Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

PYRETHRINS AND SYNTHETIC PYRETHROIDS
have greater persistence as topical preparations on
animals.
Generally, these compounds are metabolized quickly
and efficiently by mammals. Factors influencing the rate
of metabolism include the cis isomer content, which is
metabolized more slowly than trans isomers, and the
presence of an α-cyano function, which also slows
metabolism.
While these compounds have a high order of safety in
mammals, some individual cats appear sensitive to the
more recent SPs. The nature of the increased sensitivity is
not known, but it is known from studies in laboratory
mammals that single amino acid substitutions in the
sodium ion channel pyrethroid-binding site can change
sensitivity dramatically. It is possible that cats may be a
pharmacogenomically distinct species in this respect, but
this awaits investigation.
Two syndromes of toxicity in mammals have been
described.
● Type I. Associated with pyrethrins and non-αcyano
SPs (resmethrin, permethrin).
– Progressive development of whole-body tremor
(which can lead to hyperthermia), exaggerated
startle reflex, muscle twitching.
– Treatment is described in the permethrin entry
below.
● Type II. Associated with α-cyano SPs
(cypermethrin, deltamethrin, flumethrin). In
addition to inhibition of sodium channels, type II
pyrethroids may also block voltage-gated chloride
channels and this effect may be attenuated by use
of ivermectin or phenobarbital.
– Salivation, increased extensor tone, incoordination,
writhing spasms, seizures, apnea,
death.
– In addition to actions on sodium channels, type
II SPs act as antagonists to GABA receptors in
mammals.
Pyrethrins
EXAMPLES
Pyrethrin I, II, cinerin I, II, jasmolin I, II.
Pyrethrum extract is obtained from the flower heads of
Chrysanthemum cinerariaefolium and consists of a
mixture of esters. The esters are unstable in the presence
of ultraviolet light and are rapidly metabolized and
inactivated by both insects and mammals. The inclusion
of mixed-function oxidase inhibitors (such as PBO) in
pyrethrin formulations enhances their longevity and
insecticidal efficacy.
Although the selective toxicity of the pyrethroids has
traditionally been attributed to differences in metabo-
lism between arthropods and mammals, experimental
evidence suggests that mammalian nerves have reduced
sensitivity of around 250-fold (lower intrinsic sensitivity
(10×) and lower sensitivity at mammalian body temperature
(5×) combined with faster recovery time (5×))
which must be multiplied by a more rapid detoxification
(9×) (related to enzyme activity and body size differences)
for a total differential sensitivity of approximately
2000 times.
Mechanism of action
Pyrethrins have rapid knockdown activity against susceptible
flying insects and fleas and a separate delayed
lethal effect. Knockdown effects are almost immediate
and thought to be due to excessive sensory hyperactivity
of the peripheral nervous system. Resistance to this
action is due to selection of a target site with altered
amino acid sequence and insensitive to pyrethrin
binding. The pyrethroids slow the kinetics of both
opening and closing of individual sodium channels,
resulting in delayed and prolonged ion channel opening.
This causes prolongation of the whole-cell sodium
current during a depolarizing pulse and marked slowing
of the tail sodium current upon repolarization. Pyrethroids
also cause a shift of the activation voltage in the
direction of hyperpolarization. These changes in sodium
channel kinetics lead to membrane depolarization and
an increase in depolarizing after-potential. The latter
reaches the threshold for excitation, causing repetitive
after-discharges. The membrane depolarization of
sensory neurones increases discharge frequency and that
of nerve terminals increases the release of transmitter
and the frequency of spontaneous miniature postsynaptic
potentials.
Synthetic pyrethroids
Resmethrin
5-benzyl-3-furylmethyl (1RS,3RS;1RS,3SR)-2,2-
dimethyl-3-(2-methylprop-1-enyl) cyclopropanecarboxylate.
Resmethrin (named after Rothamstead Experimental
Station where it was developed in 1967) is considerably
more active than natural pyrethrins and has lower mammalian
toxicity but is unstable in UV light. It is available
for use as an insecticidal shampoo.
Permethrin
3-phenoxybenzyl (1RS,3RS;1RS,3SR)-3-(2,2-
dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate.
Permethrin was first described in 1973 as a synthetic
pyrethroid with improved heat- and photostability. It is
widely used in agriculture and both veterinary and
human medicine. The active constituent is available in
various cis : trans ratios varying from 40 : 60 to 25 : 75.
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