines improve membrane penetration of cephalosporins?

Quaternary amine is positively charged at every pH

Improved membrane penetration due to negatively charged membrane components (especially LPS)

Describe the structure of carbapenems

beta-lactam ring attached to a 5 membered ring with a double bond

What drugs are carbapenems?

Imipenem

Meropenem

Ertapenem

Describe the absorption of carbapenems

Not absorbed orally

Describe the distribution of carbapenems

Moderate

Describe the metabolism of imipenem

Hydrolyzed rapidly by a dipeptidase (DPEP-1) found in brush border of the proximal tubule

Describe the metabolism of carbapenems (besides imipenem)

Minimal = no CYP

Describe the elimination of carbapenems

Mostly renal excretion

Renal impairment requires dose reduction

What is DPEP-1?

An endogenous peptidase/protease

What is imipenem co-dosed with?

Cilastatin, a DPEP1 inhibitor

Why is imipenem co-dosed with cilastatin?

In order to improve PK exposure by reducing DPEP-1 hydrolysis

Half-life of imipenem is extended

Why do meropenem and ertapenem not need to be co-dosed with a DPEP-1 inhibitor?

Addition of a methyl group on the beta-lactam core prevents hydrolysis by DPEP1

Improves PK exposure compared to imipenem

What drug is a monobactam?

Aztreonam

When is aztreonam mainly used?

Against hospital-acquired Gram negative infections

What does aztreonam not have activity against?

No useful activity against Gram positive bacteria

Does not bind as well to Gram positive PBP

When may aztreonam be useful?

When penicillin and cephalosporin allergies are a problem

Describe the absorption of aztreonam

Poor/low oral absorption

Give as IV or IM administration

Describe the distribution of aztreonam

Widely through most body tissues

Good CNS penetration

Describe the metabolism of aztreonam

Minimal = no CYP

Describe the elimination of aztreonam

Mostly renal excretion

Renal impairment requires dose reduction