High I/O because of MariaDB

i'm using nginx with php-fpm and mariadb. Sometimes my pages are loading slow. By checking munin I saw that my average I/O waiting time is very high, up to 8 seconds. In the php-slowlog are mysql-functions listed as reason, for example mysql_query(). I try to tweak the mariadb server (e.g. increase cache, move tmp dir from hdd to a ramdisk). But my I/O gets randomly high.

For example at the beginning of the graph. I thought I fixed the problem, but then the waiting time increases without any visible reason. When I restart mariadb it goes rapidly down (you can see how it goes down at the end, I restarted mariadb here).

I'm not really using much I/O, the peak is about 8MB/s:

Noticeable is that the ratio of Table_locks_immediate to Table_locks_waited is increasing. As i restart mariadb, it was 2.5%. The server is up for ~ 30 minutes now and it had increased to 3.5%. I also noticed that when the server is hanging the number of running threads (Threads_running) is high (up to 30). When this number goes down, the server stops hanging.

My my.cnf:

[client]
port        = 3306
socket      = /var/run/mysqld/mysqld.sock

[mysqld_safe]
socket      = /var/run/mysqld/mysqld.sock
nice        = 0

[mysqld]
sync_binlog = 3

user        = mysql
pid-file    = /var/run/mysqld/mysqld.pid
socket      = /var/run/mysqld/mysqld.sock
port        = 3306
basedir     = /usr
datadir     = /var/lib/mysql
#tmpdir     = /tmp
tmpdir      = /var/mysqltmp
lc_messages_dir = /usr/share/mysql
lc_messages = en_US
skip-external-locking
log-bin=/var/mysqltmp/mysql-bin.log
#log=/var/mysqltmp/mysql.log
log-error=/var/mysqltmp/mysql-error.log
log-slow-queries=/var/mysqltmp/mysql-slowquery.log

bind-address        = 127.0.0.1

max_tmp_tables      = 100
max_connections     = 150
connect_timeout     = 5
#wait_timeout            = 600
wait_timeout        = 800
max_allowed_packet  = 16M
thread_cache_size       = 128
#sort_buffer_size        = 4M
sort_buffer_size    = 8M
bulk_insert_buffer_size = 8M
max_heap_table_size     = 128M
tmp_table_size      = 128M
#tmp_table_size          = 64M

# * MyISAM
myisam_recover          = BACKUP
key_buffer_size         = 256M
#open-files-limit   = 2000
table_open_cache    = 1000
myisam_sort_buffer_size = 8M

#concurrent_insert  = 2
#read_buffer_size        = 2M
read_buffer_size    = 4M
#read_rnd_buffer_size    = 1M
read_rnd_buffer_size    = 2M

# * Query Cache Configuration
query_cache_limit       = 256M
query_cache_size        = 256M
# for more write intensive setups, set to DEMAND or OFF
query_cache_type        = ON
#table_cache                    = 400
table_open_cache        = 2000
join_buffer_size        = 4M

# * Logging and Replication
log_warnings        = 2
slow_query_log      = 1
slow_query_log_file = /var/log/mysql/mariadb-slow.log
long_query_time = 1
#log_slow_rate_limit    = 1000
log_slow_verbosity  = query_plan

log_bin         = /var/log/mysql/mariadb-bin
log_bin_index       = /var/log/mysql/mariadb-bin.index
# not fab for performance, but safer
#sync_binlog        = 1
expire_logs_days    = 10
max_binlog_size         = 128M

# * InnoDB
default_storage_engine  = InnoDB
#innodb_log_file_size   = 50M
#innodb_buffer_pool_size    = 256M
innodb_buffer_pool_size = 256M
innodb_log_buffer_size  = 32M
innodb_file_per_table   = 1
innodb_open_files   = 400
innodb_io_capacity  = 400
#innodb_flush_method    = O_DIRECT
innodb_flush_method     = O_DSYNC

[mysqldump]
quick
quote-names
max_allowed_packet  = 16M

[isamchk]
#key_buffer     = 16M
key_buffer             = 32M

!includedir /etc/mysql/conf.d/