Psych 345 Drugs Pharmacology Kinetics

Pharmacology

The study of drug actions and their effects on living organisms

Drugs before the 20th century

Mostly naturally occurring substances from plants

Ethnobotanists gave away medicines and advice for free

Neuropharmacology

study of drug-induced changes in nervous system cell functioning

Psychopharmacology

emphasizes drug-induced changes in mood, thinking, and behavior

Neuropsychopharmacology

identifies on chemical substances that interact with the nervous system to alter behavior, emotions, and cognition

- uses chemical agents as probes to gain understanding of the neurobiology of behaviour

Drug action

molecular changes produced by a drug when it binds to a target site or receptor

- the molecular changes alter physiological or psychological functions called drug effects

The site of drug action may be different to

the site of the drug effects

- drugs act at several target sites and have multiple effects

What does the statement "drugs are dirty" refer to in terms of drug action and effects?

Drugs act at multiple target sites and receptors at different sites and result in multiple drug effects

Therapeutic effects

the drug-receptor interaction produces desired physical or behavioral changes

- all other effects besides desired ones are side effects (can be both good or bad)

Drug side effects

physiological actions of medication other than those specifically desired - either good or bad

Specific drug effects

based on physical and biochemical interactions of a drug with a target site in living tissue - most often a receptor site to a NT system (GABA, glutamate)

Nonspecific drug effects

based on certain unique characteristics of the individual (mood, expectations, attitudes) - how you are/think changes how the drug works for you

How is a placebo/nocebo effect an example of a nonspecific drug effect?

Involve getting symptoms due to outside factors - knowledge or belief in what a drug will do for you can cause real physiological effects despite lack of chemical activity

- example of a brain-body interaction

Nocebo effect

a negative placebo effect due to the expectation of adverse consequences from receiving treatment

Benefits of placebos to evaluate the effectiveness of medications

can be an inexpensive treatment that avoids interactions with other medications

they eliminate they influence of expectations

Gold standard for experimental testing

double blind (both researcher and participant unaware of placebo), placebo control, randomized trial

What does a double blind experiment ensure

that the result of a treatment will not be coloured by overt or covert bias of the participant, experimenter or observer

Problems with placebos as treatment

limited staying power - effects tend not to last (SSRIs)

they do not effect everyone - 25-75% of people are non responders

Possible explanations for the placebo effect

Pavlovian conditioning, expectations of outcomes, social learning, genetic variants

Bioavailability

amount of drug at the site of action that is free to bind at target sites

Pharmacokenetics

the dynamic factors that contribute to bioavailability or factors that determine how drugs move throughout the body

Pharmacokinetic factors

1. Routes of administration

2. Absorption and distribution

3. Binding

4. Inactivation

5. Excretion

Drugs administration types

Oral, intravenous, intraperioneal, subcutaneous, intramuscular, inhalation

Absorption and distribution

Membranes of oral cavity, gastrointestinal tract, peritoneum, skin, muscles, lungs

Drug Binding

binds at target site on a neuron receptor or inactive storage depots in bone and fat

Drug Excretion

into feces, urine, water vapor, sweat, saliva

ADME

absorption, distribution, metabolism, excretion

What factors determine how quickly a drug reaches equilibrium in the body?

Concentration gradient and the blood flow of organs.

Which organs reach drug equilibrium the fastest?

Heart, liver, and kidneys.

Why do shotgunning beers have a greater impact than drinking them slowly?

Due to the speed of administration and absorption.

Which drug is highly fat soluble?

Marijuana.

What is the difference in behavior between water soluble and fat soluble drugs?

Water soluble drugs stay mostly in the blood, while fat soluble drugs enter adipose tissue.

What happens to drugs that are attached to plasma proteins vs free drugs?

They stay in circulation while free drugs cross into tissues

Drug effects depends on

How rapidly the drug reaches it's target (receptor sites) - concentration gradient, equilibrium, solubility

Frequency and history of prior drug use - though hard to study whether changes in brain are actually due to long term use

Non specific factors characteristic of individuals and their environment

FREQUENCY AND CHANGE US WHAT COUNTS

What is meant by "mindset, set, and setting"

Drug effects are dependent on one's expectations, the drug characteristics and one's environment

What is a vehicle?

What a drug is housed in that allows it to pass through barriers Ex. DMSO

What is DMSO?

Common vehicle to get drugs into system by bypassing lipid barriers and carrying drugs through the bloodstream transdermally

What are implantable controlled drug delivery systems?

administers drugs continuously for up toa month - can be used for schizophrenics who refuse drugs or have a history of stopping on their own

Why are vehicles so important?

They mediate the speed of the drug

Enteral methods of drug administration

Use the gastrointestinal tract - generally slow and produces variable blood levels

Parenteral methods of drug administration

include injection, pulmonary, and topical administration

Oral administration (PO)

-safe, self-administered, economical

- however drug must be resistant to destruction by stomach acid and enzymes Ex. insulin is not resistant and cannot be given orally

Absorption

the movement of a drug from its site of administration into the blood circulation

Factors that influence absorption

Amount of food in stomach, type of food, physical activity, intestinal-blood barrier, sex (men have more enzymes that break down alcohol than women)

First pass metabolism

the substance degradation of an orally administered drug caused by enzyme metabolism via the portal vein in the liver where they are chemically altered before the drug reaches the systemic circulation

- livers job is to enzymatically break down the drug so it can be water soluble and leave the body

How much of a drug gets taken out by the liver during first pass metabolism?

50%

Why is inhalation one of the most popular ways of drug administration?

Because it skips first pass metabolism in the liver

Rectal adminsistration

Placement of a drug filled suppository

- MAY avoid first pass metabolism depending on placement

- used for infants or patients who are vomiting, unconscious or unable to take orally

Intravenous injection (IV)

Most rapid and accurate method

- quick onset of drug effect can be a HAZARD, no time to correct an overdose or allergic reaction as drug cannot be removed by stomach pumping

- lends to drug abuse as drug reaches brain very rapidly

- uncertain doses + additives and lack or sterility can result in infectious diseases

Intramuscular injection (IM)

Slower, more even absorption

- absorption can be slowed by combining the drug with another drug that constricts blood vessels or alter it's solubility

Intraperitoneal Injection (IP)

Drug is injected through the abdominal wall into the space surrounding the abdominal organs

- rarely used with humans, common for small lab animals

- rich spot for absorption as there is lots of surface area

Subcutaneous injection (SC)

Injection just below the skin

- absorption is slow but can be variable

- can be slowed by vegetable oils, implantation of a pellet or delivery device

Inhalation

Drug is absorbed by the lungs rapidly due to the large surface area and many capillaries

- drug effect is rapid Ex. nicotine, TCH, crack cocaine

- gets past first pass metabolism!!

Topical administration

drug is applied to mucous membranes

- mostly local effects, but drug can also be absorbed into the bloodstream Ex. Lidocaine at the dentist

Sublingual administration

drug is placed under the tongue

- avoids gastric acid, enzymes, and first pass metabolism

Intranasal administration

can cause local effects such as relieving nasal congestion but can also have systemic effects

- MAY avoid first pass metabolism by bypassing the BBB, allowing high brain concentrations

- absorption occurs with cocaine snorting

- drug effect peaks in 15-30 minutes

- intranasal oxytocin for autism?

Transdermal

administration of drugs through skin patches for controlled and sustained delivery

- can be used for vaccinations

- also used for motion sickness, nicotine patches, nitroglycerin and hormones

- use vehicles like DMSO to cross the dermatome and lipid bilayer

Epidural injection

spinal anesthetics delivered directly to cerebrospinal fluid, bypasses the BBB

- research techniques include micro injection of drugs to discrete brain areas (intracranial) or ventricles (intraventricular)

Infusion pumps

implanted under the skin of the scalp, programmed to deliver a constant dose of antibiotic into cerebral ventricles

- used to treat brain infection; antibiotics normally do not cross the BBB

How do routes of administration affect bioavailability?

Alter the rate of absorption, the blood levels of a drug and therefore the amount of drug available to the receptors in the brain

Most important factor for determining plasma drug levels

The rate of passage through cell membranes - phospholipids

Phospholipids

Have a negatively charged region that is hydrophilic and two uncharged tails that are hydrophobic arranged in a bilayer

- proteins are inserted into it and serve as receptors or channels

- the molecular characteristics prevent most molecules from passing through unless they are fat soluble, while lipid soluble drug pass through by passive diffusion

Example of a lipid soluble drug that gets through membranes by passive diffusion

Alcohol

The greater the concentration gradient

the faster the diffusion

Confirmational change

receptors changing shape caused by electrical charge

Effect of lipid solubility on absorption

Increases drug absorption and determines how readily it will enter the brain Ex. heroin is more lipid soluble than morphine and is delivered to the brain faster

Which three drugs are the same structurally but change as they cross the blood-brain-barrier?

Heroin, codeine, morphine - heroin is more lipid soluble and gets to the brain faster while codeine is the slowest

Why are most drugs not lipid soluble?

Because they are weak acids or bases that ionize in water

- the extent of ionization depends on pH of the solution and an intrinsic property of the molecule (pKa)

What is pKa?

Measures the strength of an acid or base and indicates the pH at which 50% of the drug is ionized (hydrophilic) and 50% is non-ionized (lipophilic)

Why does level of ionization make a difference in bioavailibility?

Drugs that are weak acids ionize more readily in an alkaline environment and become less ionized in an acidic environment - pH of different body fluids affects drug movement

Other factors affecting absorption

Rate stomach empties- small intestine has more surface area and slower movement of material and thus more absorption can occur

Size and sex of individual- a larger person has more body fluid to dilute a drug (women tend to have less body fluid than males)

Highest concentration of a drug will occur where blood flow is greatest

Drugs can leave capillaries through pores, even if not lipid soluble

Drug redistribution

As plasma levels fall, drug concentration in highly vascularized organs will be greater than in the blood, so the drug will move from those organs back into the plasma to maintain equilibrium - can terminate action of a drug

as they get pulled out of the brain the drugs will get to the point they have no more effect

Cerebrospinal fluid (CSF)

clear fluid that fills that subarachnoid space around the brain and spinal cord, ventricles and canals

- circulates around the brain 6 times a minute

- plays a huge protective role (acts as cushion)

- is a bidirectional conduit (communication pathway)

Blood-Brain Barrier

the separation between brain capillaries and the brain/blood

- not the only barrier in the brain

- important as many substances in the blood fluctuate and would have disruptive effects on the brain if they could move freely between blood/brain/CSF

What chemical travels through the cerebrospinal fluid?

Oxytocin

Distinct morphology of brain capillaries

Are designed to to allow movement of material between blood and surrounding cells

Have no openings or pinocytotic sites; movement of water soluble molecules is minimized

Surrounded by glial feet - astrocytes

What does the BBB reduce diffusion of?

Water soluble (ionized) molecules

- does not impeded lipid soluble molecules

Brain area NOT isolated by the BBB

Area postrema of CTZ (chemical trigger zone) - cluster of cells in the brainstem that responds to toxins/bacteria in the blood and induces vomiting

Other brain areas NOT isolated by the BBB

posterior pituitary gland, pineal gland, circumventricular organ, median eminence

Example of drug that can cross the BBB

Physostigmine - used to treat intoxication from agricultural pesticides, increases the availability of the neurotransmitter acetylcholine

Neostigmine

Does not cross the BBB, increases acetylcholine peripherally - used to treat diseases such as myasthenia gravis (heart disorder) without CNS side effects

Placental barrier

a protective barrier between the baby's and mother's blood circulation

- not a very robust barriers

- potentially damaging effects include acute toxicity, teratogenic effects and shortage of oxygen

Why can drugs remaining in a newborn at birth have prolonged action?

incomplete metabolism due to incomplete development of the liver

Drugs that can cause acute toxicity in the fetus

Tranquilizers, anesthetics, alcohol, barbiturates, cocaine

Drugs that can deprive the fetus of oxygen

Alcohol, cocaine, carbon monoxide in cigarette and marijuana smoke

Teratogens

Agents that damage the process of development and induce developmental abnormalities

- drugs, x-rays, maternal infections

- effects depend on timing of exposure (most damage occurs in first trimester during formation of fetal organs - 3 months)

Advantages and disadvantages of oral administration

advantages - safe, self administered, economical, no needle related complications

disadvantages - slow and highly variable absorption, subject to first pass metabolism, less predictable blood levels

Advantages and disadvantages of intravenous administration

advantages - most rapid, accurate blood concentration

disadvantages - overdose danger, cannot be readily reversed, requires sterile needles, drug abuse

Advantages and disadvantages of intramuscular administration

advantages - slow and even absorption

disadvantages - localized irritation at site, needs sterile equipment

Advantages and disadvantages of subcutaneous administration

advantages - slow and prolonged absorption

disadvantages - variable absorption depending on blood flow

Advantages and disadvantages of inhalation

advantages - large absorption surface; very rapid onset

disadvantages - irritation of nasal passages

Advantages and disadvantages of topical administration

advantages - localized action and effects, easy to self administer

disadvantages - may be absorbed into general circulation

Advantages and disadvantages of transdermal administration

advantages - controlled and prolonged absorption

disadvantages - local irritation, useful only for lipid soluble drugs

Advantages and disadvantages of epidural administration

advantages - bypasses BBB, very rapid effect on CNS

disadvantages - not reversible, needs trained personnel

How are drugs eliminated?

Via biotransformation - metabolism, then excretion

Drug clearance from the blood

is usually exponential (first order kinetics)

- rate is concentration dependent

- can be calculated by half lives ( each results in half the drug coming out of your system

Half-lives of drugs

the amount of time required for removal of 50% of the drug

t1/2

How many half-lives until a drug with a 12 hr half life is functionally out of your system?

5-6 hrs for 50% of drug removal

Why does a drug's half life determine the interval between doses?

a drug given once a day should have a half life of about 8 hours - longer half life or taking more than once a day could lead to accumulation which increases potential side effects and toxicity

First order kinetics

Reaction rate is directly proportional to concentration